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In chronic lymphocytic leukemia (CLL)
Introducing an anti-CD20 antibody with a membrane proximal binding site
Potent complement-dependent cytotoxicity (CDC) for killing CLL cells
Mechanism of action
The potent CDC activity of ARZERRA leads to cell death in cells expressing both high and low levels of CD20 and in rituximab-resistant cells1
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MECHANISM OF ACTION
In chronic lymphocytic leukemia (CLL)
1,2
ARZERRA is highly effective at inducing CDC even at low levels of CD20 expression2 — ARZERRA even achieved cell lysis for cells expressing approximately 4,500 CD20 molecules per cell2
ARZERRA Binding site
Surface CD20 expression
CD20 Molecules/Cell3
CD20
Small LOOP
LARGE LOOP
ARZERRA binds to a small loop epitope* close to the cell membrane
1,2
The small loop has greater membrane proximity to activating the complement pathway than the large loop This unique binding site may explain why ARZERRA delivers potent, complementdependent cytotoxicity (CDC) directly to the cell surface
#$ EXPRESSION
(EALTHY INDIVIDUALS
" #,, PATIENTS
The complement activation by ARZERRA leads to CDC activity and lysis of tumor cells —Closer proximity to the cell membrane increases the chance of cell lysis Also induces cell death through antibody-dependent, cell-mediated cytotoxicity (ADCC) *ARZERRA also binds to a large extracellular loop epitope.
The surface CD20 expression level on B cells is downregulated in B-CLL patients compared with healthy patients3 In vitro results do not necessarily correlate with clinical efficacy.
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In chronic lymphocytic leukemia (CLL)
In chronic lymphocytic leukemia (CLL)
A study population of heavily pretreated patients with advanced CLL: in need of new options
Patients with advanced CLL responded to ARZERRA
ARZERRA was studied in a single-arm trial of 154 patients with CLL wh0 1:
Patients met the primary study endpoint of objective response* 1
1
1
ORR (%)
rogressed during or relapsed within 6 months of receiving a fludarabine-based P regimen and presence of bulky disease (BF-Relapsed)†
50
Were intolerant/ineligible for fludarabine and/or intolerant of alemtuzumab
40
* Received at least 2 cycles of a fludarabine-based regimen and 12 subsequent doses of alemtuzumab (FA-Relapsed). † Received at least 2 cycles of a fludarabine-based regimen and were inappropriate candidates for alemtuzumab due to bulky disease (BF-Relapsed). Bulky disease is defined as at least 1 lymph node >5 cm in diameter.
Baseline characteristics for patients with CLL in ARZERRA study (N=138) 1
60
58%
56% 47%
STUDY POP./EFFICACY
P rogressed during or relapsed within 6 months of receiving a fludarabine-based regimen and subsequently also progressed during or relapsed within 6 months of receiving alemtuzumab (FA-Relapsed)*
30 20 10 0
Patient characteristic
Median age, yrs (range) Median number of prior therapies
FA-Relapsed (n=59)
BF-Relapsed (n=79)
63 (41-86)
63 (41-86)
5
5
Most patients (80%) had chromosomal abnormalities, including1: —17p deletion (22%)
FA-Relapsed† (n=59)
BF-Relapsed‡ (n=79)
Other § (n=16)
* Response by 1996 NCI-WG criteria, with evaluation every 4 weeks during treatment, 2 months’ minimum response duration, and independent review committee (IRC) analysis, with interim analysis to determine if ORR is different from 15% for either patient group. † Progressed during or relapsed within 6 months of receiving at least 2 cycles of a fludarabine-based regimen and also progressed during or relapsed within 6 months of receiving 12 subsequent doses of alemtuzumab (FA-Relapsed). ‡ Progressed during or relapsed within 6 months of receiving at least 2 cycles of a fludarabine-based regimen and presence of bulky disease (BF-Relapsed). Bulky disease is defined as least 1 lymph node >5 cm in diameter. § Patients intolerant/ineligible for fludarabine and/or intolerant of alemtuzumab.
FA-Relapsed patients: 31% stable disease; 3% progressive disease BF-Relapsed patients: 41% stable disease; 10% progressive disease; 1% complete remission
—11q deletion (33%)
57%
57% of patients had prior exposure to rituximab1
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NEW Please see Important Safety Information on page 9 and complete Prescribing Information in pocket.
