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S UMMER 2010

VOL. 19, NO. 2


Inside . . . Cancer In The Elderly ................ p. 1 Message From The Group Chair .............................p. 2 Spotlight On CALGB Trials ... p. 3 ASCO / CALGB Abstracts............ p. 6 CALGB Research Awards .............. p. 9 Oncology Nursing Perspective ......p. 10 IS Corner .........p. 12 2010 Summer Group Meeting ...........................p. 13 CALGB Group News .................p. 15 Protocol News ...........................p. 17 CALGB Support ...........................p. 19

Cancer and Leukemia Group B Central Office 230 W. Monroe Street Suite 2050 Chicago, IL 60606-4703 (773) 702-9171

CALGB Expands Cancer Research in Older Patients Statistics show that persons 65 years and older represent the fastest growing segment of the United States population. In the year 2030, it is estimated that 20 percent of the population, or 70 million Americans, will be 65 years and older compared with 12 percent at present. What’s more, life expectancy also dramatically increased in the latter half of the 20th century. Statistics show that the average life expectancy in the year 2000 for females and males in the U.S. was 79.9 and 74.2, respectively. So what does this mean for this population? “As the population ages, cancer will ultimately overtake heart disease as the major cause of death in America,” say CALGB Cancer in the Elderly Committee Co-Chairs Hyman B. Muss, M.D., and Harvey J, Cohen, M.D. “Cancer is mainly a disease of aging with an increase in incidence that almost parallels increasing age. The older patient with cancer poses unique problems. Coincident with the increased risk of cancer in the elderly is an increased incidence of other major illnesses (comorbidity). Such illnesses frequently have profound effects on patient management, including the type of cancer treatment offered and the potential for increased toxicity of treatment.”

According to Dr. Muss, Professor of Medicine at the University of North Carolina at Chapel Hill and Director of Geriatric Oncology at the Lineberger Comprehensive Cancer Center, the CALGB has been very interested in cancer in the elderly. “In response to a request by several Group members for the CALGB to expand its research programs for older patients, the Working Group on Cancer in the Elderly was established in 1995,” he said. “The charge of the Working Group was to provide a forum for CALGB members interested in cancer in the elderly to share ideas; to transform the most promising and innovative ideas into concepts and, ultimately, protocols; and to provide input to other CALGB committees about — see CANCER IN THE ELDERLY, page 18


Cancer and Leukemia Group B Newsletter

MESSAGE FROM THE GROUP CHAIR Response to the Institute of Medicine’s Report

A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program At the request of the Director of the National Cancer Institute, the Institute of Medicine (IOM) of the National Academy of Sciences conducted a comprehensive review of the NCI Cooperative Group Program. The final report of this review was released in April 2010, and can be viewed at: Monica M. Bertagnolli, M.D. Activities/Disease/CanClinTrialsNCI.aspx In its statement of purpose, the committee clearly supports the mission of the Cooperative Groups, emphasizing that the ability to translate biomedical discoveries into advances in cancer care depends upon an effective clinical trials system. In addition, the review acknowledges that publicly funded clinical trials play an essential role because they address questions that are important to patients, but that are unlikely to be priorities of industry. The IOM committee voiced strong opinions concerning the current state of the Cancer Cooperative Group system. In his opening remarks, committee chair John Mendelsohn described the system for conducting cancer clinical trials in the United States as “approaching a state of crisis.” Several key reasons for this were articulated, including: 1) excessive complexity and redundancy in design and initiation of trials; 2) lack of an adequate system-wide process for prioritizing trials and selecting those more likely to succeed; and 3) inadequacy of NCI funding and lack of insurance plan reimbursement for nonexperimental costs of care in clinical trials. In addition, the report acknowledged the importance of the Cooperative Groups in mentoring the next generation of cancer clinical researchers, and the unfortunate fact that this is hampered by relatively low value placed upon Cooperative Group trials by many academic institutions in evaluating faculty accomplishments and by the NCI in evaluating cancer center achievements. Given these problems on top of ever-increasing time demands upon all clinicians, it is easy to understand why we are in a near-crisis situation.

The IOM committee was specifically charged with recommending ways to improve, modernize and streamline the process of conducting cancer clinical trials, emphasizing the need to conduct studies that address the utility of new targeted therapies. Importantly, the committee recognized that progress could not be made by changing individual components of the system in isolation, but that “all participants and stakeholders, including physicians, patients and health care insurers, as well as the NCI and regulatory agencies, must reevaluate their combined roles and contributions to a successful streamlined process…” In brief, the recommendations call upon the stakeholders to “consolidate functions and processes, streamline oversight, enhance collaboration, select and prioritize trials more stringently, fully fund the most innovative and promising studies, and open and complete trials with greater speed.” I urge all CALGB members to review the IOM report, as it clearly articulates the challenges that we face and suggests a number of (equally challenging) potential solutions. This new view of the Cooperative Groups may provide us with some opportunities for additional support that will improve or expand CALGB’s programs. Many of these suggestions involve broader application of initiatives already well underway in CALGB. For example, our Central Office has made achieving the timeline goals of the NCI’s Operational Efficiency Working Group its highest priority. This process is aided by a new Group-wide prioritization of studies in development, which was initiated at the March 2010 committee meetings. In order to foster greater collaboration between CALGB and other Cooperative Groups, I have asked Dr. Richard Goldberg to serve in an Associate Chair position, with the title of Associate Chair for Intergroup Affairs. As a senior scientific liaison to other Cooperative Groups, Rich will help address the need for greater coordination of concept review by the NCI’s Disease Specific Steering Committees. He will work with the CALGB committee chairs to eliminate obstacles that delay the process of — see GROUP CHAIR’S MESSAGE, page 4

Summer 2010


SPOTLIGHT ON CALGB TRIALS / 80802 CALGB Initiates First Phase III Hepatocellular Carcinoma Trial in Cooperative Group Setting 80802 Phase III randomized study of sorafenib plus doxorubicin versus sorafenib in patients with advanced hepatocellular carcinoma (HCC) Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third leading cause of cancer death.1 While the current incidence of HCC in the United States is relatively low, it has risen here over the past two decades.2,3 A nearly two-fold increase in the age-adjusted rates for HCC, up to 7 per 100,000 patients observed in the U.S., is explained by the increasing incidence of hepatitis C infection during the previous two decades.3 The current distribution of patients seen for HCC by most medical oncologists mirrors the distribution of HCC attributable to hepatitis C, hepatitis B, alcoholic liver disease, and non-alcoholic-steatohepatitis (NASH), in addition to the less commonly reported metabolic diseases with hemochromatosis, possibly the most recognized.4 Since the only curative therapies for HCC are surgery and liver transplantation, an urgent need exists for effective therapies that will improve survival in advanced HCC.5 Currently sorafenib is the standard of care for advanced HCC. It is an oral multi-kinase inhibitor that blocks tumor cell proliferation and exerts an anti-angiogenic effect, and has been approved by the U.S. Food and Drug Administration (FDA) for treatment of patients with advanced HCC.6 Preclinical data suggest that combining sorafenib with a variety of chemotherapeutic agents results in additive anti-tumor activity.7 Doxorubicin in combination with sorafenib results in tumor growth delay (when 5 x 106 cells are injected into the flank of NCr Nu/Nu female mice). This combination, with sorafenib at the maximum tolerated dose level, caused a tumor growth delay (expressed in days relative to control tumors) of 12.4 days compared to single agent sorafenib (6.6 days) and single agent doxorubicin (6.1 days). In addition, the percent weight change of tumors at day 13 was 11.9 percent for the combination versus 4.6 percent for sorafenib and 3.8 percent for doxorubicin.

CALGB 80802 will enroll 480 patients with advanced HCC over two years to compare the overall survival of those treated with sorafenib and doxorubicin to that of those treated with sorafenib. This study will evaluate any additive or synergistic effects of doxorubicin by randomizing patients to doxorubicin versus no added therapy.

