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MARCH 2012

JOURNAL OF

VOL 2 I NO 1

HEMATOLOGY ONCOLOGY ™ PHARMACY THE PEER-REVIEWED FORUM FOR ONCOLOGY PHARMACY PRACTICE

ORIGINAL RESEARCH Tolerability of Carboplatin When Using Rounded Serum Creatinine Values Amy L. Mazloom, PharmD; Daniel J. Bestul, PharmD, BCOP

REVIEW ARTICLE A Review of PARP Inhibitors in Clinical Development Sarah A. Hopps, PharmD; Carla D. Kurkjian, MD; Shubham Pant, MD

From the Literature Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy Robert J. Ignoffo, PharmD, FASHP, FCSHP

©2012 Green Hill Healthcare Communications, LLC www.JHOPonline.com

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EDITORIAL BOARD

CO-EDITORS-IN-CHIEF Patrick J. Medina, PharmD, BCOP Associate Professor Department of Pharmacy University of Oklahoma College of Pharmacy Oklahoma City, OK

Val R. Adams, PharmD, BCOP, FCCP Associate Professor, Pharmacy Program Director, PGY2 Specialty Residency Hematology/Oncology University of Kentucky College of Pharmacy Lexington, KY

SECTION EDITORS CLINICAL CONTROVERSIES

ORIGINAL RESEARCH

Christopher Fausel, PharmD, BCPS, BCOP Clinical Director Oncology Pharmacy Services Indiana University Simon Cancer Center Indianapolis, IN

R. Donald Harvey, PharmD, FCCP, BCPS, BCOP Assistant Professor, Hematology/Medical Oncology Department of Hematology/Medical Oncology Director, Phase 1 Unit Winship Cancer Institute Emory University, Atlanta, GA

REVIEW ARTICLES Scott Soefje, PharmD, BCOP Associate Director, Oncology Pharmacy Smilow Cancer Hospital at Yale New Haven Yale New Haven Hospital New Haven, CT

PRACTICAL ISSUES IN PHARMACY MANAGEMENT Timothy G. Tyler, PharmD, FCSHP Director of Pharmacy Comprehensive Cancer Center Desert Regional Medical Center Palm Springs, CA

FROM THE LITERATURE Robert J. Ignoffo, PharmD, FASHP, FCSHP Professor of Pharmacy, College of Pharmacy Touro University–California Mare Island Vallejo, CA

EDITORS-AT-LARGE Joseph Bubalo, PharmD, BCPS, BCOP Assistant Professor of Medicine Oncology Clinical Specialist and Oncology Lead OHSU Hospital and Clinics Portland, OR

Steve Stricker, PharmD, MS, BCOP Assistant Professor of Pharmacy Practice Samford University McWhorter School of Pharmacy Birmingham, AL

Sandra Cuellar, PharmD, BCOP Director Oncology Specialty Residency University of Illinois at Chicago Medical Center Chicago, IL

John M. Valgus, PharmD, BCOP Hematology/Oncology Senior Clinical Pharmacy Specialist University of North Carolina Hospitals and Clinics Chapel Hill, NC

Sachin Shah, PharmD, BCOP Associate Professor Texas Tech University Health Sciences Center Dallas, TX

Daisy Yang, PharmD, BCOP Clinical Pharmacy Specialist University of Texas M. D. Anderson Cancer Center Houston, TX

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MARCH 2012

VOLUME 2, NUMBER 1 PUBLISHING STAFF Senior Vice President, Sales & Marketing Philip Pawelko phil@greenhillhc.com Publisher John W. Hennessy john@greenhillhc.com 732.992.1886 TM

THE PEER-REVIEWED FORUM FOR ONCOLOGY PHARMACY PRACTICE

TABLE OF CONTENTS

Associate Editor Lara J. Lorton

ORIGINAL RESEARCH 6

Editorial Director Dalia Buffery dalia@greenhillhc.com 732.992.1889

Tolerability of Carboplatin When Using Rounded Serum Creatinine Values Amy L. Mazloom, PharmD; Daniel J. Bestul, PharmD, BCOP

REVIEW ARTICLE 18 A Review of PARP Inhibitors in Clinical Development Sarah A. Hopps, PharmD; Carla D. Kurkjian, MD; Shubham Pant, MD

Editorial Assistant Jennifer Brandt jennifer@generaladminllc.com 732.992.1536 Directors, Client Services Joe Chanley joe@greenhillhc.com 732.992.1524 Jack Iannaccone jack@greenhillhc.com 732.992.1537 Production Manager Stephanie Laudien Quality Control Director Barbara Marino

FROM THE LITERATURE 30 Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy Robert J. Ignoffo, PharmD, FASHP, FCSHP

Business Manager Blanche Marchitto blanche@greenhillhc.com Editorial Contact: Telephone: 732.992.1536 Fax: 732.656.7938 E-mail: JHOP@greenhillhc.com

MISSION STATEMENT The Journal of Hematology Oncology Pharmacy is an independent, peer-reviewed journal founded in 2011 to provide hematology and oncology pharmacy practitioners and other healthcare professionals with highquality peer-reviewed information relevant to hematologic and oncologic conditions to help them optimize drug therapy for patients.

Journal of Hematology Oncology Pharmacy™, ISSN applied for (print); ISSN applied for (online), is published 4 times a year by Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2012 by Green Hill Healthcare Communications LLC. All rights reserved. Journal of Hematology Oncology Pharmacy™ logo is a trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, Journal of Hematology Oncology Pharmacy™, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. E-mail: JHOP@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues, $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. The ideas and opinions expressed in Journal of Hematology Oncology Pharmacy™ do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in Journal of Hematology Oncology Pharmacy™ should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director.

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ORIGINAL RESEARCH

Tolerability of Carboplatin When Using Rounded Serum Creatinine Values Amy L. Mazloom, PharmD; Daniel J. Bestul, PharmD, BCOP Background: Carboplatin doses are calculated based on an estimate of creatinine clearance (CrCl), most often calculated with the Cockcroft-Gault formula. When a patient’s serum creatinine (SCr) is low, the concern is that the Cockcroft-Gault formula may overestimate CrCl and result in an intolerable carboplatin dose. Controversy exists about the proper way to calculate CrCl and carboplatin doses for patients with SCr <1 mg/dL. Objective: To determine the tolerability of carboplatin in patients with SCr <1 mg/dL who had their doses calculated using actual versus rounded SCr values. Methods: This retrospective analysis includes patients with baseline SCr <1 mg/dL who received their first dose of carboplatin. All patients had their carboplatin dose determined using the Calvert formula and CrCl calculated using the Cockcroft-Gault formula. Patients were divided into 3 groups based on the SCr value used to calculate the CrCl: actual SCr group, SCr rounded to 0.8 mg/dL (ie, SCr 0.8 group), and SCr rounded to 1 mg/dL (ie, SCr 1 group). Patient records were reviewed to determine demographic data, platelet and neutrophil nadirs, use of asneeded antiemetics and acute nausea and vomiting episodes, and treatment delays. Results: A total of 128 patients met the inclusion criteria (actual SCr, N = 50; SCr 1, N = 41; SCr 0.8, N = 37). Baseline mean SCr values differed significantly between groups: actual SCr, 0.79; SCr 1, 0.69; SCr 0.8, 0.56 (P <.001). Calculated CrCl was significantly different between J Hematol Oncol Pharm. the actual SCr and the SCr 1 groups (P <.001). Carboplatin doses did not differ between the 3 2012;2(1):6-13. groups (P = .31). There were no differences between groups with respect to nausea and vomwww.JHOPonline.com iting, hematologic toxicity, or treatment delays. Disclosures are at end of text Conclusion: For patients with baseline SCr as low as 0.8 mg/dL, there is no difference in carboplatin tolerability when the dose is calculated using an actual SCr versus a rounded SCr value.

C

arboplatin is a platinum chemotherapeutic agent introduced in 1981 as an alternative to cisplatin. The 2 agents have similar antitumor activity and spectrum.1 Although carboplatin’s degree of activity depends heavily on the disease state, it is frequently used because of its documented activity against a broad range of tumors.2 Although not proved efficacious for some disease states, the advantage of carboplatin compared with cisplatin is a decrease in nonhematologic toxicities (eg, nephrotoxicity, ototoxicity, and peripheral neurotoxicity).1 The dose-limiting toxicity is bone marrow suppression, specifically thrombocytopenia. Although carboplatin does not cause significant renal toxicity, pretreatment renal function is an important factor in the severity of carboplatin-induced thrombocy-

Dr Mazloom is Clinical Pharmacy Coordinator, Department of Pharmacy, WellStar Kennestone Hospital, Marietta, GA; Dr Bestul is Oncology Clinical Specialist, Department of Pharmaceutical Services, Beaumont Hospital-Royal Oak, Royal Oak, MI.

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topenia.1 Approximately 70% of an administered carboplatin dose is eliminated in the urine, and the renal clearance is closely correlated with glomerular filtration rate (GFR).3,4 This suggests that the renal excretion of the drug is exclusively by glomerular filtration.1 The area under the concentration/time curve (AUC) for carboplatin is determined primarily by the pretreatment GFR. The AUC determines toxicity of carboplatin.1 Therefore, the formula used most often in clinical practice to dose carboplatin, the Calvert formula, takes into account the patient’s GFR and desired AUC.5 This formula—dose (mg) = AUC (mg/mL-1 min) × [GFR (mL/min) + 25 (mL/min)]—has proved to be a reliable tool to calculate the optimal dose of carboplatin in retrospective and prospective studies.5 Although the Calvert analysis used chromium 51– ethylenediaminetetra-acetic acid measurements because of its ability to directly measure GFR,1 prediction of GFR for use in the Calvert formula is often accomplished by estimating the creatinine clearance (CrCl) using the Cockcroft-Gault formula. The Cockcroft-

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Tolerability of Carboplatin When Using Rounded Serum Creatinine Values

Gault formula uses variables such as age, weight, sex, and serum creatinine (SCr). In clinical practice, patients may have low SCr values that are not always accurate representations of their renal function. For example, in elderly patients who have decreased muscle mass, the corresponding decreased SCr could be misinterpreted as better-than-actual renal function.6 There is concern about the accuracy of CrCl estimates when these low SCr values are used in the CockcroftGault formula.7 Some institutions round low values up to 1 mg/dL to prevent overestimation of renal function.7 Controversy exists regarding how to properly calculate CrCl values, and therefore dose carboplatin by using the Calvert formula for patients with an SCr <1 mg/dL. Some clinicians use actual SCr when it is <1 mg/dL, whereas others are concerned that the CrCl could be overestimated and choose to round the SCr value up for purposes of the calculation. It is unknown whether the use of rounded-up SCr values impacts the tolerability of carboplatin. The objective of this study was to determine the tolerability of carboplatin based on adverse events, including nausea, vomiting, and myelosuppression, for patients with SCr values <1 mg/dL who had their dose calculated using rounded-up SCr values compared with patients who had their dose calculated using actual SCr values.

Methods Study Patients Patients receiving a carboplatin-containing chemotherapy regimen were identified through pharmacy chemotherapy records. Patients were included in the study if they initiated their first cycle of carboplatin-containing chemotherapy and received their first dose of carboplatin as an inpatient between January 1, 2004, and December 31, 2009. Additional inclusion criteria were SCr <1 mg/dL, carboplatin dose determined using the Calvert formula, CrCl calculated using the Cockcroft-Gault formula, and patients receiving 100% of the calculated dose. Exclusion criteria were SCr â&#x2030;Ľ1 mg/dL, carboplatin dose determined using any method other than the Calvert formula, and CrCl calculated using any method other than the Cockcroft-Gault formula. Patients were excluded if they initiated and received their first dose of carboplatin-containing chemotherapy outside of the institution or in the outpatient setting but received subsequent doses as an inpatient during the study period. Those who initiated carboplatin therapy as an outpatient were excluded primarily as a result of the limited availability of outpatient medical records to accurately access tolerability. Patients meeting the inclusion criteria were divided

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into 3 groups based on the practices observed at our institution. The first group included patients whose CrCl was calculated using the actual SCr value (ie, the actual SCr group). The remaining 2 groups included patients whose CrCl was calculated using a rounded-up SCr value: 1 group used a rounded SCr value of 1 mg/dL (ie, the SCr 1 group) and 1 group used a rounded SCr value of 0.8 mg/dL (ie, the SCr 0.8 group). For all patients, the decision to use the actual SCr value or a rounded SCr value was made by the prescribing oncologist. This in turn dictated the placement of patients within the 3 study groups. Institutional Review Board approval was obtained before initiation of the study.

In clinical practice, patients may have low SCr values that are not always accurate representations of their renal function. There is concern about the accuracy of CrCl estimates when these low SCr values are used in the Cockcroft-Gault formula. Data Collection and Analysis This study was a retrospective chart review. Demographic data (ie, age, sex, weight, height, and diagnosis) were collected for all patients included in the study. Information regarding the chemotherapy regimen, antiemetic regimen, and use of granulocyte colony-stimulating factor (GCSF) was also collected. The incidence of nausea within the first 24 hours of carboplatin administration as noted in the medical record was recorded. The number of times rescue antiemetics were administered to the patients and the number of emetic episodes charted were collected from pharmacy and medical charts to assess acute nausea and vomiting (within the first 24 hours of carboplatin administration). Laboratory records were reviewed for all patients, and nadir platelet and nadir neutrophil counts were recorded to assess bone marrow toxicity. The severities of bone marrow suppression and emesis were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 3.0 (Appendix, page 13).8 The date of cycle 2 was collected to assess for delays in treatment. End Points The study end points were the incidence of nausea, frequency of rescue antiemetic use, and incidence and severity of emesis, thrombocytopenia, and neutropenia. Treatment delays between cycle 1 and cycle 2 of carboplatin were also evaluated.

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ORIGINAL RESEARCH

Figure 1 Patient Selection

351 patients identified Received first cycle of carboplatincontaining chemotherapy between 1/1/2004 and 12/31/2009

223 patients excluded: • 178 SCr >1 mg/dL • 27 received 100% dose • 16 CrCl determined by method other than C-G • 1 carboplatin dose based on BSA • 1 no information available

128 patients included

Actual SCr group N = 50

SCr 1 group N = 41

SCr 0.8 group N = 37

BSA indicates body surface area; C-G, Cockroft-Gault; CrCl, creatinine clearance; SCr, serum creatinine.