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In chronic lymphocytic leukemia (CLL)
In chronic lymphocytic leukemia (CLL)
Patients with advanced CLL respond to ARZERRA monotherapy 1
Median overall survival1
Adverse reactions in ≥ 5% of patients1
13.7 months
15.4 months
for FA-Relapsed patients*
for BF-Relapsed patients
BoDY System/ Adverse events
†
Intent-to-treat (ITT) population (n=154) ALL GRADES (%)
GRADES ≥3 (%)
Fludarabine and ALemtuzumab relapsed (n=59) ALL GRADES (%)
GRADES ≥3 (%)
INFECTIONS AND INFESTATIONS*
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Pneumonia
16
10
17
10
Upper respiratory tract infection
11
0
3
0
Bronchitis
11
<1
19
2
Nasopharyngitis
8
0
8
0
Herpes zoster
6
1
7
2
Neutropenia
16
12
15
10
Anemia
16
5
17
8
7
0
10
0
6
0
7
0
BLOOD AND LYMPHATIC SYSTEM DISORDERS
PSYCHIATRIC DISORDERS
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-/.4(3 &2/- 34!24 /& 42%!4-%.4 * Progressed during or relapsed within 6 months of receiving at least 2 cycles of a fludarabine-based regimen and also progressed during or relapsed within 6 months of receiving 12 subsequent doses of alemtuzumab (FA-Relapsed). † Progressed during or relapsed within 6 months of receiving at least 2 cycles of a fludarabine-based regimen and presence of bulky disease (BF-Relapsed). Bulky disease is defined as least 1 lymph node >5 cm in diameter.
5.7 months
5.9 months
for FA-Relapsed patients*
for BF-Relapsed patients†
CARDIOVASCULAR DISORDERS Hypertension
5
0
8
0
Hypotension
5
0
3
0
Tachycardia
5
<1
7
2
Cough
19
0
19
0
Dyspnea
14
2
19
5
Diarrhea
18
0
19
0
Nausea
11
0
12
0
14
<1
17
2
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS
EFFICACY/SAFETY
Median progression-free survival (PFS) was approximately 6 months1
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GASTROINTESTINAL DISORDERS
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
ARZERRA safety information
Rash† Urticaria
8
0
5
0
Principal adverse events (AEs) were infusion-related hypersensitivity reactions and infections
Hyperhidrosis
5
0
5
0
8 5
1 0
12 3
2 0
1
Overall infusion-related AEs were most common with the first infusion (44%), declined at the second dose (26%), and decreased further with subsequent infusions Among the 181 patients, 121 (67%) experienced infections. Respiratory tract infections were reported in 85 patients (47%), sepsis in 12 patients (7%). 53 patients (29%) had serious infections; 17 (9%) had fatal infections. Patients who received >2 previous courses of therapy and/or had advanced stage CLL were more prone to infections
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Back pain Muscle spasms GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Pyrexia
20
3
25
5
Fatigue
15
0
15
0
Edema peripheral Chills
9 8
<1 0
8 10
2 0
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NEW * Infection-related fatalities occurred in 16 (10%) of 154 patients in the total population and in 10 (17%) of the 59 patients in the fludarabine and alemtuzumab relapsed group. † Rash includes rash, rash macular, and rash vesicular.
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In chronic lymphocytic leukemia (CLL)
In chronic lymphocytic leukemia (CLL)
The ARZERRA dosing schedule
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Indication ARZERRA (ofatumumab) is a human monoclonal antibody against CD20 that has been given accelerated approval for the treatment of chronic lymphocytic leukemia (CLL) based on studies that have investigated response rate, a surrogate endpoint for clinical benefit. Studies to determine whether ARZERRA confers clinical benefit are ongoing.
IV ARZERRA is administered as 12 infusions over a 6-month period1 Premedication prior to each infusion: —Corticosteroid (prednisolone 100 mg IV or eq) —Analgesic (acetaminophen 1000 mg PO or eq) —Antihistamine (cetirizine 10 mg PO or eq)
Important safety information
TREATMENT
The following serious adverse events (SAEs) were observed with ARZERRA: severe infusion reactions, tumor lysis syndrome, progressive multifocal leukoencephalopathy (PML), and small bowel obstruction. Patients should be monitored closely for infusion reactions, renal function, electrolyte status, and neurologic function. If a severe infusion reaction occurs, the infusion must be interrupted immediately and supportive care measures instituted as medically indicated. If a diagnosis of PML is suspected, ARZERRA should be discontinued.