Why This Study Is Important The NCI GI Steering Committee created the Hepatobiliary Cancer Task Force in 2007, and shortly thereafter, sorafenib was shown to improve survival in selected patients with HCC. Subsequent research has focused on combination therapies with and without sorafenib, and a recent randomized phase II trial suggests that the combination of sorafenib and doxorubicin could further improve outcomes for patients with HCC. CALGB 80802 is a first effort for the CALGB and Hepatobiliary Cancer Task Force, the first phase III trial in HCC in the cooperative groups, and is timely in combating the highly and increasingly prevalent and deadly HCC. The study protocol (CALGB 80802) can be found on the CALGB Member Web site ( for complete information about the trial design, patient eligibility, treatment plan and substudies. The CALGB Study Chair is Ghassan Abou-Alfa, M.D., Memorial Sloan-Kettering Cancer Center, e-mail: The CALGB Study co-chair is Bhoomi Mehrotra, M.D., Long Island Jewish Medical Center, e-mail: ___________________ References 1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74-108. 2. The American Cancer Society. Cancer Facts & Figures 2008. Available at Accessed March 13, 2008. 3. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999;340:745-750. 4. Kowdley KV. Iron, hemochromatosis, and hepatocellular carcinoma.Gastroenterology. 2004 Nov;127(5 Suppl 1):S79-86. 5. Arciero CA, Sigurdson ER. Liver-directed therapies for hepatocellular carcinoma. J Natl Compr Canc Netw. 2006;4:768-774. 6. Llovet J, Ricci S, Mazzoferro V, et al. Sorafenib in advanced hepatocellular carcinoma N Engl J Med, 359:378-90, 2008. 7. Vincent P, Zhang X, Chen C et al. Preclinical chemotherapy with the Raf kinase inhibitor BAY 43–9006 in combination with gefitinib, venorelbine, gemcitabine or doxorubicin. Proc Am Assoc Cancer Res 2003; 44 (2nd edn): Abstr 719.


The CAL.GAB is published by the Cancer and Leukemia Group B quarterly and distributed to CALGB active membership through the CALGB Web site ( Suggestions for articles are encouraged. Forward articles, suggestions and all correspondence to The CAL.GAB reserves the right to make corrections, changes and deletions in submitted copy in conformity with the newsletter’s editorial policies.


Cancer and Leukemia Group B Newsletter

SPOTLIGHT ON CALGB TRIALS / 40503 Advanced Breast Cancer Study Changes to Open-Label Design to Enhance Accrual Efforts 40503 Endocrine therapy with or without anti-VEGF therapy: A randomized, phase III trial of endocrine therapy alone or endocrine therapy plus bevacizumab (NSC 704865; IND 7921) for women with hormone receptor-positive advanced breast cancer Advanced breast cancer remains an incurable illness despite a number of effective treatments for metastatic disease. Although recent evidence suggests an improved prognosis for patients with recurrent breast cancer, more than 40,000 women are expected to die of metastatic disease this year.1,2 New targeted treatments that delay disease progression would represent a significant advance in the care of women with breast cancer. For postmenopausal women with hormone-receptor positive advanced stage disease, estrogen deprivation with a third generation aromatase inhibitor (AI) is more effective than tamoxifen for first-line endocrine treatment.3-5 While this represents a significant advance for these patients, the major limitation of endocrine therapy remains the near universal development of resistance. Endocrine therapy resistance is also evident in the adjuvant setting where endocrine manipulations are only partially effective in reducing the death rate from breast cancer, even in populations of patients selected upon the basis of tumor estrogen receptor expression.6 Although there are no proven clinical strategies to reverse or prevent endocrine therapy resistance, several pre-clinical investigations suggest opportunities for therapeutic intervention. CALGB 40503 is designed to evaluate whether antiVEGF therapy with bevacizumab can delay resistance and prolong progression-free survival when added to first-line endocrine therapy for hormone-receptor positive metastatic breast cancer.

Introduction of Open-Label Design Since CALGB 40503 was activated on May 15, 2008, concerns have been raised that the placebo infusions presents several barriers to study activation at local institutions, patient enrollment and continued participation. In an effort to address concerns raised by local investigators and to lessen barriers to enrollment, the protocol study design was amended on May 15, 2010 to an open-label trial design.

In the re-designed trial, which will become effective August 12, 2010, patients will be randomized to endocrine therapy plus bevacizumab or endocrine therapy alone; the placebo infusion will be eliminated. Patients already enrolled on this study have been unblinded, notified of their treatment assignment, and re-consented to the new study design. The primary endpoint, stratification factors and the total number of patients enrolled in this study have not changed. The study protocol (CALGB 40503) and updates can be found on the CALGB Member Web site ( for complete information about the trial design, patient eligibility, treatment plan and substudies. The CALGB Study Chair is Maura Dickler, M.D., Memorial Sloan-Kettering Cancer Center, e-mail: ___________________ References 1. Giordano, S.H., et al., Is breast cancer survival improving? Cancer, 2004. 100(1): p. 44-52. 2. Jemal, A., et al., Cancer statistics, 2005. CA Cancer J Clin, 2005. 55(1): p. 10-30. 3. Mouridsen, H., et al., Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol, 2001. 19(10): p. 2596-606. 4. Nabholtz, J.M., et al., Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol, 2000. 18(22): p. 3758-67. 5. Paridaens, R., et al., First line hormonal treatment (HT) for metastatic breast cancer (MBC) with exemestane (E) or tamoxifen (T) in postmenopausal patients (pts): A randomized phase III trial of the EORTC breast group. Proceedings Am Soc Clin Oncol, 2004. 22(14S). 6. Early Breast Cancer Trialists' Collaborative Group, Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and a 15-year survival: an overview of the randomised trials. Lancet, 2005. 365: p. 1687-1717.

GROUP CHAIR’S MESSAGE / continued from page 2 concept review and approval by the NCI, specifically acting as a mediator for aspects of this process that do not reside within CALGB. It is gratifying to see how many of the changes proposed in the IOM report are already in progress within CALGB. Now we need to advocate for the other partners in this process to do their part. Specifically, we call upon the NCI Director to increase the percentage of the NCI budget allocated to practice-changing cancer clinical trials, and for all insurance carriers, at a minimum, to reimburse clinical centers for non-experimental care of patients on clinical trials. In addition, we believe that third party payers should reimburse clinical centers for the costs of already-approved drugs when they are used as study treatments in cancer clinical trials. Regulatory agencies can also do much to improve the efficiency and lower the cost of clinical trials without sacrificing important protections to patients and society in general. Finally, we all need to remember why we are here: to conduct clinical studies that meaningfully improve the lives of our patients. Any obstacle that keeps us from achieving our goal can and should be challenged.

Summer 2010


SPOTLIGHT ON CALGB TRIALS / 30801 New Study Looks to Confirm Positive Effects of COX-2 Inhibition in Patients with Non-Small Cell Lung Cancer 30801 A randomized phase III double blind trial evaluating selective COX-2 inhibition in COX2 expressing advanced non-small cell lung cancer Of 150,000 patients who will develop non-small cell lung cancer (NSCLC) in the United States in the next year, at least 40 percent will present with metastatic disease, and most of the remainder will eventually develop metastases. Recent advances in chemotherapy have improved the outlook for patients with stage IV disease. Studies employing “best supportive care” result in a 4-6 month median survival with only 10 percent of patients alive at one year. By comparison, median survival of about 6-8 months and one-year survival of 20 percent are achieved with “older” platinum-based (cisplatin or carboplatin) regimens. Most recent studies evaluating combinations of platinums with “newer agents” (carboplatin/paclitaxel, cisplatin/ gemcitabine, cisplatin/vinorelbine) have reported improved median survivals to 8-10 months with one-year survival of 30-35 percent, and/or reduced toxicity relative to older combinations.1-3 Cyclooxygenase-2 (or COX-2), the enzyme that converts arachidonic acid to prostaglandins (or locally acting messenger molecules), is overexpressed in a variety of malignancies. It has been demonstrated that overexpression of COX-2 is common in non-small cell lung cancer and associated with poor prognosis.4 Nearly 80 percent of NSCLC express the COX-2 enzyme.5,6 COX-2 has been shown to be expressed not only in the tumor cells but also in the tumor vasculature.7,8 Inhibition of COX-2 has resulted in reduced proliferation of cancer cells in vitro.9 Celecoxib, a selective inhibitor of COX-2, inhibits tumor growth of Lewis lung carcinoma implanted in mice in a dosedependent manner. The extent of inhibition ranges from 48 percent to 85 percent with increasing doses of celecoxib.8 A selective COX-2 inhibitor, ns-398, enhanced the effects of radiation in COX-2 overexpressing cells.10 In addition, it has recently been shown that expression of COX-2 could be associated with overexpression of p-glycoprotein.11 Inhibition of COX 2 could potentially reverse drug resistance. COX-2 inhibitors are now commercially available. Selective COX -2 inhibitors, such as celecoxib, have the potential to inhibit tumor angiogenesis and metastases and might serve as ideal agents for long-term