Statistical Analysis A 1-way analysis of variance was used for parametric data, including age, height, weight, body surface area, body mass index (BMI), CrCl, dose, platelet and neutrophil nadirs, and treatment delays. The KruskallWallis test was used for nonparametric data and data that were not normally distributed (ie, SCr and AUC). The chi-square test was used for categorical data, including sex, scheduled antiemetics, GCSF use, diagnosis, chemotherapy regimen, rescue antiemetic use, and incidence and grade of nausea, emesis, thrombocytopenia, and neutropenia. A Tukey posttest was performed as needed (ie, only if P <.05). Differences were considered statistically significant if P <.05. Results Patients A total of 351 patients were identified who received their first cycle of carboplatin-containing chemotherapy as an inpatient between January 1, 2004, and December 31, 2009. Of these, 128 patients were included in the study and were divided into 3 groups: actual SCr group (N = 50), SCr 1 group (N = 41), and SCr 0.8 group (N = 37). The reasons for patient exclusion are shown in

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Figure 1. Baseline characteristics of the patient population are shown in Table 1. Many demographic characteristics were similar between the groups, although some differences were observed. Diagnoses were numerically different among the groups, but this difference was not significant (P = .26). In addition, variation was noted with respect to chemotherapeutic regimens and the use of more than standard antiemetics between groups, differences that approached significance (P = .05 for each comparison). Although baseline SCr significantly differed among the 3 groups (P <.001), and the calculated CrCl was significantly different between the actual SCr and SCr 1 groups and the actual SCr and SCr 0.8 groups (P <.001), carboplatin doses did not differ significantly (P = .31) among the 3 groups.

Nausea and Emesis Results for nausea and emesis were available for all 50 patients in the actual SCr group, for 40 patients in the SCr 1 group, and for 36 patients in the SCr 0.8 group. The incidence results for nausea and emesis are summarized in Table 2. Nausea and emesis data were not available for 1 patient in the SCr 1 group and for 1 patient in

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Tolerability of Carboplatin When Using Rounded Serum Creatinine Values

Table 1 Emetogenic Level Associated with Injectable Chemotherapy Agents Actual SCr (N = 50)

SCr 1 (N = 41)

SCr 0.8 (N = 37)

P value

Age, yrs ± SD

57 ± 15

62 ± 13

63 ± 12

.06

Female, N (%)

32 (64)

24 (59)

26 (70)

.56

Height, cm ± SD

168.9 ± 10

166.8 ± 10.1

166.9 ± 9

.51

Weight, kg ± SD

69 ± 14.4

72.4 ± 21.2

67.9 ± 17.2

.49

2

1.8 ± 0.21

1.8 ± 0.27

1.75 ± 0.21

.54

24.1 ± 14.4

25.9 ± 6.85

24.4 ± 5.84

.30

0.79 ± 0.1 (0.5-0.9)

0.69 ± 0.15 (0.3-0.9)

0.56 ± 0.11 (0.3-0.7)

<.001

91.5 ± 26.3 (47.9-184)

72.1 ± 26.1 (33.8-120)

78.7 ± 20.8 (46-123)

<.001

524.5 ± 179.8

476.3 ± 173.5

477.5 ± 154.9

.31

4.61 ± 1.28

4.83 ± 1.05

4.62 ± 1.3

.87

50 (100)

41 (100)

37 (100)

1 (2)

3 (7.3)

6 (16.2)

.05

20 (40)

22 (53.7)

18 (48.6)

.42

NSCLC

15 (30)

10 (24.4)

13 (35.1)

Lymphoma

15 (30)

7 (17.1)

3 (8.1)

SCLC

7 (14)

12 (29.3)

6 (16.2)

Ovarian cancer

5 (10)

4 (9.8)

6 (16.2)

Breast cancer

3 (6)

1 (2.4)

0 (0)

Unknown primary

1 (2)

3 (7.3)

3 (8.1)

Head and neck

1 (2)

1 (2.4)

3 (8.1)

Other

3 (6)

3 (7.3)

3 (8.1)

Carboplatin/paclitaxel

15 (30)

11 (26.8)

16 (43.2)

RICE/ICE

15 (30)

7 (17.1)

3 (8.1)

Carboplatin/etoposide

8 (16)

13 (31.7)

7 (18.9)

Carboplatin/gemcitabine

5 (10)

5 (12.2)

2 (5.4)

Carboplatin

3 (6)

1 (2.4)

0 (0)

Other

4 (8)

4 (9.8)

9 (24.3)

BSA, m ± SD 2

BMI, kg/m ± SD SCr, mg/dL ± SD (range) CrCl, mL/min ± SD (range) Carboplatin information Dose, mg ± SD -1

AUC, mg/mL min ± SD a

Antiemetic information, N (%) Standard Standard plus GCSF use, N (%) Diagnosis, N (%)

.26

Chemotherapy regimen, N (%)

.05

a Prophylactic antiemetic use was classified as either “standard” (according to institutional practices based on current national guideline sources) or “standard plus” (defined as the scheduled use of antiemetics in addition to those considered “standard”). Standard prophylactic antiemetic use consisted of a serotonin receptor antagonist plus a corticosteroid in all patients, and a neurokinin-1 receptor inhibitor in 4 patients (1 patient in the SCr 1 group and 3 patients in the SCr 0.8 group). The details of standard plus prophylactic scheduled antiemetic use were in the actual SCr group, 1 patient received lorazepam; in the SCr 1 group, 2 patients received lorazepam and 1 patient received 1 additional scheduled dose of ondansetron; in the SCr 0.8 group, 3 patients received dronabinol, 2 patients received 1 additional scheduled dose of ondansetron, and 1 patient received lorazepam.

AUC indicates area under the concentration/time curve; BMI, body mass index; BSA, body surface area; CrCl, creatinine clearance; GCSF, granulocyte colony-stimulating factor; ICE, ifosfamide/carboplatin/etoposide; NSCLC, non–small-cell lung cancer; RICE, rituximab/ifosfamide/carboplatin/etoposide; SCLC, small-cell lung cancer; SCr, serum creatinine; SD, standard deviation.

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ORIGINAL RESEARCH

Table 2 Emetogenic Level Associated with Injectable Chemotherapy Agents Actual SCr (N = 50)

SCr 1 (N = 40)

SCr 0.8 (N = 36)

P value

Nausea, N (%)

13 (26)

6 (15)

7 (19.4)

.43

Rescue antiemetics, N (%)

21 (42)

11 (27.5)

9 (25)

.18

1

10 (20)

6 (14.6)

7 (19.4)

2

8 (16)

1 (2.5)

2 (5.6)

3

1 (2)

3 (7.5)

0 (0)

4

2 (4)

1 (2.5)

0 (0)

4 (8)

3 (7.5)

2 (5.6)

Grade 1

3 (6)

1 (2.5)

2 (5.6)

Grade 2

1 (2)

2 (5)

0 (0)

.16

Emesis, N (%)

.9 .61

SCr indicates serum creatinine.

Figure 2b Platelet Nadir

Figure 2a Incidence and Grade of Thrombocytopenia

70%

149

55%

55% Platelet count, 109/L

148

50%

36%

40%

36%

30%

18%

20%

150

150

63%

60%

Patients, %

151

Any Grade Grade 3/4

147 146

146

145

144

144 143

10%

142

0%

141

Platelet nadir (P = .98) Actual SCr (N = 44)

SCr 1 (N = 38)

SCr 0.8 (N = 33)

Group

Thrombocytopenia and Neutropenia Results for thrombocytopenia and neutropenia were available for 44 patients in the actual SCr group, 38 patients in the SCr 1 group, and 33 patients in the SCr 0.8 group. Results for thrombocytopenia are shown in Figure 2a and Figure 2b. There was no significant difference in the incidence or severity of thrombocytopenia (P = .68) or platelet nadir (P = .98) among the 3 groups. Results for neutropenia are shown in Figure 3a and

Journal of Hematology Oncology Pharmacy

SCr 0.8 (N = 33)

SCr indicates serum creatinine.

the SCr 0.8 group. There was no significant difference among the 3 groups in nausea (P = .43) or in rescue antiemetic use (P = .18). Differences in emesis did not reach significance (P = .9). No patient in any group experienced grade 3 or 4 emesis.

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SCr 1 (N = 38)

Group

SCr indicates serum creatinine.

10

Actual SCr (N = 44)

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Figure 3b. There was no significant difference in the incidence or severity of neutropenia (P = .53) or neutrophil nadir (P = .47) among the 3 groups.

Treatment Delays Results for treatment delays were available for 33 patients in the actual SCr group, 25 patients in the SCr 1 group, and 23 patients in the SCr 0.8 group. The average number of days that cycle 2 of carboplatin was delayed was 2.2 days (± 4 days) in the actual SCr group, 4.8 days (± 8.9 days) in the SCr 1 group, and 4.2 days (± 7.1 days) in the SCr 0.8 group (P = .42). Discussion Our results indicate that the tolerability of carboplatin

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Tolerability of Carboplatin When Using Rounded Serum Creatinine Values

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Figure 3a Incidence and Grade of Neutropenia 50%

47%

Neutropenia, %

40%

36%

Any Grade Grade 3/4

36%

34%

33%

30%

20%

20%

10%

0%

Actual SCr (N = 44)

SCr 1 (N = 38)

SCr 0.8 (N = 33)

Group

SCr indicates serum creatinine.

Figure 3b Neutrophil Nadir 5

Neutrophil count, 109/L

was unchanged when the dose was calculated using the actual SCr value versus the rounded SCr value. The prescriberâ&#x20AC;&#x2122;s decision to use actual SCr values rather than rounded values to calculate CrCl and subsequently dose carboplatin using the Calvert formula appeared to be largely influenced by the patientâ&#x20AC;&#x2122;s baseline SCr values. This is evident from the finding that patients with an SCr closer to 1 mg/dL were more likely to have CrCl calculated using their actual SCr value (average baseline SCr in the actual SCr group, 0.79 mg/dL). Patients with lower SCr values were largely included in the SCr 1 group (the average baseline SCr in the SCr 1 group was 0.69 mg/dL), whereas patients with the lowest SCr values were mostly included in the SCr 0.8 group (the average baseline SCr in the SCr 0.8 group was 0.56 mg/dL). Despite significant differences in baseline SCr, the calculated CrCl did not differ between the SCr 1 and SCr 0.8 groups. The differences were significantly different between the actual SCr and SCr 1 groups (average CrCl, 91.5 mL/min and 72.1 mL/min, respectively; P <.001), and between the actual SCr and the SCr 0.8 groups (average CrCl, 91.5 mL/min and 78.7 mL/min, respectively; P <.05). Although the CrCl varied slightly among the groups, these differences were not substantial enough to translate into significantly dissimilar carboplatin doses (average doses, 524.5 mg, 476.3 mg, and 477.5 mg for the actual SCr, SCr 1, and SCr 0.8 groups, respectively). This similarity in dose could account for the observed similarity in tolerability. Indeed, the data would indicate that for patients with an SCr of approximately 0.8 mg/dL to 1 mg/dL, despite small differences in calculated CrCl, the resultant carboplatin dose would not be expected to differ significantly, and therefore no increased toxicity would be anticipated. Although it seems illogical that significant differences in SCr and CrCl would not result in significant differences in carboplatin doses when the AUC is similar between groups, this scenario can be explained. Both CrCl and AUC contribute to the carboplatin dose calculated by use of the Calvert formula; however, differences in AUC influence the carboplatin dose to a greater extent than CrCl, because the AUC is a multiplier whereas the CrCl is additive. The difference in CrCl between the actual SCr and the SCr 1 groups is 26.9%, which decreases to 19.9% when the constant of 25 is added. Although not statistically different, the average AUC is 4.4% higher in the SCr 1 group than in the actual SCr group. These 2 factors tend to move the groups closer to each other and make the differences in carboplatin doses insignificant. The same explanation can be applied to the observed carboplatin doses in the actual SCr and the SCr 0.8

4

3

2

1

Platelet nadir (P = .47 0

Actual SCr (N = 44)

SCr 1 (N = 38)

SCr 0.8 (N = 33)

Group

SCr indicates serum creatinine.

groups. Interpretation and application of the study results are more difficult for patients with a baseline SCr of <0.8 mg/dL, although the approach at our institution of using a rounded SCr value of 0.8 mg/dL for calculating CrCl results in carboplatin doses that are well tolerated.

Limitations There were several limitations to this study. The small sample size may have compromised the statistical power to detect meaningful differences between groups. The retrospective analysis posed limitations in the availability of medical records and documentation of tolerability

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ORIGINAL RESEARCH

Table 3 Use of Various CrCl Calculation Methods and Effect on Carboplatin Dose Actual SCr (N = 50) Avg SCr 0.79 mg/dL Method of CrCl calculation and carboplatin dosing

SCr 1 (N = 41) Avg SCr 0.69 mg/dL

SCr 0.8 (N = 37) Avg SCr 0.56 mg/dL

Carboplatin CrCl Carboplatin CrCl Carboplatin CrCl (mL/min ± SD) dose (mg ± SD) (mL/min ± SD) dose (mg ± SD) (mL/min ± SD) dose (mg ± SD)

Use of rounded SCr values (as performed in study)

91.5 ± 26.3

524.5 ± 179.8

72.1 ± 26.1

476.3 ± 173.5

79.1 ± 20.9

477.5 ± 154.9

Use of CrCl max 125 mL/min

90.2 ± 22.9

531 ± 180.4

100.4 ± 30.5

592.7 ± 218.9

105.8 ± 20.4

584.9 ± 182.2

26.3

179.8

40.7

255.2

38.9

242.7

Use of actual SCr values

CrCl indicates creatinine clearance; SCr, serum creatinine; SD, standard deviation.

information, causing a loss of some patients in the tolerability analysis. In addition, for the end point involving treatment delays in cycle 2 of carboplatin, although it was presumed that these delays were related to carboplatin toxicity, it was not feasible to determine the exact reasons for treatment delays. The various diagnoses and chemotherapy regimens made for a very heterogeneous group of patients, which could be considered a limitation, because these factors may affect carboplatin tolerability in different ways. Although not significantly different, there were numeric differences in CSF use among the groups. Patients who received CSF would be expected to have higher neutrophil nadir counts. It is unknown how this affects the interpretation of the neutrophil tolerability results among the 3 groups. Furthermore, more patients in the SCr 0.8 group received additional scheduled antiemetics compared with the other 2 groups, which could confound the nausea and vomiting tolerability results. The appropriate body weight to use for CrCl calculations using the Cockcroft-Gault formula in obese patients is a known area of controversy. Although not addressed in this study, the majority of patients had their doses calculated using actual body weight. An adjusted body weight was used in a small number of patients who were considered overweight or obese. The overall study population could be described as normal in size, with an average weight of 69.7 kg and BMI of 24.7 kg/m2. It is unlikely that the small number of overweight and obese patients who had their CrCl calculated with an adjusted body weight affected the observed tolerability results. A disadvantage of the Calvert formula is that the GFR must be assayed, involving inconvenient and invasive methods. Several studies have used CrCl in place of GFR in the Calvert formula, determined either by a 24-hour urine collection with the SCr or by another method.5 The formula that best estimates CrCl for dosing car-