300 mg ofatumumab 2000 mg ofatumumab
12 infusions
In patients who received at least 1 infusion of 2000 mg ARZERRA, the most common adverse events (AEs) were infusion reactions and infections. Infusion-related AEs were most common with the first infusion (44%) and decreased with subsequent infusions. In patients who experienced infections, 29% were serious, 9% were fatal. 0
2
4
6
8
10
12
14
16
18
20
22
24
WEEKS
How to administer IV ARZERRA
1
Other frequently reported AEs (>10%) included fever, cough, diarrhea, rash, neutropenia, fatigue, pneumonia, bronchitis, anemia, shortness of breath, and nausea. Other adverse events associated with anti-CD20 class of drugs are severe mucocutaneous reactions and hepatitis B reactivation with related fulminant hepatitis.
Start with an initial 300 mg infusion Follow with weekly 2000 mg infusions until week 7 Then administer monthly 2000 mg infusions until week 24
The majority of patients received almost all of the infusions 55% received all 12 infusions Monitor for infusion reactions. If an infusion reaction occurs, treat appropriately as medically necessary. Please see the accompanying complete Prescribing Information.
DOSING/SAFETY
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References: 1. Arzerra Prescribing Information. 2. Teeling JL, Mackus WJM, Wiegman LJJM, et al. The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J Immunol. 2006;177:362-371. 3. Wang L, Abbasi F, Gaigalas AK, et al. Comparison of fluorescein and phycoerythrin conjugates for quantifying CD20 expression on normal and leukemic B-cells. Cytometry. 2006; 70B:410-415. 4. Data on file, Interim Clinical Trial Report, HX-CD20-406, YM2008/00232/00, 2008.
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Introducing a NEW monoclonal antibody to expand your options in chronic lymphocytic leukemia therapy1 Unique binding site1,2 ARZERRA binds to a small loop epitope* close to the cell membrane This unique binding site may explain why ARZERRA delivers potent, complement-dependent cytotoxicity (CDC) directly to the cell surface
ARZERRA was studied in a single-arm trial of 154 patients with CLL who1 : Progressed during or relapsed within 6 months of receiving a fludarabine-based regimen and subsequently also progressed during or relapsed within 6 months of receiving alemtuzumab (FA-Relapsed) Progressed during or relapsed within 6 months of receiving a fludarabine-based regimen and presence of bulky disease† (BF-Relapsed) Were intolerant/ineligible for fludarabine and/or intolerant of alemtuzumab (Other)
Efficacy in difficult-to-treat patients1 5 8% of patients who were FA-Relapsed, 47% of patients who were BF-Relapsed, and 56% of other patients met the primary study endpoint of objective response 80% of patients had chromosomal abnormalities, including 17p and/or 11q deletion 57% had prior exposure to rituximab Median overall survival was 13.7 months for FA-Relapsed patients and 15.4 months for BF-Relapsed patients
Safety profile1 Principal adverse events were infusion-related hypersensitivity reactions and infections
Intravenous dosing1 After an initial infusion of 300 mg, patients received 7 weekly 2000 mg doses, followed by monthly doses of 2000 mg for a total of 12 doses administered over 6 months *ARZERRA also binds to a large extracellular loop epitope. † Bulky disease is defined as at least 1 lymph node >5 cm in diameter.
Customer Access Reimbursement & Education Support (CARES) by GlaxoSmithKline Oncology featuring Arzerra Mail: PO BOX 220225, Charlotte, NC 28222-2065
Tel: 888-ONE-GSKCARES
Fax: 866-272-9439
Operating hours are Monday–Friday, 8:30 am to 8:00 pm ET
Callers can also leave a confidential message for reimbursement specialists 24 hours a day. Reimbursement specialists can assist you in English, Spanish, and many other languages.
Please see Important Safety Information on page 9 and complete Prescribing Information in pocket.
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©2009 The GlaxoSmithKline Group of Companies. All rights reserved. Printed in USA. AZA016R0 [Date]
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