maintenance therapy. Celecoxib is generally well tolerated and has no overlapping toxicities with standard chemotherapy agents (carboplatin, gemcitabine, paclitaxel and docetaxel). Celecoxib is a proven and approved agent for the reduction of adenomatous polyps (a premalignant lesion) in patients with familial adenomatous polyposis.12 Several trials have evaluated cyclooxygenase inhibition in general, and COX-2 inhibition specifically, in lung cancer. Of note, there is considerable epidemiological evidence that inhibition of cyclooxygenase is effective for the prevention of lung cancer inhibition specifically, in lung cancer.13 CALGB 30801 will help confirm the beneficial effect of COX-2 inhibition in patients who have NSCLC that express COX-2. The primary endpoint is to demonstrate improvement in progression-free survival in patients with a COX-2 index ≥4 with an estimated hazard ratio of 0.6. Patients’ tumor samples will be tested to determine if they have high levels of COX-2. If not, patients will not continue with the treatment trial. If they do, patients will be randomized to receive standard chemotherapy (either gemcitabine/carboplatin or pemetrexed/ carboplatin, depending on their type of NSCLC), along with either celecoxib or a placebo. The study protocol (CALGB 30801) can be found on the CALGB Member Web site ( for complete information about the trial design, patient eligibility, treatment plan and substudies. The CALGB Study Chair is Martin Edelman, M.D., University of Maryland Greenebaum Cancer Center, e-mail:

___________________ References 1. Bonomi P, Kim K, Fairclough D, et al. Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2000 Feb;18:623-31. 2. Wozniak AJ, Crowley JJ, Balcerzak S, et al. Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small cell lung cancer: A cooperative group study. J Clin Oncol 10:1066-1073, 1992. 3. Sandler A, Nemunatis J, Denham C, et al. Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced and metastatic non-small cell lung cancer. J Clin Oncol 18:122-130, 2000. 4. Kelly K, Crowley J, Bunn PA et al. Randomized phase three trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol 19:3210-8, 2001. 5. Khuri FR, Hong W, Lee JJ et al. Cyclooxygenase 2 overexpression is a marker of poor prognosis in stage I non-small cell lung cancer. Clin Cancer Res 7: 861-7, 2001. 6. Wolff, K. Saukkonen, et al. (1998). “Expression of cyclooxygenase-2 in human lung carcinoma.” Cancer Research 58(22): 4997-5001. 7. Ochiai, M., T. Oguri, et al. (1999). Cyclooxygenase-2 (COX-2) mRNA expression levels in normal lung tissues and non-small cell lung cancers.. Japanese Journal of Cancer Research 90(12): 1338-43. 8. Masferrer, J. L., K. M. Leahy, et al. (2000). Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors.. Cancer Research 60(5): 1306-11. 9. Asktorab H, Larbi D, Tackey R, et al. Cyclooxygenase-2 inhibitor celecoxib alone and in combination with folic acid inhibits proliferation of colon cancer cell lines. Proc AACR 42: abstr 3305, 2001. 10. Pyo H, Choy H, Amorino GP et al. A selective cyclooxygenase-2 inhibitor, NS-398 enhances the effect of radiation in vitro and in vivo preferentially on the cells that express cycloxygenase-2. Clin Cancer Res 2998-3005, 2001. 11. Ratnasinghe, D., P. J. Daschner, et al. (2001). Cyclooxygenase-2, P-glycoprotein-170 and drug resistance; is chemoprevention against multidrug resistance possible? Anticancer Research 21(3C): 2141-7. 12. Steinbach G, Lynch PM, Phillips RKThe effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med. 2000 Jun 29;342(26):1946-52 13. Moysich KB, Menezes RJ, Ronsani A et al. Regular aspirin use and lung cancer risk. BMC Cancer. 2002 Nov 26;2:31


Cancer and Leukemia Group B Newsletter

CALGB ABSTRACTS / ASCO 2010 ABOUT ASCO The American Society of Clinical Oncology (ASCO) is the world's leading professional organization representing physicians who treat people with cancer. Its annual meeting, held this year in early June, is considered the premier educational and scientific event in the oncology community. The Cancer and Leukemia Group B presented 20 abstracts at this year’s 46th Annual ASCO Meeting. Four abstracts are featured in their entirety below and on the next page, and the others are listed on pages 7 and 8. Phase III intergroup study of lenalidomide versus placebo maintenance therapy following single autologous stem cell transplant (ASCT) for multiple myeloma (MM): CALGB 100104 McCarthy PL, Owzar K, Anderson KC, Hofmeister CC, Hassoun H, Hurd DD, Stadtmauer EA, Giralt S, Hars V, Linker CA Abstract No. 8017 Background: Disease relapse/progression is the primary cause of treatment failure after ASCT for MM. Methods: The primary objective of CALGB 100104 was to investigate if maintenance lenalidomide would prolong time to progression (TTP) following single ASCT. Eligibility included: Stage I-III disease, ≤ 1 year from diagnosis, ≥ 2 months of induction with Stable Disease or better (≥ SD) and age < 70 years. ASCT regimen was melphalan 200 mg/m2. Patients (pts) with ≥ SD were randomized double-blind at day 100110 post-ASCT to lenalidomide or placebo until disease progression, after stratification by diagnostic β-2 microglobulin (β-2M) level and prior thalidomide or lenalidomide therapy. Starting dose was 10 mg/day, escalated to 15 mg/day after 3 months. Drug was held for ≥ Gr 3 toxicity, restarted at resolution to ≤ Gr 2 and was de-escalated by 5 mg or maintained at 5, 10 or 15 mg/day as tolerated. Results: 568 pts were enrolled (04/15/05 - 07/03/09). The second interim analysis, based on 418 randomized pts occurred on 09/09 after 28% of the required number of events (progression or death before progression) had been observed. The median follow-up was 12 months. The number of events among 210 pts randomized to lenalidomide was 29 compared to 58 among 208 pts randomized to placebo. The one-sided unadjusted P-value was < 0.0001. The estimated hazard ratio was 0.42 (95% CI=0.27,0.67) corresponding to a 58% reduction in event risk in the lenalidomide arm. The estimated median TTP was 25.5 months for the placebo arm. The median TTP has not been reached for the study arm. Deaths in the study and placebo arms were 11 and 17 respectively (P=0.2). Significant

delay in TTP in the lenalidomide arm was observed regardless of β-2M level or prior thalidomide or lenalidomide therapy. For 285 reported pts, the post-randomization, highest grade, overall AEs were Gr 3 (n=19), Gr 4 (n=111) and Gr 5 (n=1) for the lenalidomide arm and Gr 3 (n=4) Gr 4 (n=115) and Gr 5 (n=1) for placebo. The majority of AEs were hematologic in both arms. Conclusion: Lenalidomide initiated at day 100-110 postASCT in MM patients significantly delays TTP and has a similar AE profile when compared to placebo.