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boplatin is not clear. In our study, CrCl was estimated using the Cockcroft-Gault formula, which has been validated as a reliable estimation of CrCl in patients with cancer.9 Jelliffe and Chatelut formulas have been studied as well, with varying results.2,10-12 Recently, the US Food and Drug Administration (FDA) in conjunction with the NCI/Cancer Therapy Evaluation Program informed oncology practitioners about the potential for inadvertent carboplatin overdosing.13 This concern resulted from a change in the method of the SCr measurement by laboratories in the United States that was to be completed by the end of 2010. The new isotope dilution mass spectrometry method would appear to underestimate the SCr values compared with older methods, especially when the SCr is low. To avoid toxicity, the FDA recommended to limit the GFR used in the Calvert formula to 125 mL/min, regardless of the SCr value. For example, for a target AUC of 5, the maximum dose of carboplatin would be 750 mg.13 Although the impetus of this communication from the FDA was related to the change in the SCr measurement method, their recommended strategy of placing a limit on the GFR for dosing carboplatin would be effective in any case in which the prescriber is concerned about overestimation of the CrCl when the SCr is low. To investigate what effect the use of this strategy would have on the existing study data, a post hoc analysis was conducted. Compared with the doses administered to patients, application of a maximum CrCl of 125 mL/min would result in higher average doses with greater deviation in the SCr 1 and SCr 0.8 groups (approximately 24% and 22% higher, respectively). To provide perspective, had the actual SCr values been used to calculate CrCl, carboplatin doses would be approximately 32% higher in the SCr 1 group and 34% higher in the SCr 0.8 group (approximately 6% and 10% higher, respectively, than the doses achieved

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Tolerability of Carboplatin When Using Rounded Serum Creatinine Values

Appendix NCI Common Terminology Criteria for Adverse Events, Version 3.0 Adverse effect Grade 1 Grade 2 Grade 3 Vomiting 1 episode in 24 hrs 2-5 episodes in ≥6 episodes 24 hrs 24 hrs Neutropenia <LLN-1500/mm3 <1500/mm3<1000/mm31000/mm3 500/mm3 Thrombocyopenia

<LLN-75,000/mm3 <75,000/mm350,000/mm3

<50,000/mm325,000/mm3

Grade 4

Grade 5

Life-threatening consequences

Death

<500/mm3

Death

<25,000/mm3

Death

LLN indicates lower limit of normal; NCI, National Cancer Institute. Source: Reference 8.

by using a maximum CrCl of 125 mL/min). Details of this analysis are presented in Table 3. Although the doses achieved differ greatly, application of a maximum CrCl of 125 mL/min could represent an alternative to using a rounded SCr value for CrCl and carboplatin dose calculations.

Conclusions Future studies will need to address the effect of rounded SCr values in patients with SCr <1 mg/dL on the efficacy of carboplatin. Because of the heterogeneity of the patients (ie, diagnoses and chemotherapy regimens) and retrospective design of our study, only tolerability was assessed. Conclusions regarding tolerability would be more straightforward in future studies of patients with similar baseline SCr values who had their carboplatin doses calculated in different ways (ie, actual SCr, SCr rounded to 1 mg/dL, and SCr rounded to 0.8 mg/dL) that resulted in significantly different doses. This scenario, however, is not what is observed in practice at our institution, because baseline SCr was found to dictate carboplatin prescribing practices. Results of such studies would complement the results of this study and give prescribers a clearer answer on how to best estimate CrCl and dose carboplatin in these patients. For prescribers who are questioning how to calculate CrCl in patients with low SCr, the results from this study suggest that for patients with a baseline SCr as low as 0.8 mg/dL, using the actual SCr will yield a similar carboplatin dose and will not result in decreased tolerability compared with rounding SCr to 1 mg/dL. Future studies are needed to clarify the appropriate dosing strategy for patients with a baseline SCr <0.8 mg/dL, as well as the effect of using rounded SCr values on carboplatin efficacy. ■

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Acknowledgement The authors would like to thank John M. Koerber, PharmD, for his assistance with the statistical analysis. Author Disclosure Statement Dr Mazloom and Dr Bestul have reported no conflicts of interest. References 1. Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol. 1989;7:1748-1756. 2. Donahue A, McCune JS, Faucette S, et al. Measured versus estimated glomerular filtration rate in the Calvert equation: influence on carboplatin dosing. Cancer Chemother Pharmacol. 2001;47:373-379. 3. Harland SJ, Newell DR, Siddik ZH, et al. Pharmacokinetics of cis-diammine-1,1cyclobutane dicarboxylate platinum(II) in patients with normal and impaired renal function. Cancer Res. 1984;44:1693-1697. 4. Gaver RC, Colombo N, Green MD, et al. The disposition of carboplatin in ovarian cancer patients. Cancer Chemother Pharmacol. 1988;22:263-270. 5. van Warmerdam LJ, Rodenhuis S, ten Bokkel Huinink WW, et al. The use of the Calvert formula to determine the optimal carboplatin dosage. J Cancer Res Clin Oncol. 1995;121:478-486. 6. Charleson HA, Bailey RR, Stewart A. Quick prediction of creatinine clearance without the necessity of urine collection. N Z Med J. 1980;92:425-426. 7. Dooley MJ, Singh S, Rischin D. Rounding of low serum creatinine levels and consequent impact on accuracy of bedside estimates of renal function in cancer patients. Br J Cancer. 2004;90:991-995. 8. National Cancer Institute. Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events, Version 3.0. August 9, 2006. http://ctep. cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf#search=.” Accessed February 15, 2012. 9. Robinson BA, Frampton CM, Colls BM, et al. Comparison of methods of assessment of renal function in patients with cancer treated with cisplatin, carboplatin or methotrexate. Aust N Z J Med. 1990;20:657-662. 10. Okamoto H, Nagatomo A, Kunitoh H, et al. Prediction of carboplatin clearance calculated by patient characteristics or 24-hour creatinine clearance: a comparison of the performance of three formulae. Cancer Chemother Pharmacol. 1998;42:307-312. 11. van Warmerdam LJ, Rodenhuis S, ten Bokkel Huinink WW, et al. Evaluation of formulas using the serum creatinine level to calculate the optimal dosage of carboplatin. Cancer Chemother Pharmacol. 1996;47:266-270. 12. Nagao S, Fujiwara K, Imafuku N, et al. Difference of carboplatin clearance estimated by the Cockcroft-Gault, Jelliffe, Modified-Jelliffe, Wright or Chatelut formula. Gynecol Oncol. 2005;99:327-333. 13. US Food and Drug Administration Center for Drug Evaluation and Research. About FDA. Carboplatin dosing. Updated October 8, 2010. www.fda.gov/ AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm2289 74.htm. Accessed July 7, 2011.

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SUBCUTTANEOUS ANEOUS ADMINISTRA NOW APPROVED FOR OR SUBCUTANEOUS AN ADMINISTRATION NISTRA ATION TION VISIT BOOTH BOOTH #200 #200 A HOP PA A ANNUAL CONFERENCE VISIT ATT THE HOPA

Subcutaneous VELCADE Demonstrated Efficacy Consistent With IV for the Primary Endpoint RESPONSE RATES† IN RELAPSED MULTIPLE MYELOMA (MM): SUBCUTANEOUS AND IV AT 12 WEEKS WEEKS (AFTER (AFTER 44CYCLES) CYC CYCLES) CYC Single-agent VELC ADE® (bortezomib)

AT 24 WEEKS (AFTER 8 CYCLES) VELCADE±dexamethasone

53% 51%

43% 42%

11% 12%

7% 8% ORR Primary Endpoint

CR

SC (n=148) IV (n=74)

ORR

CR

▼ The study met its primary non-inferiority objective that single-agent subcutaneous VELCADE retained at least 60% of the overall response rate after 4 cycles relative to single-agent IV VELCADE SUBCUTANEOUS VS IV TRIAL: a non-inferiority, phase 3, randomized (2:1), open-label trial compared the efficacy and safety of VELCADE administered subcutaneously (n=148) with VELCADE administered intravenously (n=74) in patients with relapsed MM. The primary endpoint was overall response rate at 4 cycles. Secondary endpoints included response rate at 8 cycles, median TTP and PFS (months), 1-year overall survival (OS), and safety. *INDICATIONS: VELCADE is indicated for the treatment of patients with multiple myeloma. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. †

Responses were based on criteria established by the European Group for Blood and Marrow Transplantation.1

VELCADE IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS ▼ Peripheral neuropathy, including severe cases, may occur – manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Hypotension can occur. Use caution when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated ▼ Closely monitor patients with risk factors for, or existing heart disease ▼ Acute diffuse infiltrative pulmonary disease has been reported ▼ Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement ▼ Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment ▼ Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

IN T


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IN A LL INDICATIONS* INDICATIONS* IN ALL TO LEARN LEARN MORE MORE TO

Difference in Incidence of Peripheral Neuropathy With Subcutaneous VELCADE PERIPHERAL NEUROPATHY (PN) IN RELAPSED MM: SUBCUTANEOUS AND IV GRADE ≥ ≥33

6%

SC (n=147) IV (n=74)

16% ALL GRADES

38% 53% ▼ Starting VELCADE® (bortezomib) subcutaneously may be considered for patients with preexisting PN or patients at high risk for PN. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Treatment with VELCADE may cause PN that is predominantly sensory. However, cases of severe sensory and motor PN have been reported. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, or weakness ▼ Patients experiencing new or worsening PN during therapy with VELCADE may require a decrease in the dose, a less-dose-intense schedule, or discontinuation. Please see full Prescribing Information for dose modification guidelines for PN

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS CONTINUED ▼ Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the potential harm to the fetus ▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inducers is not recommended

ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported

Please see Brief Summary for VELCADE on next page. For Patient Assistance Information or Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.com Reference: 1. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12(5):431-440.


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Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.

WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs. intravenous the incidence of Grade ≥ 2 peripheral neuropathy events was 24% for subcutaneous and 41% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of VELCADE vs. Dexamethasone following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/ postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been

isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%. Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients. Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. (continued)


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Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE (bortezomib). Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/ prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%). In the phase 3 VELCADE subcutaneous vs. intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse events in this study were peripheral neuropathy NEC (38% vs 53%), anemia (36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea (24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%), nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation (14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%), insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%), hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence of serious adverse events was similar for the subcutaneous treatment group (36%) and the intravenous treatment group (35%). The most commonly reported SAEs

were pneumonia (6%) and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%), peripheral sensory neuropathy (3%) and renal failure (3%) in the intravenous treatment group.

DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE (bortezomib) is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.

USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information. Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication. Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2012, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA

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A Review of PARP Inhibitors in Clinical Development Sarah A. Hopps, PharmD; Carla D. Kurkjian, MD; Shubham Pant, MD

J Hematol Oncol Pharm. 2012;2(1):18-28. www.JHOPonline.com Disclosures are at end of text

Background: The development of poly(ADP-ribose) polymerase (PARP) inhibitors has expanded the potential for targeting DNA damage in cancer cells. The efficacy of PARP inhibitors in cancer therapy is being investigated in a number of clinical trials in a variety of tumor types, including and beyond the expected BRCA mutation malignancies. Objective: To review the evidence from ongoing clinical trials regarding PARP inhibitors currently in development and to describe the growing role of PARP inhibition in biomarker development and in personalized medicine. Discussion: PARP inhibitors possess a unique mechanism of action, targeting cancer cells that have deficient DNA damage repair mechanisms. Preclinical studies have shown that PARP inhibitors are especially cytotoxic in cells with BRCA mutations compared with the wild-type cells. Clinical trials are investigating new PARP inhibitors for the treatment of a variety of tumors, with maximal efficacy demonstrated in patients with mutations in the BRCA genes. This review outlines the mechanism of action of PARP inhibitors that are furthest in clinical development and the available evidence from these clinical trials. There are currently at least 9 PARP inhibitors in development; of these, the PARP-1 and PARP-2 inhibitors olaparib, veliparib, and iniparib are furthest along, with all 3 showing promising results. Conclusion: The benefits of the PARP inhibitors will have to be weighed against their toxicities in the long-term. The strength of these novel agents lies in targeting the weakness of tumors, and that improves clinical outcomes. The results of ongoing clinical trials will help to determine whether these medications will be effective in a wide range of tumors or only in the subset of BRCA mutation carriers.

T

he development of poly(ADP-ribose) polymerase (PARP) inhibitors has expanded the potential for targeting DNA damage in cancer cells. The efficacy of PARP inhibitors in cancer therapy is the subject of an increasing number of clinical trials in a variety of tumor types, including and beyond the expected BRCA mutation malignancies. The established mechanism of action of PARP inhibitors is an important addition to the field of rationally designed drug development through novel trial design, as well as to the development of biomarker investigation. There are currently at least 9 PARP inhibitors in clinical development (Table 1). In this review article we describe the evolving role of PARP inhibition in the landscape of personalized therapy, focusing on the 3 PARP inhibitors that are furthest in clinical development.

Dr Hopps is Clinical Specialist, Hematology/Oncology, Rush University Medical Center; Dr Kurkjian is Assistant Professor of Medicine; and Dr Pant is Assistant Professor of Medicine, Peggy and Charles Stephenson Cancer Center at the University of Oklahoma Health Sciences Center, Oklahoma City.