A randomized, double-blind, placebo controlled phase III trial comparing docetaxel, prednisone, and placebo with docetaxel, prednisone, and bevacizumab in men with metastatic castrateresistant prostate cancer (mCRPC): Survival results of CALGB 90401 Kelly WK, Halabi S, Carducci MA, George DJ, Mahoney JF, Stadler WM, Morris MJ, Kantoff P, Monk III JP, Small EJ Abstract No. LBA4511 Background: The preclinical activity of vascular endothelial growth factor (VEGF) blockade, the inverse relationship of plasma and urine VEGF levels and survival in mCRPC patients (pts), and encouraging phase II data testing estramustine and docetaxel with bevacizumab suggested that VEGF blockade was an appropriate potential strategy in mCRPC. A phase III study testing the effect of adding bevacizumab to standard docetaxel and prednisone therapy administered every 3 weeks in pts with mCRPC was conducted. Methods: 1050 pts with chemotherapy naïve, mCRPC with evidence of progressive disease despite castrate testosterone levels and anti-androgen withdrawal, ECOG performance status ≤ 2, and adequate bone marrow, hepatic and renal function were eligible. Pts were prospectively randomized with equal probability to receive docetaxel (D:75 mg/m2 IV over 1 hour q 21 days), plus prednisone (P) 5 mg po BID with either bevacizumab (B:15 mg/kg given intravenously q 3 weeks following D) or placebo. All

patients received dexamethasone 8 mg PO 12, 3 and 1 hour prior to D. Randomization was stratified by predicted 24 mo survival probability, age and history of prior arterial thrombotic event. The primary endpoint was overall survival (OS). The trial was designed with 86% power to detect a 21% decrease in the hazard rate of death (equivalent to an increase in median OS from 19 months to 24 months) assuming a two-sided significance level of 0.05. The primary analysis was based on the stratified log-rank statistic adjusted for the stratification factors following observation of 748 deaths. Results: See Table 1 on next page. Conclusion: Despite an improvement in PFS, measurable disease response and posttherapy PSA decline, the addition of bevacizumab to docetaxel and prednisone did not improve OS in men with mCRPC, and was associated with greater morbidity and mortality. The median OS of pts treated with standard DP (21.5 m) was longer than previously reported (19 m).

Inherited genetic variation in EPHA5, FGD4, and NRDG1 and paclitaxel (P)-induced peripheral neuropathy (PN): Results from a genome-wide association study (GWAS) in CALGB 40101 Kroetz DL, Baldwin RM, Owzar K, Jiang C, Zembutsu H, Kubo M, Nakamura Y, Shulman LN, Ratain MJ Abstract No. 3021 Background: CALGB 40101 is an ongoing phase III trial comparing the efficacy of standard therapy cyclophosphamide and doxorubicin (AC x 4 or 6 cycles) with singleagent paclitaxel (P x 4 or 6 cycles) as adjuvant therapy for breast cancer in women with 0-3 positive axillary lymph nodes. AC and P are associated with significant toxicities, with peripheral neuropathy being the major toxicity of P. As part of this study, we have collected germline DNA for a pharmacogenetic GWAS to identify genetic predictors of toxicity. Methods: Germline DNA was isolated from 1,040 patients on the P arm of CALGB 40101 and genotyped using — see CALGB ABSTRACTS, next page

Summer 2010


CALGB ABSTRACTS / ASCO 2010 Table 1 – Survival Results from CALGB 90401

continued from page 6 the Illumina 610-Quad platform. Following QC analysis, genotypes were available for 520,679 SNPs. Principal component (PC) analysis identified 859 genetic Europeans that were the focus of this analysis. Patients with grade 2 or greater sensory PN during one or more cycles of P (n = 200) were compared to patients with grade 0 or 1 toxicity (n = 610) using an additive logistic regression model incorporating treatment duration and three PCs. Results: Although no SNPs reached genome-wide significance (p <10-8), three of the top ten hits were in genes implicated in congenital or experimental PN. Patients carrying a variant EPHA5 allele had an increased risk of P-induced PN (OR 1.81, p = 2.2 × 10-6). EPHA5 is expressed in the dorsal root ganglion and related genes in the EPH family contribute to neuropathic pain. Risk alleles were also identified in two genes implicated in congenital PN, FGD4 (OR 1.69, p = 1.9 × 10-5) and NDRG1 (OR 0.58, p = 1.9 × 10-5). These findings are further supported by a significant enrichment for SNPs annotated in neuronal development pathways. Conclusion: Heritable variation in EPHA5, FGD4, and NRDG1 may modify a patient's risk of developing P-induced sensory PN. If these findings are replicated, the ability to identify patients at risk of this common toxicity could influence the choice of adjuvant breast cancer therapy.

Galiximab, an anti-CD80 primatized monoclonal antibody, in relapsed Hodgkin lymphoma: Final results of CALGB 50602 Smith SM, Bartlett N, Johnson JL, Lister J, Cashen AF, Jung S, Schöder H, Egan K, Cheson BD Abstract No. 8039 Background: Relapsed HL patients (pts) ineligible for transplant or relapsed despite stem cell transplant have a poor prognosis and a median survival of approximately six months. Most are heavily pretreated and poorly tolerant of additional cytotoxic therapies. Targeted and non-cytotoxic therapies are needed. Galiximab is a primatized IgG1λ monoclonal antibody which binds with high affinity to CD80 (B7.1), and induces cross-linking of CD80 molecules and cell-death via ADCC. CD80 is an excellent target in HL with expression on the majority of Reed-Sternberg cells, while expression on normal tissues is limited to activated B-cells, antigen-presenting cells, and T-cells. Methods: CALGB 50602 is a phase II study of galiximab in relapsed HL after ≥ 2 prior regimens. Entry criteria included ANC ≥ 500/µL and plts ≥ 50K/µL. Galiximab dose was 500 mg/m2 weekly x 4 weeks followed by 500 mg/m2 q 4 weeks until progression or toxicity. The primary endpoint was response, with 4 responders in the first 21 pts required to proceed to the second stage. Samples for tissue microarray, PK, cytokine analysis, and FcR polymorphisms were 15 males and 15 females had a median age collected. Results: Between 6/2008-1/2009, 30 pts with classical HL were accrued at 10 CALGB institutions.

of 36 yrs (range, 22-70) and a median of 3 (range, 1-7) prior regimens. 20 pts (74%) had prior RT and 23 pts (85%) had failed prior autologous and/or allogeneic stem cell transplant. 1 pt never started treatment. There was 1 CR and 1 PR, with ORR 6.9% (95% CI 0.9, 22.8%); both responders progressed at 7.5 and 3 mos, respectively. 24 pts came off treatment for PD. The median TTP was 1.6 months. Galiximab was welltolerated, with grade 3 or 4 non-hematologic toxicities limited to hypophosphatemia (n=3), elevated SGOT/SGPT (n=2), and infection (n=2). Conclusion: Despite being welltolerated, galiximab had minimal activity in heavily pretreated pts with relapsed HL. CALGB's prompt accrual of a rare population and rapid screening for activity supports the ongoing unmet clinical need for targeted and non-cytotoxic agents in relapsed HL.

OTHER 2010 CALGB ABSTRACTS Randomized phase II trial of adding carboplatin and/or bevacizumab to neoadjuvant weekly paclitaxel and dose-dense AC in triple-negative breast cancer Sikov WM, Perou CM, Golshan M, Collyar D, Berry DA, Hahn OM, Singh B, Hudis C, Winer EP Abstract No. TPS#110 Lumpectomy plus tamoxifen with or without irradiation in women age 70 or older with early breast cancer Hughes KS, Schnaper LA, Cirrincione C, Berry DA, McCormick B, Muss HB, Shank B, Hudis C, Winer EP, Smith BL Abstract No. 507 Use of progression-free survival (PFS) to predict overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) Halabi S, Rini BI, Stadler WM, Small EJ Abstract No. 4525 Dose-intensified daunorubicin induction and consolidation plus combined modality maintenance therapy for children with newly diagnosed acute promyelocytic leukemia (APL): North American Intergroup Study C9710 Feusner JH, Gregory J, Moser BK, Hars V, Willman CL, Powell BK, Larson RA Abstract No. 9510 — more CALGB ABSTRACTS, next page