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The Rationale for PARP Inhibition The accumulation of DNA damage is central to carcinogenesis.1 The mechanisms for repairing singlestrand DNA breaks include the base excision repair pathway, in which the PARP family plays a key role.2,3 The most abundant of this group of enzymes is PARP1; its inhibition leads to double-strand breaks at the replication forks, in the absence of homologous repair.4 The PARP enzymes function through the transfer of ADP-ribose moieties from intracellular nicotinamide adenine dinucleotide, which leads to the creation of ADP-ribose polymers on the PARP protein and surrounding histones.5 It is believed that these negatively charged ADP-ribose polymers then attract DNA repair proteins, such as XRCC1.6 The products of the tumor-suppressor genes BRCA1 and BRCA2 are integral to homology-directed repair, and a deficiency in these genes leads to disordered DNA damage repair and subsequent carcinogenesis.7-9 Based on the premise that in BRCA mutation cells the base excision repair pathway becomes essential to viability,

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BRCA-deficient cells have been shown to be exceptionally sensitive to PARP inhibition.10, 11 In vitro data in support of PARP inhibition in BRCA mutation cells demonstrated up to 1000-fold increased sensitivity compared with wild-type cells. Furthermore, the selectivity of PARP inhibition was demonstrated through the absence of cytotoxicity in heterozygotic cells, which are capable of repairing double-strand breaks.10 The notion of inducing synthetic lethality through the inhibition of the base excision repair and homologous recombination pathways provided the basis for clinical evaluation of PARP inhibition in tumors known to have BRCA mutations. Some sporadic tumors also appear to be phenotypically similar to BRCA1 or BRCA2 mutation tumors, without actually bearing germ-line mutations in either the BRCA1 or the BRCA2 gene, a phenomenon that has been described as “BRCAness.”12 The phenotypic likeness between germ-line BRCA1 mutation breast cancers and the basal epithelial subtype of breast cancer (ie, estrogen receptors-negative, progesterone receptors-negative, or HER2-negative, also known as “triple-negative”) has been noted and suggest a common sensitivity to PARP inhibition, a concept that led to clinical trials of PARP inhibition in patients with triple-negative breast cancer.13,14 Although the disruption of homologous recombination through BRCA deficiency comprised a significant fraction of the initial research into the efficacy of PARP inhibition, there is increasing evidence that deficiencies in other proteins involved in homologous repair, such as ATM, CHK2, and FANCF, also impart sensitivity to PARP inhibitors.15 A depletion of these homologous repair proteins is found in a variety of cancers, including chronic lymphocytic leukemia; mantle-cell lymphoma; lung, cervical, and oral cancers; and others.16-20 The possibility that chemotherapy or radiation resistance could be overcome with concomitant PARP inhibition is also a subject of ongoing investigation.21 The cytotoxic effects of chemotherapy and radiation result in PARP-1 activation as a response to DNA damage; hence, PARP inhibitors can potentiate the cellular toxicity induced by DNA-targeted therapies.22-25 Clinical studies of combination therapies were initiated after preclinical findings revealed increased cytotoxicity associated with PARP inhibition in combination with ionizing radiation, platinum agents, temozolomide, and topoisomerase I inhibitors.26-28 Among the PARP inhibitors currently in clinical development, olaparib inhibits both PARP-1 and PARP-2 through binding of the PARP enzymes’ active site, thereby blocking association with the principal substrate, nicotinamide.29 Veliparib has a mechanism of

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Table 1 PARP Inhibitors in Development Route of Stage of clinical Agent administration trial Veliparib Oral Phase 2 Olaparib Oral Phase 2 Iniparib IV Phase 3 AG014699 IV Phase 2 INO-1001 IV Phase 1 MK-4827 Oral Phase 1 AZD2461 Oral Phase 1 CEP-9722 Oral Phase 1/2 E7016 Oral Phase 1 IV indicates intravenous; PARP, poly(ADP-ribose) polymerase. action similar to that of olaparib in its competitive inhibition of the PARP enzyme.30 In contrast, iniparib appears to irreversibly inhibit the PARP enzyme through a covalent modification.31 This review describes in further detail the available data from clinical studies investigating PARP inhibitors and their potential role in future cancer therapy.

PARP Inhibitors in Clinical Trials Olaparib Olaparib is an oral, single-digit nanomolar inhibitor of PARP-1 and PARP-2.29 In vitro studies with olaparib demonstrated inhibition of BRCA1-deficient breast cancer cell lines. In xenograft studies of a genetically engineered mouse model of BRCA1-induced breast cancer, olaparib prolonged survival with no observed toxicity.32 In vivo studies demonstrated that olaparib, in combination with chemotherapeutic agents, confers even greater improvement in survival compared with monotherapy and was associated with acceptable adverse effects.32,33 On the basis of preclinical data, olaparib was evaluated in a phase 1 dose-escalation study involving 60 patients with advanced tumors.34 In this study, eligible patients were initially not required to have BRCA mutations, but provisions in the protocol permitted enrichment of the study population with BRCA mutation carriers. The initial dose was 10 mg once daily for 2 of every 3 weeks. The maximum tolerated dose was established at 400 mg twice daily.34 Responses were observed only in patients with breast, ovarian, or prostate cancer who had BRCA1 or BRCA2 mutations. In all, 63% of patients who were BRCA carriers received clinical benefit from treatment. The toxicities were predominantly grade 1 and 2 and consisted mostly of nausea, fatigue, vomiting, taste alteration, and anorexia.35

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To further evaluate this activity, the investigators expanded the study to assess women with BRCA mutation ovarian cancer.35 The majority of patients (39 of 50) received olaparib 200 mg twice daily. The response rate was 40% (95% confidence interval [CI], 26.4%-54.8%), and the median duration of response was 28 weeks. Although the study was not powered to analyze this, the response rate differed in patients with platinum-sensitive disease (61.5%), platinum-resistant disease (41.7%), and platinum-refractory disease (15.4%).35 The drug-related toxicities were predominantly grade 1 or grade 2 and included nausea (32%), fatigue (30%), vomiting (20%), taste alteration (13%), and anorexia (12%).34 Olaparib was further evaluated in two phase 2 studies in patients with BRCA mutations and advanced breast cancer36 or recurrent ovarian cancer.37 In both studies, the dose of olaparib was 400 mg twice daily in cohort 1 and 100 mg twice daily in cohort 2. The rationale for the lower dose was based on pharmacodynamic data from a previous phase 1 trial, in which olaparib at 100 mg twice daily achieved drug concentration sufficient to saturate inhibition of the target in surrogate tissues (peripheral blood mononuclear cells and hair follicles).34 Among 54 patients with breast cancer enrolled in the first study, the overall response rate (ORR) was 42% in cohort 1 and 25% in cohort 2.36 The median progression-free survival (PFS) also seemed to be lower in cohort 2 (3.8 months vs 5.7 months in cohort 1). Patients progressing after platinum chemotherapy rarely had a confirmed response to olaparib.36 Of the 57 patients with ovarian cancer evaluated in the second study, the ORR was 33% in cohort 1 and 13% in cohort 2. Response to olaparib was seen both in patients with platinum-sensitive (38%) or platinumresistant (30%) disease. The most common nonhematologic toxicities were nausea and fatigue, and anemia was the most common hematologic toxicity.37 Although the response rate was better in patients who received the higher dose (ie, 400 mg twice daily), it is important to note that the 2 cohorts were not randomized; therefore, the results must be interpreted with caution. However, these results do point to the limitations of surrogate markers in determining the â&#x20AC;&#x153;biologically effective dose,â&#x20AC;? because target inhibition within tumors may differ from inhibition in surrogate tissues. Overall, these 2 trials demonstrate the efficacy and tolerability of olaparib in patients with BRCA1 or BRCA2 mutations.36,37 Phase 1 studies combining olaparib and chemotherapy in the treatment of other solid tumors are ongoing. In one study, the combination of gemcitabine, cisplatin, and olaparib was associated with significant myelosuppression.38 Similarly, in a study of olaparib therapy in

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combination with dacarbazine, the dose-limiting toxicities were neutropenia and thrombocytopenia. No responses were observed in chemotherapy-naĂŻve patients with melanoma who received the optimally tolerated dose.39 Table 2 lists PARP inhibitors investigated as a single-agent therapy.34,36,37,40-43

Iniparib Iniparib is an intravenous (IV) PARP-1 and PARP-2 inhibitor. When combined with gemcitabine and carboplatin in an MDA-MB-468(-) triple-negative breast cancer cell line, iniparib increased induction of apoptosis, S-phase and G2/M-cell cycle arrest, and DNA damage coinciding with mitotic arrest.44 Initial dose-escalation studies demonstrated no dose-limiting toxicities at doses ranging from 0.5 to 8 mg/kg.41 Iniparib and its metabolites cross the blood-brain barrier.45 In one case report, iniparib was used by a patient with relapsed triple-negative breast cancer who had developed carcinomatous meningitis.45 The duration of disease-free progression was 5 months, and central nervous system exposure to iniparib was 8% of the total systemic area under the curve (AUC).45 Temozolomide and concurrent radiation therapy are used in the treatment of gliomas; however, resistance to this combination has been demonstrated through DNA repair mechanisms.46 Because iniparib crosses the blood-brain barrier, phase 1 clinical trials are investigating iniparib and temozolomide in patients with malignant glioma.47 In an open-label, randomized, phase 2 study, gemcitabine plus carboplatin, with or without iniparib, was analyzed in 123 women with metastatic triple-negative breast cancer. Gemcitabine 1000 mg/m2 plus carboplatin (in a dose equivalent to an AUC of 2) was given every 21 days on days 1 and 8, with or without IV iniparib 4 mg/kg, on days 1, 4, 8, and 11.47 Among patients who received iniparib, the median PFS was 5.9 months versus 3.6 months in those receiving chemotherapy alone (hazard ratio [HR], 0.59; 95% CI, 0.39-0.09; P = .01), and the median overall survival (OS) was 12.3 months versus 7.7 months, respectively (HR, 0.57; 9% CI, 0.36-0.90; P = .01). Adverse events were similar between the 2 groups.47 Based on these encouraging phase 2 data, a phase 3 trial in patients with triple-negative metastatic breast cancer was launched. The doses and schedule of drugs were identical to the phase 2 trial. A total of 519 patients were enrolled between July 2009 and March 2010, and the final results were reported at the 2011 American Society of Clinical Oncology (ASCO) annual meeting.48 The study failed to meet its coprimary end points of

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Table 2 PARP Inhibitors Studied as Single-Agent Therapy Agent (study) Stage of clinical trial Cancer type Olaparib (Fong 200934)

Phase 1

Preliminary results/conclusions

Study population enriched in carriers of BRCA1 or BRCA2 mutations

Antitumor activity only in mutation carriers Clinical benefit benefit rate, 63%

Toxicity of active drug Mood alteration, fatigue, thrombocytopenia, somnolence, mild gastrointestinal symptoms

Olaparib (Tutt 201036)

Phase 2

BRCA1 or BRCA2 mutations in advanced breast cancer

ORR, 42% with 400 mg Fatigue, nausea, twice daily and 25% with vomiting, anemia with 100 mg twice daily 400 mg twice daily

Olaparib (Audeh 201036)

Phase 2

BRCA-deficient advanced ovarian cancer

ORR, 33% with 400 mg twice daily, 12.5% with 100 mg twice daily

Nausea, fatigue, leukopenia, anemia

Clinical benefit rate, 57.6% with 400 mg twice daily, 16.7% with 100 mg twice daily Olaparib (Ledermann 201140)

Phase 2

Platinum-sensitive relapsed serous ovarian cancer

Median PFS, 8.4 mo with Nausea, fatigue, olaparib vs 4.8 mo with vomiting, anemia placebo (HR, 0.35, 95% CI 0.25-0.49; P <.001)

Iniparib (Kopetz 200841)

Phase 1, dose escalation

Advanced solid tumors

Stable disease in 6 of 23 patients

Gastrointestinal adverse events

AG014699 (Drew 201142)

Phase 2

BRCA1 or BRCA2 mutation, advanced ovarian and/or locally advanced or metastatic breast cancer

ORR, 5%

Fatigue, nausea, diarrhea, dizziness

BRCA1-deficient tumors and sporadic ovarian cancers

PR, n = 12

MK-4827 (Schelman 201143)

Phase 1

Clinical benefit rate, 32% Stable disease lasting ≥4 mo, 26% Stable disease lasting ≥120 days, n = 8

No dose-limiting toxicity observed Fatigue, reversible pneumonitis, thrombocytopenia, myelosuppression

CI indicates confidence interval; HR, hazard ratio; ORR, objective response rate; PARP, poly(ADP-ribose) polymerase; PFS, progression-free survival; PR, partial response.

PFS and OS. The median OS in the gemcitabine plus carboplatin alone arm was 11.1 months versus 11.8 months in the iniparib arm (HR, 0.876; P = .284), and the median PFS was 4.1 months versus 5.1 months, respectively (HR, 0.794; P = .027). Grade 3/4 adverse effects were similar in the 2 groups and included neutropenia, anemia, thrombocytopenia, and leukopenia.48 The consent requirement was modified to allow patients to disclose their BRCA mutation status, if known, or to undergo testing as part of the trial, but only few patients consented. In a subset analysis also discussed at the 2011 ASCO meeting by Dr O’Shaughnessy, the addition of iniparib to chemotherapy in a second- or third-line setting demon-

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strated a modest benefit in PFS (4.2 vs 2.9 months; P = .031) and OS (10.8 vs 8.1 months; P = .05).48 One possible explanation for the lack of efficacy is that triple-negative breast cancer is a heterogeneous disease with numerous subtypes. A biomarker analysis may help identify a patient population that benefits from the addition of iniparib. Further analysis of these data is being conducted to determine whether certain populations, such as patients receiving second- or third-line chemotherapy or those with certain molecular subtypes of triple-negative cancer, could benefit from iniparib. Currently, numerous phase 1 and 2 trials are under way, the majority involving iniparib in combination

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Table 3 PARP Inhibitors Studied in Combination with Chemotherapy Agent (study)

Chemotherapy

Stage of clinical trial

Cancer type

Preliminary results/conclusions

Toxicity

Metastatic breast cancer (36% TNBC)

CR (unconfirmed), n = 1

Phase 1

Refractory solid tumors, lymphomas

Confirmed PR, n = 3

Lymphopenia, neutropenia

Cyclophosphamide 450-750 mg/m2 every 21 days

Phase 1

Refractory solid tumors

PR, n = 1 Stable disease, n = 4

Fatigue, neutropenia, thrombocytopenia, vomiting

Veliparib (Ji 201052)

Topotecan IV (multiple dose amounts)

Phase 1

Refractory solid tumors, lymphomas

Veliparib potentiated DNA damage caused by topotecan

Myelosuppression

Veliparib (Tan 201153)

Doxorubicin 60 mg/m2 IV and cyclophosphamide 600 mg/m2 IV

Phase 1

Breast cancer, other solid tumors

PR, n = 3 in 5 BRCA mutationâ&#x20AC;&#x201C;positive TNBC Stable disease >12 wks, n = 8 breast cancer

Fatigue, myelosuppression

Veliparib Irinotecan (LoRusso 201154) 100 mg/m2 IV on days 1, 8 every 21 days

Phase 1

Advanced solid tumors

Clinical benefit rate: 61% PR, n = 5 MR, n = 2 Stable disease, n = 10

Diarrhea, nausea, leukopenia, fatigue, neutropenia, anemia, vomiting

Veliparib Temozolomide (Pishvaian 201155) 150 mg/m2 orally on days 1-5

Phase 2

Heavily pretreated metastatic colorectal cancer

Disease control rate, n = 23% Myelosuppression Time to progression, 11 wks overall, 23 wks in patients with controlled disease

TNBC

Confirmed PR, n = 7 Confirmed + unconfirmed PR, n = 10

Fatigue, nausea, diarrhea, neutropenia

Veliparib (Isakoff 201049)

Temozolomide 150 mg/m2 orally on days 1-5

Phase 2

Veliparib (Kummar 201050)