Cancer and Leukemia Group B Newsletter

CALGB ABSTRACTS / ASCO 2010 continued from page 7 Treatment of older patients with de novo acute myeloid leukemia (AML) with one or more postremission chemotherapy courses: Analysis of four CALGB studies Baer MR, George SL, Sanford BL, Stone RM, Marcucci G, Mayer RJ, Larson RA Abstract No. 6531 A phase II trial of bortezomib plus lenalidomide for relapsed/refractory mantle cell lymphoma (MCL) (CALGB 50501): Results of a planned interim analysis Morrison VA, Johnson JL, Jung S, Leonard JP, Cheson BD Abstract No. 8106 A randomized phase II trial of maintenance versus consolidation bortezomib therapy following aggressive chemo-immunotherapy and autologous stem cell transplant for previously untreated mantle cell lymphoma Kaplan LD, Jung S, Johnson JL, Linker CA, Byrd JC, Stock W, His ED, Cheson BD Abstract No. TPS#306 Interim analysis of CALGB 150607: A pilot project to study the expression of MET and P53 in resected lung adenocarcinoma specimens Salama AK, Pang H, Kratzke RA, Richards WG, Vokes EE, Salgia R Abstract No. 10633

Serum VEGF and COX-2/5LOX inhibition in advanced non-small cell lung cancer: Cancer and Leukemia Group B 150304 Edelman MJ, Hodgson L, Wang XF, Christenson R, Vokes EE, Kratzke RA Abstract No. 7614

Comparison of in-dwelling catheters and talc pleurodesis in the management of malignant pleural effusions Demmy TL, Gu L, Burkhalter JE, Toloza EM, D'Amico TA, Sutherland S, Wang XF, Archer L, Veit LJ, Kohman L Abstract No. 9031

Combination chemotherapy with sunitinib (IND 74019; NSC 736511) for untreated extensive-stage small cell lung cancer (SCLC): CALGB 30504 phase IB safety results Ready N, Dunphy F, Pang H, Heinze R, Crawford J, Vokes EE Abstract No. 7056

Impact of KRAS mutations on adjuvant carboplatin/paclitaxel in surgically resected stage IB NSCLC: CALGB 9633 Capelletti M, Wang XF, Gu L, Graziano SL, Kratzke RA, Strauss GM, Maddaus M, Green MR, Vokes EE, Janne PA Abstract No. 7008

CALGB 30601: A phase II study of dasatinib (D) in patients (pts) with previously treated malignant mesothelioma (MM) A. Dudek, H. Pang, R. A. Kratzke, G. A. Otterson, E. E. Vokes, H. L. Kindler Abstract No. 7037 Randomized phase II trial of erlotinib (E) alone or in combination with carboplatin/paclitaxel (CP) in never or light former smokers with advanced lung adenocarcinoma: CALGB 30406 Janne PA, Wang XF, Socinski MA, Crawford J, Capelletti M, Edelman MJ, Villalona-Calero MA, Kratzke RA, Vokes EE, Miller VA Abstract No. 7503

CALGB 80403/ECOG 1206: A randomized phase II study of three standard chemotherapy regimens (ECF, IC, FOLFOX) plus cetuximab in metastatic esophageal and GE junction cancer Enzinger PC, Burtness B, Hollis D, Niedzwiecki D, Ilson D, Benson AB, Mayer RJ, Goldberg RM Abstract No. 4006 The role of patient advocates in clinical trials: Perspectives from investigators and advocates in the Cancer and Leukemia Group B (CALGB) Katz ML, Archer L, Peppercorn JM, Kereakoglow S, Collyar D, Burstein HJ, Schilsky RL, Partridge AH Abstract No. 6148

Summer 2010


CALGB RESEARCH AWARDS Five Researchers Receive 2010 CALGB Research Grants The Cancer and Leukemia Group B Foundation annually invites applications for grants to support research activities of oncology junior faculty working at CALGB institutions. This research includes studies that assess interventions in cancer patients and/or examines biological specimens obtained from cancer patients. This year, with the support of Novartis Oncology, Amgen Oncology and Celgene, the Cancer and Leukemia Group B Foundation presented grants to five young investigators from the nation’s leading medical institutions at the CALGB Summer Group Meeting in Chicago, IL. The application deadline for next year’s awards is January 18, 2011. For more information or application instructions, visit the CALGB Web site at (under CALGB Foundation).

2010 Award Recipients

2010 Award Rec ipients. From top left: Marie Bakitas, A.P.R.N., D.Nsc., A.O.C.N., F.A.A.N.; Arati Rao, M.D.; W. Kimryn Rathmell, M.D., Ph.D.; Rachel Freedman, M.D., M.P.H.; and Daniel Boffa, M.D.

CALGB Clinical Scholar Awards sponsored by Novartis Oncology

CALGB Investigator Award sponsored by Celgene

Marie Bakitas, A.P.R.N., D.Nsc., A.O.C.N., F.A.A.N. Assistant Professor Departments of Anesthesiology and Medicine Palliative Medicine Dartmouth-Hitchcock Medical Center “Translating Effective Concurrent Oncology Palliative Care (TECOPc) into Rural Community-Based Oncology Practice”

Rachel Freedman, M.D., M.P.H. Instructor in Medicine Harvard Medical School Dana-Farber Cancer Institute “Changes in Cognitive Function in Elderly Women Treated with Standard Chemotherapy and Capecitabine within CALGB 49907”

Arati Rao, M.D. Assistant Professor of Medicine Duke University Medical Center “A Clinico-Genomic Strategy to Optimize Therapy of Elderly Patients with Acute Myeloid Leukemia” W. Kimryn Rathmell, M.D., Ph.D. — see CALGB GROUP of NEWS, page 12and Genetics Assistant Professor Medicine University of North Carolina at Chapel Hill “Molecular Stratification of Renal Cell Carcinoma to Predict Response to Treatment”

CALGB Investigator Award sponsored by Amgen Oncology Daniel Boffa, M.D. Assistant Professor Thoracic Surgery Yale University School of Medicine “Evaluation of a Novel Molecular NSCLC Classification System. A Companion Study to CALGB 9761”

First Richard L. Schilsky Achievement Award Recipient

John C Byrd, M.D.

John C. Byrd, M.D., Director of the Hematologic Malignancies Program at The Ohio State University, is the first recipient of the Richard L. Schilsky CALGB Achievement Award. Dr. Byrd holds the D. Warren Brown Professorship in Leukemia Research and academic rank of Professor of Medicine and Medicinal Chemistry. His research accomplishments include work completed in the laboratory and clinic with several different therapeutic agents active in chronic lymphocytic leukemia and related leukemia and lymphoma. In particular, he is very active in the development of therapeutic antibodies and other targeted agents. Dr. Byrd has authored or been a co-author on more than 100 peer-reviewed publications. For more information about this award or the nomination process, visit the CALGB Web site at (under CALGB Foundation).


Cancer and Leukemia Group B Newsletter


Bisphosphonate-Related Osteonecrosis of the Jaw By Vicki Lagerwey, R.N., B.S.N., O.C.N. Wake Forest University Comprehensive Cancer Center

The primary action of bisphosphonates is inhibition of osteoclastic activity. Because osteoblastic activity is coupled tightly to osteoclastic activity, the end result is suppression of bone turnover.1 This action makes bisphosphonates an important tool in the management of osteoporosis and cancers affecting the bone. In patients with multiple myeloma and metastatic solid tumors, bisphosphonates reduce skeleton-related events such as hypercalcemia, pathological fracture, spinal cord compressions, bone pain and the need for surgery or radiation.2 Recent evidence suggests they may also improve survival in patients with multiple myeloma or breast cancer.3 Commonly used bisphosphonates include zoledronic acid (Zometa®), pamidronate (Aredia®), alendronate (Fosamax®), risedronate (Actonel®) and ibandronate (Boniva®). Bisphosphonate-related osteonecrosis of the jaw (ONJ) is most frequently defined by current or previous treatment with a bisphosphonate, exposed necrotic bone that fails to heal after appropriate intervention for more than eight weeks and no history of radiation therapy to the jaws.4 Bisphosphonate-related ONJ was first described in 2002, nine months after zolendronic acid was approved by the U.S. Food and Drug Administration (FDA).5 By December, 2006, 3,607 cases had been reported to the FDA and 2,227 cases had been reported to the manufacturer of intravenous bisphosphonates.6 Cases of ONJ have been associated with the use of both intravenous and oral bisphosphonates; however, the overwhelming majority of ONJ diagnoses have been associated with intravenous administration of bisphosphonates. Several factors are linked to the risk of developing ONJ including both the potency of and length of exposure to bisphosphonates, trauma, such as tooth extractions, and preexisting dental disease. The pathophysiology of ONJ is unclear.

“It is not known whether ONJ is the primary process due to direct oral toxicity to the bone and/or soft tissues from accumulated bisphosphonates that becomes secondarily infected; if this disorder represents primary osteomyelitis, often due to actinomyces, exacerbated by the use of bisphosphonates; or if it is the consequence of a combination of events, including the inhibition of bone resorption and reduction of bone remodeling capacity secondary to the use of bisphosphonates, poor dental hygiene, including poorly fitting dentures, and/or a dental manipulation of some sort.”7 Patients taking bisphosphonates monthly for oncologic purposes have a reported incidence rate varying from 1.2 percent to 19 percent for developing ONJ.8 The most common presenting symptom of ONJ is pain, which is speculated to be secondary to infection. Clinical and radiographic presentations may not be obvious since patients may be asymptomatic or complain of vague symptoms related to the jaws. — see ONCOLOGY NURSING, next page

Summer 2010


ONCOLOGY NURSING PERSPECTIVE continued from page 10 Other symptoms may include numbness in the affected area, loose teeth, soft tissue swelling and a foul-tasting discharge. The American Association of Oral and Maxillofacial Surgeons (AAOMS) defines the following stages of bisphosphonate-related ONJ:4  Stage 0: Clinical nonspecific symptoms of pain, loose teeth not explained by periodontal disease, intra-oral fistula not explained by pulp necrosis and radiographic findings suggesting ONJ.  Stage 1: Exposed bone with absence of pain and infection  Stage 2: Pain associated with suppuration or infection and intraoral sinus track formation  Stage 3: Extraoral fistula, exposed necrotic bone extending beyond the regions of the alveolar bone pathological fracture, osteolysis extending to the inferior border or oroantral communication. In earlier stages, the bony exposure is generally treated conservatively with antimicrobial rinses, such as chlorhexidine mouth rinses, and filing off the rough edges of exposed bone.2 If the exposed area becomes secondarily infected, systemic antibiotics may be required. Stage III disease may also require surgical intervention. Elective surgery is discouraged for patients receiving bisphosphonates; root canals and crowns rather than tooth extraction are the preferred treatment options for nonvital teeth. However, when teeth are extremely mobile and associated with periodontal abscess, ONJ may already be present and extractions cannot be avoided. It is unlikely that the extraction will worsen the existing necrotic process.2 Discontinuing bisphosphonate use before surgery is controversial because the half-life of the drug is measured in years. Discontinuation of bisphosphonate therapy at the time of the diagnosis of ONJ, reinitiation of therapy after treatment of ONJ, as well as the optimal duration of therapy with bisphosphonates are all subjects of debate.9 In multiple myeloma, many patients have been able to continue monthly intravenous bisphosphonate therapy without further exacerbation. These decisions must be based on the clinical effects of ONJ on the patient compared with the benefits of ongoing bisphosphonate therapy on preventing skeletal complications.

In view of the difficulty in treating this complication, prevention is of the utmost importance. All cancer patients should receive a comprehensive dental examination and appropriate preventive dentistry before starting treatment with bisphosphonates. Active oral infections should be treated and sites at high risk for infection should be eliminated. Removable dentures should be examined for their potential to induce soft-tissue injury, especially tissue overlying bone, and adjusted if required. While on therapy, patients should maintain excellent oral hygiene along with regular dental care and avoid invasive dental procedures, if possible. Routine dental cleanings should be performed carefully with emphasis on avoiding soft-tissue injuries.10 Although the occurrence of bisphosphonate-related ONJ is considered rare, it can have a broad health impact by compromising quality of life and creating dilemmas in patient management. Incidence, cause, prevention and treatment have yet to be clearly defined. The oncology team, along with the oral and maxillofacial surgeon and general dentist, should be aware of the latest management strategies and treatment options to reduce the risk of skeletal-related events while maintaining oral health. Educating our patients about the potential problem and encouraging good dental hygiene as well as examining the oral cavity should be a routine approach for this patient population. Clearly, there is a need for reliable studies to provide answers related to this debilitating complication. ___________________ References 1. Russell RG. Bisphosphonates: mode of action and pharmacology. Pediatrics 2007;119 (suppl 2):5150-5162. 2. Almazrooa SA, Woo S-B. Bisphosphonate and nonbisphosphonate-associated osteonecrosis of the jaw: A review. Journal of the Amerian Dental Association 2009;140(7):864-875. 3. Gnant M, Mlineritsch B, Schippinger W, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. New England Journal of Medicine 2009;360:679-691. 4. Ruggiero SL, Dodson TB, Assael LA, et al. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws: 2009 update. Journal of Oral and Maxillofacial Surgery 2009;67:2-12. 5. Edwards BJ, Gounder M, McKay JM, et al. Pharmacovigilance and reporting oversight in US FDA fast-track process: bisphosphonates and osteonecrosis of the jaw. Lancet Oncology 2008;9:1166 6. Wikipedia. Osteonecrosis of the jaw. (n.d.). Retrieved from Wikipedia: 7. Bereneson, JR. (2009). Risks of bisphosphonate therapy in patients with malignancy. Retrieved from 8. Walter C, Al-Nawas B, duBois A, et al. Incidence of bisphosphonate-associated osteonecrosis of the jaws in breast cancer patients. Cancer 2009;115:1631. 9. Badros A, Terpos E, Katodritou E, et al. Natural history of osteonecrosis of the jaw in patients with multiple myeloma. Journal of Clinical Oncology 2008;26:5904. 10. Migliorati CA, Casiglia J, Epstein J, Jacobsen PL, Siegel MA, Woo S-B. Managing the care of patients with bisphosphonate-associated osteonecrosis: An American Academy of Oral Medicine position paper. Journal of the American Dental Association 2005;136:1658-68.


Cancer and Leukemia Group B Newsletter

IS CORNER Meet the Staff: CALGB Information Systems Help Desk & CALGB Systems Administration Every CALGB member benefits from the work of the CALGB Information Systems Help Desk and Systems Administration teams. “The teams are core IT resources because they support all members and keep the IT infrastructure functioning at a high level of reliability,” says Josh Yoder, M.B.A., CALGB Deputy Director of IT. “It is these folks who ensure that the technological resources needed to execute the CALGB mission are always available to the membership.” Who’s Who Eric Frye interacts daily by telephone and e-mail with CALGB members. As new member of the Help Desk team, Frye enjoys learning the intricacies of cancer research as he speaks each day with CALGB members. His tasks include solving access and Web application use issues for CALGB members, and providing desktop support to CALGB Statistical Center staff. Likely a recordsetter within IS, Frye won an Employee of the Month award just two months after starting earlier this year in recognition of his hard work, helpfulness and attitude.

CALGB IS Help Desk and CALGB Systems Administration. Front row (l-r): Tressa Chan and Jason Yanoff. Back row: JD Henderson, Josh Yoder, and Eric Frye.

Help Desk Analyst Tressa Chan, also new to CALGB, very much appreciates the IS team environment. Fielding Help Desk calls and e-mails, she works constantly to master the details of intra-and intergroup processes. Chan is especially thankful that CALGB staff are always willing to answer questions so she can address an expanding variety of Help Desk requests. System Administrators, JD Henderson and Jason Yanoff, maintain the complex arrays of hardware and software that make up the state-of-the-art CALGB computing environment. As Senior IT Analyst, Henderson maintains the servers and software that support the work of CALGB members. He updates and backs up all Statistical Center servers, and ensures their availability and smooth functioning by monitoring for potential and actual problems, investigating to locate the source, and providing solutions. Senior IT Analyst Yanoff is the newest member of the System Administration team. He works to improve the administration and security of the CALGB network infrastructure and works with statisticians, data coordinators and the Information Systems team.