Cyclophosphamide 50 mg orally once daily

Veliparib (Tan 201051)

Olaparib (Dent 201056)

Paclitaxel 90 mg/m2 Phase 1/2 IV once weekly, 3 wks on, 1 wk off

Thrombocytopenia

PR (unconfirmed), n = 2 Stable disease (unconfirmed), n = 7 Progressive disease, n = 14

Olaparib Cisplatin 60 mg/m2 (Giaccone 201038) on day 1 and gemcitabine 500 mg/m2 IV on days 1, 8 every 21 days

Phase 1

Advanced solid tumors

PR, n = 2 Stable disease, n = 7 Progressive disease, n = 10

Myelosuppression

Olaparib (Khan 201039)

Dacarbazine IV 600-800 mg/m2 on day 1 every 21 days

Phase 1

Advanced solid tumors

PR, n = 2 with melanoma

Neutropenia, thrombocytopenia

Olaparib (Liu 201057)

Cediranib (multiple doses)

Phase 1

Recurrent ovarian or TNBC

Ovarian cancer CR, n = 1 confirmed PR, n = 3 confirmed, 1 unconfirmed Stable disease, n = 3 confirmed, 1 unconfirmed TNBC Stable disease, n = 1 confirmed, 2 unconfirmed Progressive disease, n = 2

Neutropenia, thrombocytopenia, hypertension, fatigue, anorexia, nausea, asymptomatic pulmonary embolism

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Table 3 PARP Inhibitors Studied in Combination with Chemotherapy (Continued) Agent Stage of Preliminary (study) clinical trial Chemotherapy Cancer type results/conclusions Olaparib (Lee 201058)

Carboplatin IV (AUC 3-5)

Phase 1

Iniparib (Moulder 201059)

Irinotecan 80, 100, and 125 mg/m2 IV on days 1, 8 every 21 days

Phase 1b

Iniparib (Blakeley 201046)

BRCA mutation Ovarian cancer carriers with breast or Clinical benefit rate, n = 83% PR, n = 8 of 23 ovarian cancer Stable disease, n = 11 of 23 Breast cancer Clinical benefit rate, 100% PR, n = 3 of 4 Stable disease, N = 1

Toxicity Thrombocytopenia,

delayed neutropenic recovery, anemia, fatigue

Metastatic breast cancer (65% TNBC)

PR, n = 5 Stable disease, n = 10 Progressive disease, n = 9

Diarrhea, neutropenia, anemia

Temozolomide Phase 1 75 mg/m2 orally once daily for 6 wks or 150-200 mg/m2 for 5 days every 28 days plus radiation therapy

Malignant glioma, newly diagnosed

30 patients accrued, no results available yet

Thrombosis, lymphopenia, urticaria, thromobocytpenia, elevated liver transaminase levels

AG014699 (Plummer 200860)

Temozolomide Phase 1 100-200 mg/m2 orally on days 1-5 every 28 days

Advanced solid tumors

PARP inhibition at all doses

Myelosuppression

AG014699 (Plummer 200661)

Temozolomide Phase 2 200 mg/m2 orally on days 1-5 every 28 days

Metastatic malignant melanoma

PR, n = 4 Stable disease, n = 4

Thrombocytopenia, neutropenia

Stage III or IV melanoma

No results available yet

Myelosuppression, elevation of liver transaminase levels

INO-1001 Temozolomide (Bedikian 200962) 200 mg/m2 days 1-5 every 28 days

Phase 1b

AUC indicates area under the curve; CR, complete response; IV, intravenous; MR, minor response; PARP, poly(ADP-ribose) polymerase; PR, partial response; TNBC, triple-negative breast cancer.

with chemotherapy (Table 3).38,39,46,49-62 It is not known which tumor types will be most affected by iniparib. The malignancies currently under investigation include platinum-sensitive and platinum-resistant ovarian cancer, BRCA1 and BRCA2 mutation ovarian cancer, nonâ&#x20AC;&#x201C;small-cell lung cancer, malignant gliomas, and triple-negative breast cancer, in which iniparib is being investigated as neoadjuvant therapy.

Veliparib Veliparib is an orally available potent inhibitor of PARP-1 and PARP-2.30 Similar to iniparib, veliparib has been demonstrated to cross the blood-brain barrier.30 In tumor-bearing rats that received multiple doses of veliparib (50 mg/kg daily), the maximum concentration of veliparib measured in brain tissue was 0.72 Âą 0.12 mcg/g.30 In a study of nonhuman primates that received

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oral veliparib (5 mg/kg), cerebrospinal fluid penetration measured 57%.63 Veliparib is mainly eliminated through renal secretion; 33% of the drug is metabolized in the liver.64 Cytochrome (CY) P450-2D6 has been identified as the major metabolizer of veliparib. Its allelic variants CYP2D6*10 and CYP2D6*4 are associated with lower metabolic activity.65 In a first-of-its-kind dose-finding phase 0 trial conducted at the National Cancer Institute, veliparib was administered orally in doses of 10 mg, 25 mg, and 50 mg to 13 patients with advanced malignancies. Phase 0 trials were designed in an effort to speed up the development of molecularly targeted agents. They rely on extensive preclinical development and incorporation of realtime pharmacokinetic and pharmacodynamic assays to evaluate the effects of agents at the molecular level. This

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Table 4 Ongoing Clinical Trials with PARP Inhibitors Agent(s) (ClinicalTrials.gov identifier)

Stage of clinical trial

Cancer type

Veliparib plus temozolomide (NCT01085422, recruiting) Phase 1

Metastatic, castration-resistant prostate cancer that has failed to respond to as many as 2 nonhormonal systemic therapies

Veliparib plus temozolomide (NCT01139970, recruiting) Phase 1

Acute leukemia

Veliparib plus liposomal doxorubicin (NCT01145430, not yet recruiting)

Phase 1

Recurrent ovarian cancer, fallopian tube cancer, primary peritoneal cancer, or metastatic breast cancer

Veliparib plus temozolomide (NCT00526617, ongoing, not recruiting)

Phase 1

Advanced solid tumors, including metastatic melanoma, BRCA-deficient breast, ovarian, primary peritoneal, or fallopian tube cancer, and hepatocellular carcinoma

Veliparib plus cyclophosphamide (NCT01306032, recruiting)

Phase 2

Refractory BRCA-positive ovarian, primary peritoneal or ovarian high-grade serous carcinoma, fallopian tube cancer, TNBC, and low-grade non-Hodgkin lymphoma

Veliparib plus carboplatin and gemcitabine (NCT01063816, recruiting)

Phase 2

Advanced solid tumor

Veliparib plus temozolomide (NCT01063816, recruiting)

Phase 1

Young patients (aged â&#x2030;¤21 yrs) with recurrent or refractory central nervous system tumors

Veliparib plus FOLFIRI (NCT01123876, recruiting)

Phase 1

Advanced solid tumors

Veliparib plus topotecan (NCT01012817, not yet recruiting)

Phase 1/2

Advanced solid tumors or relapsed or refractory ovarian epithelial cancer or primary peritoneal cancer after prior platinum-containing first-line chemotherapy

Veliparib plus carboplatin, paclitaxel, and bevacizumab (NCT00989651, recruiting)

Phase 1

Newly diagnosed stage II, III, or IV ovarian epithelial cancer, fallopian tube cancer, or primary peritoneal cancer

Veliparib plus temozolomide (NCT00804908, ongoing, not recruiting)

Phase 2

Metastatic melanoma

Veliparib plus carboplatin (NCT01251874, recruiting)

Phase 1

HER2-negative metastatic breast cancer

Olaparib in combination with paclitaxel and carboplatin (NCT00516724, currently recruiting)

Phase 1

Advanced solid tumors

Olaparib in combination with carboplatin (NCT01237067, currently recruiting)

Phase 1

Gynecologic malignancies and breast cancer

Olaparib in combination with gemcitabine (NCT00515866, currently recruiting)

Phase 1

Pancreatic cancer or locally advanced

Olaparib vs liposomal doxorubicin (NCT00628251, ongoing, not recruiting)

Phase 2

BRCA1- or BRCA2-positive advanced ovarian cancer that had failed to respond to previous platinum therapy

Olaparib alone (NCT00912743, recruiting)

Phase 2

Stage IV colorectal cancer

Olaparib alone (NCT00516373, ongoing, not recruiting)

Phase 1

Advanced solid tumors, enriched with BRCA1 or BRCA2 mutation

Olaparib alone (NCT00679783, ongoing, not recruiting)

Phase 2

BRCA1 or BRCA2 mutationâ&#x20AC;&#x201C;positive ovarian or breast cancer or recurrent high-grade ovarian cancer

Olaparib plus bevacizumab (NCT00710268, completed, unpublished)

Phase 1

Advanced solid tumors

Olaparib plus paclitaxel vs paclitaxel alone (NCT01063517, recruiting)

Phase 2

Gastric cancer with progression after first-line therapy

Olaparib plus carboplatin and paclitaxel vs carboplatin and paclitaxel alone (NCT01081951, ongoing, not recruiting)

Phase 2

Platinum-sensitive advanced serous ovarian cancer

Olaparib alone (NCT01078662, recruiting)

Phase 2

Advanced caners with confirmed BRCA mutation

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Table 4 Ongoing Clinical Trials with PARP Inhibitors (Continued) Agent(s) (ClinicalTrials.gov identifier)

Stage of clinical trial

Cancer type

Iniparib plus gemcitabine and carboplatin (NCT00813956, recruiting)

Phase 2

Neoadjuvant treatment of TNBC

Iniparib plus irinotecan (NCT01173497, recruiting)

Phase 2

TNBC with brain metastasis

Iniparib plus carboplatin and gemcitabine (NCT01033123, ongoing, not recruiting)

Phase 2

Platinum-sensitive recurrent ovarian cancer

Iniparib plus carbplatin and gemcitabine (NCT01033292, recruiting)

Phase 2

Platinum-resistant recurrent ovarian cancer

Iniparib plus gemcitabine and carboplatin vs gemcitabine and carboplatin alone (NCT01082549, recruiting)

Phase 3

Previously untreated stage IV squamous NSCLC

Iniparib plus temozolomide and radiation therapy (NCT00687765, recruiting)

Phase 1/2

Newly diagnosed malignant glioma

Iniparib plus gemcitabine and cisplatin vs gemcitabine and cisplatin alone (NCT01086254, ongoing, not recruiting)

Phase 2

Stage IV NSCLC, first-line therapy

Iniparib plus paclitaxel (NCT01204125, recruiting)

Phase 2

Neoadjuvant therapy in stage II-IIIa TNBC

Iniparib alone (NCT00677079, ongoing, not recruiting)

Phase 2

BRCA mutation–positive advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer

AZD2461 alone (NCT01247168, ongoing, not recruiting)

Phase 1

Refractory solid tumors

AG014699 alone (NCT00664781, recruiting)

Phase 2

BRCA mutation–positive, locally advanced or metastatic breast cancer or advanced ovarian cancer

AG014699 plus cisplatin (NCT01074970, recruiting)

Phase 2

Neoadjuvant treatment for TNBC with BRCA mutations

AG014699 plus several chemotherapy regimens (NCT01009190, recruiting)

Phase 1

Advanced solid tumors

CEP-9722 plus temozolomide (NCT00920595, recruiting)

Phase 1

Advanced solid tumors

CEP-9722 alone (NCT01311713, recruiting)

Phase 1/2

Advanced solid tumors

CEP-9722 plus gemcitabine and cisplatin (NCT01345357, not yet open)

Phase 1

Advanced solid tumors

E7016 plus temozolomide (NCT01127178, ongoing, not recruiting)

Phase 1

Advanced solid tumors and gliomas

MK-4827 alone (NCT01226901, recruiting)

Phase 1

Solid tumors

MK-4827 plus pegylated liposomal doxorubicin (NCT01227941, ongoing, not recruiting)

Phase 1

Advanced solid tumors and ovarian cancer

MK-4827 plus temozolomide (NCT01294735, recruiting)

Phase 1

Advanced glioblastoma multiforme and advanced melanoma

MK-4827 alone (NCT00749502, ongoing, not recruiting)

Phase 1

Advanced solid tumors or hematologic malignancies

MK-4827 plus carboplatin or carboplatin and paclitaxel or carboplatin and liposomal doxorubicin (NCT01110603, ongoing, not recruiting)

Phase 1

Advanced solid tumors

NSCLC indicates non–small-cell lung cancer; TNBC, triple-negative breast cancer.

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leads to selection of a biologically effective starting dose and dose escalation schema that can reduce timelines for drug development.66 The 25-mg and 50-mg doses reduced poly(ADP-ribose) (a product of PARP) levels in the tumors and reduced peripheral blood mononuclear cells, with no adverse effects.67 Multiple dosing is necessary for sustained PARP inhibition, because PARP-1 expression has been shown to increase 3 to 6 hours after a single oral dose of veliparib, which coincides with a half-life of 3.64 hours.68,69 Veliparib has also been combined with topotecan, temozolomide, and cyclophosphamide in the treatment of a variety of solid tumors and lymphomas.49-52 In in vivo studies, veliparib enhanced temozolomide tumor growth inhibition and increased the efficacy of temozolomide in cells with high levels of mismatch repair genes.70,71

The results of recent studies have demonstrated the effectiveness of PARP inhibitors against cancers in patients harboring BRCA mutations. In a single-arm phase 2 study of veliparib and temozolomide in 41 patients with metastatic triple-negative breast cancer, the initial dosing of veliparib had to be reduced from 40 mg twice daily on days 1 through 7 to 30 mg twice daily in response to a higher-than-expected incidence of thrombocytopenia.49 Limited activity was seen with the combination, leading to a complete response in 1 patient, a partial response in 2 patients, stable disease in 7, and progressive in 14.49 Topoisomerase I inhibitors bind to the topoisomerase Iâ&#x20AC;&#x201C;DNA complex, which results in accumulation of single- and double-strand DNA breaks. Veliparib has the potential to inflict further damage on the tumor cell by blocking repair of these DNA breaks.52 Veliparib was combined with topotecan in a phase 1 study in patients with solid tumors and lymphomas. The administration schedule had to be adjusted and the topotecan dose reduced in response to myelosuppression.52 Veliparib potentiated DNA damage caused by topotecan, as seen through quantitative detection of the phosphorylation of histone gamma-H2AX, which is a DNAdamage signaling pathway induced by topoisomerase I inhibitors.52 When combined with cyclophosphamide 750 mg/m2 in a study of patients with advanced cancer, veliparib 50 mg twice daily was safe and effective, with only 1 patient experiencing dose-limiting toxicity (ie, thrombocytopenia).51 As a result of the synergistic interaction between veliparib and alkylating agents, veliparib

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was also studied in combination with doxorubicin and cyclophosphamide.51,53 In this phase 1 trial, veliparib was given in doses ranging from 50 to 150 mg every 12 hours on days 1 through 4, with doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 on day 3 every 21 days; grade 3 febrile neutropenia was the dose-limiting toxicity. The maximum tolerated dose of veliparib was 100 mg twice daily, and the most frequent drug-related toxicities were myelosuppression and fatigue.53 As a single agent or in combination, veliparib has the potential to be useful in several malignancies. As with other PARP inhibitors, myelosuppression is the biggest concern when veliparib is combined with chemotherapy. Phase 2 trials of veliparib as a single agent or in combination with chemotherapy are currently under way in patients with advanced colorectal cancer, melanoma, and ovarian cancer (including BRCA mutation ovarian cancer).

PARP Inhibitors in Early Development Table 4 presents on going cliical trials with PARP in hibitors. MK-4827, an inhibitor of PARP-1 and PARP2, is in phase 1 clinical trials. MK-4827 has shown activity in BRCA mutation cell lines.72 The trials include patients with advanced ovarian cancer, melanoma, glioblastoma multiforme, and other solid tumors. In a recent study, single-agent therapy with MK-4827 showed activity in patients with BRCA mutation tumors and sporadic ovarian cancers.43 The PARP-1 inhibitor AG014699 was first studied in combination with temozolomide in phase 1 and phase 2 trials for metastatic melanoma; however, grade 4 thrombocytopenia occurred in 12% of patients and grade 4 neutropenia occurred in 15%.61 AG014699 is still being investigated in phase 1 trials for advanced solid tumors and in phase 2 trials for advanced BRCA mutation breast and ovarian cancer and as a neoadjuvant treatment in BRCA1 or BRCA2 mutation breast cancer. In another study presented at ASCO 2011, among patients who received single-agent therapy with AG014699 for BRCA mutation ovarian or metastatic breast cancer, the ORR was 5%; however, 26% of patients had stable disease for â&#x2030;Ľ4 months.42 The IV PARP-1 and PARP-2 inhibitor INO-1001 was studied in combination with temozolomide in a phase 1b trial that enrolled 12 patients with unresectable stage III or IV melanoma.62 INO-1001 was administered in doses of 100, 200, and 400 mg IV for 1 hour every 12 hours, for a total of 10 doses.62 Myelosuppression and increased liver transaminase levels were the dose-limiting toxicities at the 400-mg dose. One patient had a partial response and 4 had sta-

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ble disease. The median time to progression was 2.2 months.62 Trials involving the PARP-1 and PARP-2 inhibitors AZD2461 and CEP-9722 are currently under way. AZD2461 is being studied as a single agent for advanced solid tumors. CEP-9722 is being studied in advanced solid tumors as single-agent therapy, in combination with temozolomide, and in combination with gemcitabine and cisplatin.

Conclusion The results of recent studies have demonstrated the effectiveness of PARP inhibitors against cancers in patients harboring BRCA mutations. The main mechanism of action of PARP inhibitors is hypothesized to be their inhibition of base excision repair and homologous recombination pathways in tumor cells. Other than treating tumors that harbor BRCA mutations, these agents have been hypothesized to extend their benefits to tumors with dysfunctional homologous repair (the concept of “BRCAness”). The phenotypic similarities between BRCA1 mutation breast cancer and triple-negative breast cancer led to the testing of PARP inhibitors in patients with these cancers. The benefits of PARP inhibitors will have to be weighed against their long-term toxicities, especially as adjuvant trials in breast cancer get underway. Followup assessments of the risk of secondary neoplasia are important. PARP inhibitors are novel agents whose strength lies in targeting the weakness of tumors, leading to improved outcomes. The results of ongoing clinical trials will help us determine whether these agents will be effective in a wide range of tumors or only in the subset of BRCA mutation carriers. ■ Author Disclosure Statement Dr Hopps, Dr Kurkjian, and Dr Pant reported no conflicts of interest.

References 1. Hoeijmakers JH. Genome maintenance mechanisms for preventing cancer. Nature. 2001;411:366-374. 2. Dantzer F, de la Rubia G, Ménissier-De Murcia J, et al. Base excision repair is impaired in mammalian cells lacking poly (ADP-ribose) polymerase-1. Biochemistry. 2000;39:7559-7569. 3. Amé JC, Spenlehauer C, de Murcia G. The PARP superfamily. Bioessays. 2004;26:882-893. 4. Schultz N, Lopez E, Sale-Gohari N, Helleday T. Poly(ADP-ribose) polymerase (PARP-1) has a controlling role in homologous recombination. Nucleic Acids Res. 2003;31:4959-4964. 5. Helleday T, Bryant HE, Schultz N. Poly(ADP-ribose) polymerase (PARP-1) in homologous recombination and as a target for cancer therapy. Cell Cycle. 2005;4:1176-1178. Epub 2005 Sep 12. 6. El-Khamisy SF, Masutani M, Suzuki H, Caldecott KW. A requirement for PARP-1 for the assembly or stability of XRCC1 nuclear foci at sites of oxidative DNA damage. Nucleic Acids Res. 2003;31:5526-5533. 7. Moynahan ME, Chiu JW, Koller BH, Jasin M. BRCA1 controls homologydirected DNA repair. Mol Cell. 1999;4:511-518.

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8. Moynahan ME, Pierce AJ, Jasin M. BRCA2 is required for homology-directed repair of chromosomal breaks. Mol Cell. 2001;7:263-272. 9. Tutt A, Bertwistle D, Valentine J, et al. Mutation in BRCA2 stimulates errorprone homology-directed repair of DNA double-strand breaks occurring between repeated sequences. EMBO J. 2001;20:4704-4716. 10. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434:917-921. 11. Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434:913917. 12. Turner N, Tutt A, Ashworth A, et al. Hallmarks of “BRCAness” in sporadic cancers. Nat Rev Cancer. 2004;4:814-819. 13. Foulkes WD, Stefansson IM, Chappuis PO, et al. Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst. 2003;95:14821485. 14. Turner NC, Reis-Filho JS. Basal-like breast cancer and the BRCA1 phenotype. Oncogene. 2006;25:5846-5853. 15. McCabe N, Turner NC, Lord CJ, et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 2006;66:8109-8115. 16. Bullrich F, Rasio D, Kitada S, et al. ATM mutations in B-cell chronic lymphocytic leukemia. Cancer Res. 1999;59:24-27. 17. Bell DW, Varley JM, Szydlo TE, et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 1999;286:2528-2531. 18. Miller CW, Ikezoe T, Krug U, et al. Mutations of the CHK2 gene are found in some osteosarcomas, but are rare in breast, lung, and ovarian tumors. Genes Chromosomes Cancer. 2002;33:17-21. 19. Marsit CJ, Liu M, Nelson HH, et al. Inactivation of the Fanconi anemia/BRCA pathway in lung and oral cancers: implications for treatment and survival. Oncogene. 2004;23:1000-1004. 20. Narayan G, Arias-Pulido H, Nandula SV, et al. Promoter hypermethylation of FANCF. Cancer Res. 2004;64:2994-2997. 21. Barret JM, Hill BT. DNA repair mechanisms associated with cellular resistance to antitumor drugs: potential novel targets. Anticancer Drugs. 1998;9:105-123. 22. de Murcia G, Ménissier de Murcia J. Poly(ADP-ribose) polymerase: a molecular nick-sensor. Trends Biochem Sci. 1994;19:172-176. 23. Satoh MS, Lindahl T. Role of poly(ADP-ribose) formation in DNA repair. Nature. 1992;356:356-358. 24. Ding R, Smulson M. Depletion of nuclear poly(ADP-ribose) polymerase by antisense RNA expression: influences on genomic stability, chromatin organization, and carcinogen cytotoxicity. Cancer Res. 1994;54:4627-4634. 25. de Murcia JM, Niedergang C, Trucco C, et al. Requirement of poly(ADPribose) polymerase in recovery from DNA damage in mice and in cells. Proc Natl Acad Sci U S A. 1997;94:7303-7307. 26. Calabrese CR, Almassy R, Barton S, et al. Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361. J Natl Cancer Inst. 2004;96:56-67. 27. Dungey FA, Löser DA, Chalmers AJ. Replication-dependent radiosensitization of human glioma cells by inhibition of poly(ADP-ribose) polymerase: mechanisms and therapeutic potential. Int J Radiat Oncol Biol Phys. 2008;72:1188-1197. 28. Rouleau M, Patel A, Hendzel MJ, et al. PARP inhibition: PARP1 and beyond. Nat Rev Cancer. 2010;10:293-301. Epub 2010 Mar 4. 29. Menear KA, Adcock C, Boulter R, et al. 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1. J Med Chem. 2008;51:6581-6591. Epub 2008 Sep 19. 30. Donawho CK, Luo Y, Luo Y et al. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res. 2007;13:2728-2737. 31. Moore J, Keyt B, Burnier J, et al, inventors; BiPar Sciences, Inc, assignee. Treatment of cancer. US patent application publication US 2008/0103104 A1. May 1, 2008. 32. Rottenberg S, Jaspers JE, Kersbergen A, et al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci U S A. 2008;105:17079-17084. Epub 2008 Oct 29. 33. Calvert H, Azzariti A. The clinical development of inhibitors of poly(ADPribose) polymerase. Ann Oncol. 2011;22(suppl 1):i53-i59. 34. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123-134. Epub 2009 Jun 24. 35. Fong PC, Yap TA, Boss DS, et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol. 2010;28:2512-2519. Epub 2010 Apr 20. 36. Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010;376:235-244. Epub 2010 Jul 6.

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37. Audeh MW, Carmichael J, Penson RT, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet. 2010;376:245-251. Epub 2010 Jul 6. 38. Giaccone G, Rajan A, Kelly RJ, et al. A phase I combination study of olaparib (AZD2281; KU-0059436) and cisplatin (C) plus gemcitabine (G) in adults with solid tumors. J Clin Oncol. 2010;28(suppl):Abstract 3027. 39. Khan OA, Gore M, Lorigan P, et al. A phase I study of the safety and tolerability of olaparib (AZD2281, KU0059436) and dacarbazine in patients with advanced solid tumours. Br J Cancer. 2011;104:750-755. Epub 2011 Feb 15. 40. Ledermann JA, Harter P, Gourley C, et al. Phase II randomized placebo-controlled study of olaparib (AZD2281) in patients with platinum-sensitive relapsed serous ovarian cancer (PSR SOC). J Clin Oncol. 2011;29(suppl):Abstract 5003. 41. Kopetz S, Mita MM, Mok I, et al. First in human phase I study of BSI-201, a small molecule inhibitor of poly ADP-ribose polymerase (PARP) in subjects with advanced solid tumors. J Clin Oncol. 2008;26(suppl):Abstract 3577. 42. Drew Y, Ledermann JA, Jones A, et al. Phase II trial of the poly(ADP-ribose) polymerase (PARP) inhibitor AG-014699 in BRCA 1 and 2-mutated, advanced ovarian and/or locally advanced or metastatic breast cancer. J Clin Oncol. 2011;29(suppl):Abstract 3104. 43. Schelman WR, Sandhu SK, Moreno Garcia V, et al. First-in-human trial of a poly(ADP)-ribose polymerase (PARP) inhibitor MK-4827 in advanced cancer patients with antitumor activity in BRCA-deficient tumors and sporadic ovarian cancers (soc). J Clin Oncol. 2011;29(suppl):Abstract 3102. 44. Ossovskaya V, Lim C-U, Schools G, et al. Cell cycle effects of iniparib, a PARP inhibitor, in combination with gemcitabine and carboplatin in the MDAMB-468(-) triple-negative breast cancer cell line. Presented at the 2010 annual CTRC-AACR San Antonio Breast Cancer Symposium. Abstract P5-06-09. www.abstracts2view.com/sabcs10/view.php?nu=SABCS10L_423&terms=. Accessed December 30, 2011. 45. Castro M, Li L, Stallings TE. Pharmacokinetics of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in cerebrospinal fluid of a patient with breast cancer with carcinomatous meningitis. J Clin Oncol. 2010;28(suppl):Abstract e13559. 46. Blakeley JO, Ye X, Grossman SA, et al. Poly (ADP-ribose) polymerase-1 (PARP1) inhibitor BSI-201 in combination with temozolomide (TMZ) in malignant glioma. J Clin Oncol. 2010;28(suppl):Abstract 2012. 47. O’Shaughnessy J, Osborne C, Pippen JE, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011;364:205-214. Epub 2011 Jan 5. 48. O’Shaughnessy J, Schwartzberg LS, Danso MA, et al. A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple-negative breast cancer (TNBC). J Clin Oncol. 2011;29 (suppl):Abstract 1007. 49. Isakoff SJ, Overmoyer B, Tung NM, et al. A phase II trial of the PARP inhibitor veliparib (ABT888) and temozolomide for metastatic breast cancer. J Clin Oncol. 2010;28(suppl):Abstract 1019. 50. Kummar S, Chen AP, Ji JJ, et al. A phase I study of ABT-888 in combination with metronomic cyclophosphamide in adults with refractory solid tumors and lymphomas. J Clin Oncol. 2010;28(suppl):Abstract 2605. 51. Tan AR, Gibbon D, Stein RA, et al. Preliminary results of a phase I trial of ABT-888, a poly(ADP-ribose) polymerase (PARP) inhibitor, in combination with cyclophosphamide. J Clin Oncol. 2010;28(suppl):Abstract 3000. 52. Ji JJ, Kummar S, Chen AP, et al. Pharmacodynamic response in phase I combination study of ABT-888 and topotecan in adults with refractory solid tumors and lymphomas. J Clin Oncol. 2010;28(suppl):Abstract 2514. 53. Tan AR, Toppmeyer D, Stein MN, et al. Phase I trial of veliparib (ABT-888), a poly(ADP-ribose) polymerase (PARP) inhibitor, in combination with doxorubicin and cyclophosphamide in breast cancer and other solid tumors. J Clin Oncol. 2011;29(suppl):Abstract 3041. 54. LoRusso P, Ji JJ, Li J, et al. Phase I study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib (ABT-888; V) in combination with irinotecan (CPT-11; Ir) in patients (pts) with advanced solid tumors. J Clin Oncol. 2011;29(suppl):Abstract 3000.