Summer 2010




CALGB Elects New Group Statistician – Daniel J. Sargent, Ph.D. Monica M. Bertagnolli, M.D., CALGB Group Chair, announced the election of Daniel J. Sargent, Ph.D., Professor of Biostatistics and Oncology at the Mayo Clinic, as the new CALGB Group Statistician at the 2010 Cancer and Leukemia Group B Summer Group Meeting Plenary Session held in Chicago, IL, in June. He replaces Stephen L. George, Ph.D., Professor of Biostatistics and Bioinformatics at Duke University, who served as CALGB Group Statistician for 20 years. Dr. Sargent is former Group Statistician for the North Central Cancer Treatment Group (NCCTG) and is currently Director of Cancer Center Statistics at the Mayo Clinic Comprehensive Cancer Center. He received his B.S., M.S., and Ph.D. degrees from the University of Minnesota, and has been at Mayo Clinic since graduating in 1996. His primary research interest is in the conduct and methodology of clinical trials in cancer, and is actively involved in the research of clinical trial design, design and analysis of studies involving tumor markers, meta-analyses, and survival analysis. Dr. Sargent is a member of the U.S. Gastrointestinal Cancer Steering Committee, and co-chaired the Gastrointestinal committee for the NCI Common Data Elements Project. He co-chaired a joint NCI-EORTC committee on methodology for tumor marker studies, was a member of the FDA panel on endpoints for colon cancer clinical trials, and currently sits on the U.S. NCI Clinical Trials Advisory Committee (CTAC), which oversees all cancer clinical trials in the United States. He is also a chair or member of more than 20 Data and Safety Monitoring Committees. Dr. Sargent has published papers on innovative designs for phase I, II and III clinical trials as well as on advances in survival analysis, meta-analysis, and designs for validating tumor biomarkers. He has authored more than 150 peerreviewed manuscripts, book chapters, editorials and letters.

From left: Daniel J. Sargent, Ph.D., CALGB Group Statistician: Monica M. Bertagnolli, M.D., CALGB Group Chair; and Stephen L. George, Ph.D., former CALGB Group Statistician (1990-2010).

Passing the Torch After 20 years of dedicated service working with three CALGB Group Chairs (O. Ross McIntyre, M.D., Richard L. Schilsky, M.D., and Monica M. Bertagnolli, M.D.), Dr. George readily passes on the torch as Director of the Cancer and Leukemia Group B Statistical Center. He recalls vividly his first challenge as Group Statistician, building a team and completing a new competitive renewal grant application: “It took up all of our energy at first,” Dr. George said. “We did not have many people. We started with about three people, including Gary Rosner and Richard Dodge.” After his first year, during which Dr. George worked with a subcontractor (Frontier Science and Technology Research Foundation, Inc.), a decision was made to move “everything” in-house and hire additional staff. That meant carefully reviewing and analyzing the Group’s data management operation, and developing a plan to revise the patient registration process, improve data flow within the Group, and fine-tune day-to-day data management functions. Soon, Dr. George and his team upgraded and re-designed the old database to enable online registration, electronic data submission, laboratory specimens tracking and Webbased communications. This move enhanced the Group’s ability to better communicate with its members, providing easier access to a variety of information such as protocols and patient registration. “Today, we have about 100 or so staff,” Dr. George said. “It’s been a steady growth. I have worked to successfully manage a statistical center that produces high quality science and published results . . . ideas that lead to the development of therapies.” What’s next for Dr. George? “I’m looking forward to spending more time with my wife, my daughter in Canada and my three grandchildren,” he said. — more SUMMER GROUP MEETING, next page


Cancer and Leukemia Group B Newsletter

2010 CALGB SUMMER GROUP MEETING 10th Annual Jimmie Holland Lecture

 Geriatrician and medical oncologist Arti Hurria, M.D., Director of the Cancer and Aging Research Program at City of Hope in Duarte, CA, presented this year’s lecture, “Research in Geriatric Oncology: Meeting the Needs of an Aging Population.”

CARE Forum / Making Clinical Trials Count for Everyone: Teaming Up with CALGB Patient Advocates for Better Results  During this two-hour session, panelists and audience

members engaged in a robust discussion about the results from a recent survey on the role of CALGB Patient Advocates presented at this year’s ASCO meeting. Panelists included Ann Partridge, M.D., M.P.H., Assistant Professor in Medicine at Harvard Medical School and CALGB Cancer Control and Health Outcomes (CCHO) Committee Vice Chair; Pam McAllister, Ph.D., CALGB Patient Advocate; Richard Larson, M.D., Professor of Medicine and Director of the Hematologic Malignancies Program at the University of Chicago Medical Center and CALGB Leukemia Committee Chair; and Margaret White, R.N., Clinical Trials Director at New Hampshire Oncology-Hematology P.A., and CALGB Clinical Research Associates (CRA) Committee member.

CALGB Correlative Science Symposium

 The CALGB Biospecimen and Correlative Sciences Advisory Committee sponsored a two-hour forum that highlighted outstanding CALGB science and the promise of the biomarker field in advancing cancer treatment. This year’s symposium focused on integral and integrated biomarkers with a special emphasis on the development and implementation of biomarkers guiding therapy – all presented by innovative CALGB correlative science investigators: “EGFR Mutation and Response to Therapy in NSCLC Patients” by Pasi Janne, M.D., Ph.D., Associate Professor of Medicine at Harvard Medical School; “PIK3CA Mutations are Associated with Improved Outcome in Breast Cancer” by Mary Ellen Moynahan, M.D., Assistant Member in Developmental Biology at the Memorial Sloan-Kettering Cancer Institute; “IDH1 and IDH2 Gene Mutations Identify Novel Molecular Subsets within De Novo Cytogenetically Normal Acute Myeloid Leukemia” by Klaus Metzeler, M.D., of The Ohio State University; and “Principles and Practices for Validating Clinical Molecular Pathology Tests” by Margaret Gulley, M.D., Professor and Director of Molecular Diagnostics at the University of North Carolina at Chapel Hill.

CRA Committee Meeting

 This year’s meeting was presented in three sessions: a general session and two special breakout sessions. In the

general session, Monica M. Bertagnolli, M.D., CALGB Group Chair, provided remarks on the recently published Institute of Medicine’s report, “A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program.” CALGB Central Office and Statistical Center staff discussed operational updates, including information on the new CALGB Specimen Tracking System (STS). Representatives from the Cancer Trials Support Unit (CTSU) presented an overview and mini-training session on Oncology Patient Enrollment Network (OPEN) system, which aims to provide a standardized Web-based environment for enrolling all patients in clinical trials across the NCI-sponsored Cooperative Group Clinical Trials Program. The breakout sessions consisted of a CRA Orientation for CRAs with less than 18 months experience and an Advanced Session for those with more experience. Statistical Center staff discussed the CALGB Web site, Adobe Connect (online training), data management, adverse event reporting and disease response during the CRA Orientation. Breast cancer trials were the focus of the Advanced Session with William Sikov, M.D., Clinical Assistant Professor of Medicine at Miriam Hospital (Brown University School of Medicine), discussing accrual strategies for two CALGB neoadjuvant trials: CALGB 40601 (Randomized phase III trial of paclitaxel combined with trastuzumab, lapatinib, or both as neoadjuvant treatment of HER-2-positive primary breast cancer) and CALGB 40603 (Randomized phase II 2 x 2 factorial trial of the addition of carboplatin +/bevacizumab to neoadjuvant weekly paclitaxel followed by dose-dense AC in hormone receptor-poor/HER-2negative resectable breast cancer). Lynn Flickinger, M.S., NCCTG Research Protocol Specialist at the Mayo Clinic, shared new updates on the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) trial. Linda Veit, CALGB Surgery Committee Administrator, and Stacy Drew, M.S., Clinical Research Coordinator at Duke University, presented a brief talk on trouble-shooting surgical protocols.

Oncology Nursing/Pharmacy Educational Session

 Featured speakers Bonnie R. Braddock, M.P.H., Senior Certified Genetic Counselor in the Section of Medical Genetics at Upstate Medical University in Syracuse, NY, and R. Donald Harvey, Pharm.D., Assistant Professor of Hematology/Medical Oncology and Director of the Phase I Unit at the Winship Cancer Institute of Emory University in Atlanta, GA, lectured on “DNA and Cancer: Using Genetics to Help Predict Cancer Risks and Treatment Response.”