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55. Pishvaian MJ, Slack R, Witkiewicz A, et al. A phase II study of the PARP inhibitor ABT-888 plus temozolomide in patients with heavily pretreated, metastatic colorectal cancer. J Clin Oncol. 2011;29(suppl):Abstract 3502. 56. Dent RA, Linderman GJ, Clemons M, et al. Safety and efficacy of the oral PARP inhibitor olaparib (AZD2281) in combination with paclitaxel for the firstor second-line treatment of patients with metastatic triple-negative breast cancer: results from the safety cohort of a phase I/II multicenter trial. J Clin Oncol. 2010;28(suppl):Abstract 1018. 57. Liu J, Fleming GF, Tolaney SM, et al. A phase I trial of the PARP inhibitor olaparib (AZD2281) in combination with the antiangiogenic cediranib (AZD2171) in recurrent ovarian or triple-negative breast cancer. J Clin Oncol. 2010; 29(suppl):Abstract 5028. 58. Lee J, Annunziata CM, Minasian LM, et al. Phase I study of the PARP inhibitor olaparib (O) in combination with carboplatin (C) in BRCA 1/2 mutation carriers with breast (Br) or ovarian (Ov) cancer (Ca). J Clin Oncol. 2011; 29(suppl):Abstract 2520. 59. Moulder S, Mita M, Bradely C. A phase 1b study to assess the safety and tolerability of the PARP inhibitor iniparib (BSI-201) in combination with irinotecan for the treatment of patients with metastatic breast cancer (MBC). Presented at the 2010 annual CTRC-AACR San Antonio Breast Cancer Symposium. Abstract P5-15-01. www.abstracts2view.com/sabcs10/view.php?nu=SABCS10L_1107& terms=. Accessed December 30, 2011. 60. Plummer R, Jones C, Middleton M, et al. Phase I study of the poly(ADPribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. Clin Cancer Res. 2008;14:7917-7923. 61. Plummer R, Lorigan P, Evans J, et al. First and final report of a phase II study of the poly(ADP-ribose) polymerase (PARP) inhibitor, AG014699, in combination with temozolomide (TMZ) in patients with metastatic malignant melanoma (MM). J Clin Oncol. 2006;24(suppl):Abstract 8013. 62. Bedikian AY, Papadopoulos NE, Kim KB, et al. A phase IB trial of intravenous INO-1001 plus oral temozolomide in subjects with unresectable stage-III or IV melanoma. Cancer Invest. 2009;27:756-763. 63. Muscal JA, Thompson PA, Giranda VL, et al. Plasma and cerebrospinal fluid pharmacokinetics of ABT-888 after oral administration in non-human primates. Cancer Chemother Pharmacol. 2010;65:419-425. Epub 2009 Jun 13. 64. Li X, Delzer J, Voorman R, et al. Disposition and drug-drug interaction potential of veliparib (ABT-888), a novel and potent inhibitor of poly(ADP-ribose) polymerase. Drug Metab Dispos. 2011;39:1161-1169. Epub 2011 Mar 24. 65. Li J, Sha X, LoRusso P. Pharmacogenetics of a PARP inhibitor ABT-888 metabolic pathway. J Clin Oncol. 2009;27(suppl):Abstract e14556. 66. Kummar S, Kinders R, Rubinstein L, et al. Compressing drug development timelines in oncology using phase ‘0’ trials. Nat Rev Cancer. 2007;7:131-139. 67. Kummar S, Kinders R, Gutierrez ME, et al. Phase 0 clinical trial of the poly (ADP-ribose) polymerase inhibitor ABT-888 in patients with advanced malignancies. J Clin Oncol. 2009;27:2705-2711. Epub 2009 Apr 13. 68. Yang SX, Kummar S, Steinberg SM, et al. Immunohistochemical detection of poly(ADP-ribose) polymerase inhibition by ABT-888 in patients with refractory solid tumors and lymphoma. Cancer Biol Ther. 2009;8:2004-2009. Epub 2009 Nov 25. 69. Reinhardt S, Zhao M, Mnatsakanyan A, et al. A rapid and sensitive method for determination of veliparib (ABT-888), in human plasma, bone marrow cells and supernatant by using LC/MS/MS. J Pharm Biomed Anal. 2010;52:122-128. Epub 2009 Dec 29. 70. Horton TM, Jenkins, G, Pati D, et al. Poly(ADP-ribose)polymerase inhibitor ABT-888 potentiates the cytotoxic activity of temozolomide in leukemia cells: influence of mismatch repair status and O6-methylguanine-DNA methyltransferase activity. Mol Cancer Ther. 2009;8:2232-2243. Epub 2009 Aug 11. 71. Liu X, Shi Y, Guan R, et al. Potentiation of temozolomide cytotoxicity by poly(ADP)ribose polymerase inhibitor ABT-888 requires a conversion of singlestranded DNA damages to double-stranded DNA breaks. Mol Cancer Res. 2008; 6:1621-1629. 72. Jones P, Altamura S, Boueres J, et al. Discovery of 2-{4-[(3S)-piperidin-3yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): a novel oral poly(ADP)-ribose polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors. J Med Chem. 2009;52:7170-7185.

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FROM THE LITERATURE

Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy By Robert J. Ignoffo, PharmD, FASHP, FCSHP, Section Editor Clinical Professor Emeritus, University of California, San Francisco Professor of Pharmacy, College of Pharmacy, Touro University-California, Mare Island Vallejo, CA

â&#x2013; Bevacizumab Delays Progression in Women with Advanced Ovarian Cancer Background: For women with advanced ovarian cancer, surgery and platinum-based chemotherapy are the standard treatment, but the prognosis is poor. Angiogenesis is involved in ovarian cancer. Bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, has shown tumor response and delayed progression in women with ovarian cancer in early clinical trials. Two new, phase 3 studies have examined its effect on progression-free survival (PFS) and overall survival (OS) in women with advanced ovarian cancer. Design: In the international Gynecologic Oncology Group (GOG)-0218 study, 1873 women (median age, 60 years) with newly diagnosed stage III (incompletely resectable) or stage IV epithelial ovarian cancer who had undergone debulking surgery were randomized to receive 1 of 3 treatment options for 22 cycles of 3 weeks each: standard chemotherapy (carboplatin plus paclitaxel, cycles 1-6) followed by placebo (cycles 7-22); standard chemotherapy plus bevacizumab 15 mg/kg followed by placebo; or standard chemotherapy plus bevacizumab 15 mg/kg followed by an additional course of bevacizumab 15 mg/kg. The primary end point was PFS. The second study, the International Collaboration on Ovarian Neoplasms (ICON7) trial, had a similar design, but only 91% of the 1528 patients enrolled in the study had stage III or IV ovarian cancer; 9% had high-risk earlystage disease, and 30% were at high risk for progression. Patients (median age, 57 years) were randomized to receive either standard chemotherapy (carboplatin plus paclitaxel) every 3 weeks for 6 cycles or standard chemotherapy plus bevacizumab 7.5 mg/kg every 3 weeks for 5 or 6 cycles and continue with bevacizumab for an additional 12 cycles, or until disease progression occurred. Summary: In GOG-0218, after a median follow-up of 17.4 months, median PFS was 14.1 months in patients who received bevacizumab throughout the study (hazard ratio [HR] for progression or death vs standard chemotherapy only, 0.717; 95% confidence interval [CI], 0.6250.824; P = .001) versus 11.2 months in those who received bevacizumab only in the initial cycles (HR,

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0.908; CI, 0.795-1.040; P = .16) and 10.3 months for those who received only standard chemotherapy. The difference in OS between the treatment groups was not significant. Hypertension was the only adverse event that was significantly more common in those who received bevacizumab throughout the entire period (22.9%) or in the initial cycles (16.5%) than in those receiving standard chemotherapy (7.2%). In the ICON7 study, after a median follow-up of 19.4 months, the median PFS differed by approximately 2 months between the bevacizumab group and the standard chemotherapy group: 19.0 months versus 17.3 months, respectively (HR, 0.81; 95% CI, 0.70-0.94; P = .004). Among patients at high risk for progression, however, the difference between the 2 treatment groups was much greater: 15.9 months versus 10.3 months, respectively (HR, 0.68; 95% CI, 0.55-0.85; P = .001). At 42 months, the OS in women at high risk was 36.6 months versus 28.8 months (P = .002). As in the GOG-0218 study, hypertension was more common in the bevacizumab group than in the standard chemotherapy group (18% vs 2%, respectively). Thromboembolic events were also more frequent in the bevacizumab group (7% vs 3%, respectively). Takeaway: These 2 phase 3 studies showed that bevacizumab added to standard paclitaxel/carboplatin chemotherapy improved both PFS and OS by several months for women in the high-risk category. The median OS in the treatment arm had not yet been reached. The HR of 0.85 indicates only a modest improvement over standard chemotherapy alone. Furthermore, the toxicity range was expanded to include hypertension and the risk of bowel perforation. The dosage of bevacizumab was different in each of the studies, but not enough to produce a major difference in outcome. The study by Perrin and the ICON7 group used a dose of 7.5 mg/kg for 12 cycles (compared with 15 mg/kg for 16 cycles). Do these studies establish that this combination should be a first-line therapy for high-risk patients with ovarian cancer? I agree with the authors of the GOG0218 study, who suggest that further studies are needed to assess how to integrate bevacizumab into the standard

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FROM THE LITERATURE

front-line therapies of neoadjuvant or intraperitoneal chemotherapy. The optimal duration of therapy and its cost-effectiveness are both important questions that need to be answered before combination chemotherapy plus bevacizumab becomes the standard of care for highrisk ovarian cancer. Burger RA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365:2473-2483; Perren TJ, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365:2484-2496.

■ Combination Therapy with Pertuzumab Offers New Option in Metastatic Breast Cancer Background: Although trastuzumab, an HER2 inhibitor that binds to subdomain IV of the HER2 extracellular growth domain, is effective in inhibiting tumor growth in HER2-positive metastatic breast cancer, the disease often progresses after therapy. Pertuzumab, which binds to subdomain II of the growth domain, offers a complementary mechanism of action that, in combination with that of trastuzumab, enhances the blockade of HER2 signaling and potentially produces greater antitumor activity, as has been demonstrated in phase 2 studies. A new, phase 3 study investigated the efficacy of pertuzumab in combination with trastuzumab and docetaxel for this patient population. Design: In the international phase 3 Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) study, 808 patients from 25 countries with HER2positive metastatic breast cancer were randomized to receive trastuzumab (6 mg/kg every 3 weeks or until progression) plus docetaxel (75 mg/m2) plus either pertuzumab (420 mg every 3 weeks or until progression or unmanageable toxicity occurred) or placebo. The primary end point was PFS; objective response rate (ORR) was a secondary end point. Summary: The median duration of treatment was 18.1 months in the pertuzumab group and 11.8 months in the placebo group. At approximately 34 months, the independently assessed PFS was 6.1 months longer in the pertuzumab group (18.5 months vs 12.4 months, respectively; HR, 0.62; 95% CI, 0.51-0.75; P <.001). In addition, after a median follow-up period of 19.3 months in both treatment groups, the ORR was 80.2% in the pertuzumab group versus 69.3% in the placebo group (P = .001). Adverse events occurring more frequently (≥5%) in the pertuzumab group included diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin. The rates of grade ≥3 febrile neutropenia and diarrhea were also ≥2% higher in the pertuzumab group (13.8% and 7.9%, respectively) than in the placebo group (7.6%

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vs 5.0%). The rates of symptomatic or asymptomatic cardiac dysfunction did not increase in the pertuzumab group, however. The PFS benefit with pertuzumab was similar to that of 288 patients in the study who had received previous adjuvant or neoadjuvant chemotherapy without trastuzumab (HR, 0.60; 95% CI, 054-0.78; P <.001). Takeaway: Although this study appears to be strongly positive for the targeted combination therapy, the results should be considered preliminary. This is because the median PFS of 12.4 months in the control group is similar to that seen in previous studies of trastuzumab plus docetaxel (11.1 and 11.7 months, respectively). Furthermore, the survival data are not yet fully mature: reaching only 43% of that specified for the final analysis. In addition, the toxicity profile was expanded with the addition of pertuzumab and included more frequent events of diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin. Pertuzumab is currently an investigational agent, but, if approved by the US Food and Drug Administration (FDA), it will likely be priced like other costly targeted agents. It will require a detailed pharmacoeconomic analysis to assess its role in the management of metastatic breast cancer. Baselga J, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119.

■ Chemotherapy-Induced Changes in Brain Structure Correlate with Cognitive Dysfunction Background: Women with breast cancer often complain of cognitive difficulties after chemotherapy. Findings from several cross-sectional and longitudinal studies of women who receive chemotherapy for breast cancer have confirmed a correlation between impaired memory and other cognitive functions and chemotherapy. This study investigated the link between chemotherapy-induced structural changes in the brain and cognitive function. Design: This Dutch study of 69 premenopausal women compared 34 women (mean age, 43.7 years) with early-stage breast cancer who received chemotherapy with 16 women (mean age, 43.1 years) with earlystage breast cancer who did not receive chemotherapy and 19 matched healthy controls (mean age, 43.8 years). Before treatment initiation and at 3- to 4-month intervals, all participants underwent neuropsychologic testing involving attention, concentration, memory, executive functioning, cognitive/psychomotor processing speed, and self-reported cognitive functioning. In addition, the cerebral white matter of all participants

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was analyzed via magnetic resonance diffusion tensor imaging, which enables the visualization and characterization of the white matter architecture. Summary: Baseline testing revealed similar results among all 3 groups, but paired t-test analyses showed that the chemotherapy group scored significantly worse on attention, concentration, psychomotor speed, and memory tests 3 to 4 months after treatment than at baseline (P <.05). By contrast, the 2 control groups performed significantly better at 3 to 4 months than at baseline (P <.05) in those domains, a result consistent with a learning effect. In addition, in the chemotherapy group, fractional anisotropy (a measure of the water molecule diffusion in the white matter tissue) was significantly lower in the frontal, parietal, and occipital white matter tracts after treatment than at baseline, whereas in the 2 control groups, the baseline and posttreatment measurements were the same. A correlation analysis revealed that the decline in the attention and verbal memory domains in the neuropsychologic tests in the chemotherapy group correlated with the observed changes in fractional anisotropy (P <.05). Takeaway: This appears to be the first study of the pathophysiology of chemotherapy-induced cognitive impairment. The study correlated cognitive impairment with tests that could determine if chemotherapy could cause direct damage to brain white matter. Thirty-four patients received chemotherapy consisting of adjuvant fluorouracil, epirubicin, and cyclophosphamide. Cognitive deficits included decreased attention and verbal memory and were observed fairly rapidly, within 4 months of treatment. The investigators demonstrated changes in white matter structure after the institution of chemotherapy. The study results were partially confounded by the use of tamoxifen in 18 patients, beginning at 7 months into the study; tamoxifen may impair cognitive function. This study provides valuable new information on chemotherapy-induced cognitive dysfunction. With the use of these new tests for cognition, future studies may lead to effective agents to prevent this side effect. Deprez S, et al. Longitudinal assessment of chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning. J Clin Oncol. 2012;30:274-281.

â&#x2013; BRAF Inhibitor Therapy Linked to Squamous-Cell Carcinoma in Patients with RAS Mutations Background: As many as 15% to 30% of patients who receive BRAF inhibitors, such as vemurafenib or dabrafenib, for metastatic melanoma develop cuta-

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neous squamous-cell carcinomas and keratoacanthomas (nonmelanoma skin cancer) during their therapy. A new study investigated the nature of the oncogenic mutations in patients with the BRAF V600 mutation who received vemurafenib. Design: A molecular analysis was conducted to identify oncogenic mutations, including HRAS, KRAS, NRAS, CDKN2A, and TP53, in lesions from 23 patients with the BRAF V600 mutation in 3 separate studies (phases 1-3, respectively) who received vemurafenib 720 or 960 mg orally twice daily for metastatic melanoma. The analysis included 21 samples of cutaneous squamous-cell carcinoma or keratoacanthoma obtained from 11 patients (mean age, 60 years). In addition, a validation set of 14 samples taken from 12 patients who received vemurafenib therapy was analyzed to confirm the prevalence of RAS mutations. Summary: A total of 78% of the patients had a history and signs of chronically sun-damaged skin, and 17% had a history of cutaneous squamous-cell carcinomas or keratoacanthomas. The lesions were widely distributed, and 63% were characterized as keratoacanthomas. The mean time to diagnosis of the first lesion was 10 weeks; the earliest appeared at 3 weeks. A total of 13 of 21 of the initial samples and 8 of the 14 validation set samples (60% total) had RAS mutations. Of the lesions with RAS mutations, 12 of the 13 initial samples and 4 of the 8 validation samples had HRAS mutations (most prevalent, HRAS Q61L). The effects of BRAF inhibitors on HRAS mutations were compared by the murine cell line B9, which harbors the HRAS Q61L mutation, before and after exposure in vitro to vemurafenib or its analog PLX4720. Similar tests were conducted with HRAS Q61L expressed in the human squamous-cell carcinoma cell line A431, which harbors wild-type RAS in addition to amplified EGFR, and in NIH3T3 cells, which harbor wild-type RAS without EGFR amplification. In all 3 studies, exposure to vemurafenib led to an increased proliferation of HRAS Q61L mutation caused by an increase in oncogenic MAPK-pathway signaling, as evidenced by increased ERK phosphorylation and increased expression of ERK-regulated genes. The PLX4720 was found to accelerate the growth of the HRAS mutations, which was blocked by concomitant treatment with an MEK inhibitor. Because most tumors appeared on sun-damaged skin relatively quickly after initiating vemurafenib therapy, vemurafenib may not have any direct carcinogenic effects but rather may potentiate a preexisting cancerous process. Takeaway: Vemurafenib, the recently FDA-approved agent for malignant melanoma, appears to exacerbate

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preexisting nonmelanoma skin cancer. This report describes the mechanism by which vemurafenib potentiates skin cancers. It appears that the drug enhances MAPK activity leading to RAS gene mutations, a driver oncogene in approximately one third of cancers. This effect can be blocked with the use of MEK inhibitors. This discovery may lead to the development of BRAF inhibitors that lack the ability to stimulate MAPK and RAS mutations. Su F, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012;366:207-215.

â&#x2013; Adding Bevacizumab to Neoadjuvant Chemotherapy Improves Complete Response Rates in Patients with Breast Cancer Background: In previous studies, the addition of bevacizumab to first-line chemotherapy regimens in the treatment of metastatic cancer led to modest improvements in ORR and PFS. Now 2 separate studies have investigated the efficacy of adding the VEGF inhibitor bevacizumab to adjuvant chemotherapy regimens in patients with early-stage breast cancer. Design: In the first study, 1206 women with primary operable HER2-negative breast cancer were randomized to receive docetaxel, alone or combined with capecitabine or gemcitabine, every 3 weeks, followed by doxorubicin plus cyclophosphamide every 3 weeks, for 4 cycles. In addition, 604 of these patients also received bevacizumab (15 mg/kg) with each of the first 6 chemotherapy cycles. The primary end point was the pathologic complete response (pCR). In the second study, the German Breast Group study, 1948 women with untreated HER2-negative breast cancer (median tumor size, 40 mm) were randomized to receive neoadjuvant epirubicin and cyclophosphamide every 3 weeks, followed by docetaxel every 3 weeks, for 4 cycles. Half of this group (974 patients) also received bevacizumab (15 mg/kg) for 8 cycles, beginning with the first cycle of epirubicin and cyclophosphamide. Summary: In the first study, 59% of the tumors were hormone receptor (HR)-positive. Among 1186 evaluable patients, the addition of capecitabine or gemcitabine to docetaxel therapy did not increase the pCR rate over docetaxel alone (P = .69), but both were associated with increased toxicities, particularly hand-foot

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syndrome, mucositis, and neutropenia. Compared with the 595 patients who did not receive bevacizumab, however, the 591 patients who received bevacizumab showed a significant improvement in pCR in the breast (28.2% vs 34.5%, respectively; P = .02) but not in the breast and nodes (23.0% vs 27.6%; P = .08). The pCR with bevacizumab was more pronounced in women with HR-positive tumors (23.2% with bevacizumab vs 15.1% without; P = .007). In the second study, a similar overall benefit of bevacizumab was demonstrated. As in the first study, the pCR was greater in patients who received bevacizumab than in those who did not (18.4% vs 14.9%, respectively; odds ratio, 1.29; 95% CI, 1.02-1.65; P = .04). Unlike the other study, however, the benefit of bevacizumab was significantly greater among 663 patients with triple-negative tumors (39.3% vs 27.9%, respectively; P = .003), not among the 1262 women with HR-positive tumors (7.7% vs 7.8%; P >.05). In both studies, bevacizumab was associated with increased rates of grade 3 or 4 toxicities, including mucositis, hand-foot syndrome, and hypertension. An increased incidence of left-ventricular systolic dysfunction was also noted in the first study, and increased febrile neutropenia cases and infections were noted in the German study. Takeaway: These 2 studies evaluated the addition of bevacizumab to neoadjuvant chemotherapy for earlystage breast cancer. The study by Bear and colleagues (docetaxel chemotherapy) reported an improvement in the pCR rate of HR-positive patients. This implies that more women would be spared primary surgery for their breast cancer. In the von Minckwitz study (epirubicin plus cyclophosphamide chemotherapy), the greatest benefit was observed in women with triple-negative disease. Complete pathologic remission was 29% higher in the bevacizumab group. The authors caution that it is unclear whether this increase in pCR will translate into prolonged survival. By contrast, women with hormone-responsive tumors did not show a benefit over chemotherapy alone. This study also implies the need for fewer primary surgeries for patients with triple-negative disease. â&#x2013; Bear HD, et al. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012;366:310-320; von Minckwitz G, et al. Neoadjuvant chemotherapy and bevacizumab for HER-2 negative breast cancer. N Engl J Med. 2012;366:299-309.

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CALL FOR PAPERS The Journal of Hematology Oncology Pharmacy is the nation’s first peer-reviewed clinical journal for oncology pharmacists. As pharmacy practice and research become integral to improving both the clinical care of cancer patients as well as expanding the research literature in contemporary oncology pharmacy, new avenues are necessary to ensure this information gets disseminated to the profession. Launched in March 2011, the Journal of Hematology Oncology Pharmacy provides a new venue for the publication of peer-reviewed, high-quality pharmacy reviews and original research to help oncology pharmacy practitioners and other hematology oncology professionals optimize drug therapy for patients with cancer. Readers are invited to submit articles addressing new research, clinical, and practice management issues in oncology pharmacy. All articles will undergo a blind peer-review process, and acceptance is based on that review.

ORIGINAL RESEARCH

REVIEW ARTICLES

• Clinical • Basic science • Translational • Practice-based • Case reports • Case series

• New drug classes • Disease states • Basic science • Pharmacology • Pathways and the drugs targeting them

CLINICAL CONTROVERSIES

PRACTICAL ISSUES IN PHARMACY MANAGEMENT

• Point and counterpoint • Roundtable discussions • “How I treat”

• Logistics • Economics • Practice-influencing issues

COMMENTARIES

LETTERS TO THE EDITOR

Manuscripts should follow the Author Guidelines available at www.JHOPonline.com. For more information, call 732-992-1536.

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BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Docetaxel Injection safely and effectively. See full prescribing information for Docetaxel.

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Gemcitabine Injection safely and effectively. See full prescribing information for Gemcitabine Injection.

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Topotecan Injection safely and effectively. See full prescribing information for Topotecan Injection.

Docetaxel Injection

Gemcitabine Injection

Topotecan Injection

For intravenous infusion only. Initial U.S. Approval: 1996

For Intravenous Infusion Only. Must Be Diluted Before Use. Initial U.S. Approval: 1996

Must be diluted before intravenous infusion Initial U.S. Approval: 1996

• •

• •

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION See full prescribing information for complete boxed warning Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinum-based therapy receiving docetaxel at 100 mg/m2 (5.1) Should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 x ULN concomitant with alkaline phosphatase > 2.5 x ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle (8.6) Should not be given if neutrophil counts are < 1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia (4) Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection and administration of appropriate therapy (5.4) Contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80 (4) Severe fluid retention may occur despite dexamethasone (5.5)

CONTRAINDICATIONS • Hypersensitivity to docetaxel or polysorbate 80 (4) • Neutrophil counts of <1500 cells/mm3 (4) WARNINGS AND PRECAUTIONS • Acute myeloid leukemia: In patients who received docetaxel doxorubicin and cyclophosphamide, monitor for delayed myelodysplasia or myeloid leukemia (5.6) • Cutaneous reactions: Reactions including erythema of the extremities with edema followed by desquamation may occur. Severe skin toxicity may require dose adjustment (5.7) • Neurologic reactions: Reactions including. paresthesia, dysesthesia, and pain may occur. Severe neurosensory symptoms require dose adjustment or discontinuation if persistent. (5.8) • Asthenia: Severe asthenia may occur and may require treatment discontinuation. (5.9) • Pregnancy: Fetal harm can occur when administered to a pregnant woman. Women of childbearing potential should be advised not to become pregnant when receiving Docetaxel Injection (5.10, 8.1) ADVERSE REACTIONS Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia (6) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

INDICATIONS AND USAGE Gemcitabine is a nucleoside metabolic inhibitor indicated for: • Ovarian cancer in combination with carboplatin (1.1) • Breast cancer in combination with paclitaxel (1.2) • Non-small cell lung cancer in combination with cisplatin (1.3) • Pancreatic cancer as a single-agent (1.4) DOSAGE AND ADMINISTRATION Gemcitabine Injection is for intravenous use only. • Ovarian cancer: 1000 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.1) • Breast cancer: 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.2) • Non-small cell lung cancer: 4-week schedule, 1000 mg/m2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle: 3-week schedule; 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.3) • Pancreatic cancer: 1000 mg/m2 over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitates reducing or holding a dose), followed by a week of rest from treatment. Subsequent cycles should consist of infusions once weekly for 3 consecutive weeks out of every 4 weeks (2.4) • Dose Reductions or discontinuation may be needed based on toxicities (2.1-2.4) DOSAGE FORMS AND STRENGTHS • 200 mg/5.26 mL injection vial (3) • 1 g/26.3 mL injection vial (3) • 2 g/52.6 mL injection vial (3) CONTRAINDICATIONS Patients with a known hypersensitivity to gemcitabine (4) WARNINGS AND PRECAUTIONS • Infusion time and dose frequency: Increased toxicity with infusion time >60 minutes or dosing more frequently than once weekly. (5.1) • Hematology: Monitor for myelosuppression, which can be dose-limiting. (5.2, 5.7) • Pulmonary toxicity: Discontinue Gemcitabine Injection immediately for severe pulmonary toxicity. (5.3) • Renal: Monitor renal function prior to initiation of therapy and periodically thereafter. Use with caution in patients with renal impairment. Cases of hemolytic uremic syndrome (HUS) and/or renal failure, some fatal, have occurred. Discontinue Gemcitabine Injection for HUS or severe renal toxicity. (5.4) • Hepatic: Monitor hepatic function prior to initiation of therapy and periodically thereafter. Use with caution in patients with hepatic impairment. Serious hepatotoxicity, including liver failure and death, have occurred. Discontinue Gemcitabine Injection for severe hepatic toxicity. (5.5) • Pregnancy: Can cause fetal harm. Advise women of potential risk to the fetus. (5.6, 8.1) • Radiation toxicity. May cause severe and life-threatening toxicity. (5.8)

WARNING: BONE MARROW SUPPRESSION See full prescribing information for complete boxed warning. Do not give topotecan injection to patients with baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marroww suppression, primarily neutropenia, which may be severe and result in infection and death, monitor peripheral blood cell counts frequently on all patients receiving topotecan injection. (5.1) CONTRAINDICATIONS • History of severe hypersensitivity reactions (e.g. anaphylactoid reactions) to topotecan or any of its ingredients (4) • Severe bone marrow depression (4) WARNINGS AND PRECAUTIONS • Bone marrow suppression. Administer topotecan injection only to patients with adequate bone marrow reserves. Monitor peripheral blood counts and adjust the dose if needed. (5.1) • Topotecan-induced neutropenia can lead to neutropenic colitis. (5.2) • Interstitial lung disease: Topotecan has been associated with reports of interstitial lung disease. Monitor patients for symptoms and discontinue Topotecan Injection if the diagnosis is confirmed. (5.3) • Pregnancy: Can cause fetal harm. Advise women of potential risk to the fetus. (5.4, 8.1) ADVERSE REACTIONS Small cell lung cancer: • The most common hematologic adverse reactions were: neutropenia (97%), leukopenia (97%), anemia (89%), and thrombocytopenia (69%). (6.1) • The most common (>25%) non-hematologic adverse reactions (all grades) were: nausea, alopecia, vomiting, sepsis or pyrexia/infection with neutropenia, diarrhea, constipation, fatigue, and pyrexia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

ADVERSE REACTIONS The most common adverse reactions for the single-agent (≥20%) are nausea and vomiting, anemia, ALT, AST, neutropenia, leukopenia, alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or electronically at ProductComplaintsPP@hospira.com, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION Revised: 07/2011

Manufactured by: Hospira Australia Pty., Ltd., Mulgrave, Australia Manufactured by: Zydus Hospira Oncology Private Ltd., Gujarat, India Distributed by: Hospira, Inc., Lake Forest, IL 60045 USA GUJ DRUGS/G/28/1267

Manufactured by: Hospira Australia Pty Ltd Mulgrave VIC 3170 Australia Manufactured for: Hospira, Inc. Lake Forest, IL 60045 USA Product of Australia

Manufactured and Distributed by: Hospira, Inc. Lake Forest, IL 60045 USA Made in India


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