Summer 2010


CALGB GROUP NEWS New CALGB Appointments Gini Fleming, M.D., Professor of Medicine and Director of the Medical Oncology Breast Program at the University of Chicago, has been appointed Vice Chair of the Cancer and Leukemia Group B. Dr. Fleming is charged with oversight of CALGB Protocol Operations, including protocol development and conduct and CALGB administrative functions. She is a former CALGB Executive Officer and her specialty is in breast oncology. Richard M. Goldberg, M.D., Professor and Chief, Division of Hematology and Oncology, at the University of North Carolina at Chapel, has been appointed CALGB Associate Chair of Intergroup Affairs. In this new role, the former Chair of the CALGB Gastrointestinal (GI) Cancer Committee will help improve the protocol development process within the intergroup structure. Dr. Goldberg is also Associate Director of the Lineberger Comprehensive Cancer Center, and Director of Oncology Services at the UNC Health Care System. Alan P. Venook, M.D., Professor of Clinical Medicine (Hematology/ Oncology) at the University of California at San Francisco, has been appointed Chair of the CALGB GI Committee. Najjia Mahmoud, M.D., Assistant Professor of Surgery and Attending Surgeon at the Hospital of the University of Pennsylvania, has been appointed Vice Chair of the CALGB GI Committee. Perry Shen, M.D., Associate Professor of Surgical Oncology at Wake Forest University School of Medicine, has been appointed Vice Chair of the CALGB GI Committee.

Ann Partridge, M.D., M.P.H., Assistant Professor in Medicine at Harvard Medical School, has been appointed Vice Chair of the CALGB Cancer Control and Health Outcomes (CCHO) Committee.

Ethan Basch, M.D., Assistant Attending Physician at Memorial SloanKettering Cancer Center, has been appointed Chair of the CALGB CCHO Health Outcomes Subcommittee. Michelle Naughton, Ph.D., Professor of the Department of Social Services and Health Policy, Division of Public Health Sciences at Wake Forest University, has been appointed Vice Chair of the CCHO Health Outcomes Subcommittee. Eric Hsi, M.D., Section Head of Hematopathology and Professor of Pathology at the Cleveland Clinic Lerner College of Medicine, has been appointed Chair of the CALGB Pathology Committee. Wendy Frankel, M.D., Professor in the College of Medicine at The Ohio State University, has been appointed Vice Chair of the CALGB Pathology Committee. Blase Polite, M.D., Assistant Professor of Medicine at the University of Chicago, has been appointed Co-Chair of the CALGB Committee on Advocacy, Research Communication, Ethics and Disparities (CARE) Disparities Subcommittee. Deborah Collyar, CALGB Patient Advocate and Chair of CALGB CARE, has been appointed Co-Chair of the CALGB CARE Research Communication Subcommittee.

Institutional PIs David C. VanEcho, M.D., has been named Principal Investigator at Walter Reed Army Medical Center. Shubham Pant, M.D., has been named Principal Investigator at the University of Oklahoma. â&#x20AC;&#x201D; more GROUP NEWS, page 16


Cancer and Leukemia Group B Newsletter

CALGB GROUP NEWS STAFF UPDATES @ The Central Office Andrea Eiring, M.S.M., P.A., C.C.R.C., comes to the CALGB as the new Regulatory Affairs Manager. She is responsible for managing and implementing group-wide and study-specific regulatory requirements. She provides guidance to Institutional Review Boards (IRBs) on CALGB-related issues.

@ The Statistical Center As Senior Project Manager, Todd Crook brings a strong track record of leading global teams to develop streamlined solutions for highly complex problems to the CALGB Information Systems team. He oversees the ADOPT Program, which consists of five ongoing projects for integration of caBIG initiatives into the CALGB IT infrastructure, and coordinates interdepartmental functions to minimize delays. As Senior IT Analyst, Jason Yanoff maintains the CALGB network infrastructure, provides end user support, and makes technology recommendations to CALGB IS management. He brings to CALGB expertise in various computer and network systems such as LAN/WAN administration, Virtualization and SAN technology, and more recently worked as a systems administrator at the North Carolina State Board of Elections. As Instructional Media Designer, Stacy Brewer brings her training knowledge to CALGB and works to develop tools that ensure learners master the knowledge, skills or attitudes to achieve the criteria or standards necessary for proper task performance. She recently worked as an independent contractor in instructional technology.

AT-A-GLANCE Updated CALGB Committee Structure The CALGB disease committee members, under the direction of committee chairs, are responsible for the scientific activities of the Group. Committee members develop, review and submit to the CALGB Executive Committee study concepts for review and approval. They also develop protocols. The disease committees include: Breast, GI, GU, Leukemia, Lymphoma and Respiratory. The modality committees contribute to CALGB in a number of important ways. They provide expert advice to the disease committees regarding the appropriate application of treatments employed in the protocols; they serve as a focus for discussion of innovative treatments within the discipline and critically assess progress in the field that is relevant to the design of CALGB studies; they provide important quality assurance functions in areas such as central review of cytogenetics. Modality committees also conduct independent research programs. The modality committees of CALGB include: Cancer Control and Health Outcomes, Cancer in the Elderly, Imaging, Leukemia Correlative Sciences, Oncology Nursing, Pharmacology and Experimental Therapeutics (PET) and Transplant. Scientific Resource Committees provide expert advice to the disease committees regarding the appropriate application of treatments employed in the protocols; they serve as a focus for discussion of innovative treatments within the discipline and critically assess progress in the field which is relevant to the design of CALGB studies; they provide educational sessions at Group meetings on subjects of interest tot the membership. The Pathology and Radiation Oncology Committees provide important quality of control functions for the Group. Scientific Resource Committees are different from Modality Committees in that they do not sponsor research studies. The Scientific Resource Committees are: Clinical Research Associates (CRA), Committee on Advocacy, Research Communication, Disparities and Ethics (CARE), Pathology, Radiation Oncology and Surgery. Administrative Committees develop and implement many of the policies of the Group. These committee deal with areas such as membership, institutional performance, conflict of interest, etc., and include: Audit, Biospecimen and Correlative Sciences Advisory, Board of Directors, Executive Committee, CCOP Core, Conflict of Interest, Constitution, Data and Safety Monitoring Board (DSMB), Institutional Performance Evaluation (IPEC), Membership, Pharmacy, Radiation Oncology Quality Improvement and Surgery Quality Assurance (SQAC).

Summer 2010






40302—Endocrine therapy with or without inhibition of EGF and HER2 growth factor receptors: A randomized, double-blind, placebocontrolled phase III trial of fulvestrant with or without lapatinib (GW572016) for postmenopausal women with hormone receptor positive advanced breast cancer Study Chair: H. Burstein CTSU—IBCSG 24-02: A phase III trial evaluating the role of ovarian function suppression and the role of exemestane as adjuvant therapies for premenopausal women with endocrine responsive breast cancer Study Chair: G. Fleming CTSU—IBCSG 24-02/AN0701: Study of cognitive function in premenopausal women receiving adjuvant tamoxifen with or without ovarian function suppression for early-stage breast cancer on clinical trial IBCSG-2402 Study Chair: T. Ahles

CTSU—S0521: A randomized trial of maintenance versus observation for patients with previously untreated low and intermediate risk acute promyelocytic leukemia (APL), phase III Study Chair: B. Powell

CANCER IN THE ELDERLY COMMITTEE CLOSED 360401—Development of a geriatric assessment measure for older patients with cancer Study Chair: A. Hurria

GI COMMITTEE OPENED 80702—A phase II trial of 6 versus 12 treatments of adjuvant FOLFOX with or without celecoxib therapy for patients with stage III colon cancer Study Chair: J. Meyerhardt

CLOSED 80502—A phase II trial of irinotecan and AZD2171 (CALGB IND #101263) in patients with metastatic colorectal cancer after progression on first-line oxaliplatin, fluoropyrimidine and bevacizumab Study Chair: B. O’Neil

LEUKEMIA COMMITTEE SUSPENDED CTSU—S0535: Phase II study of ATRA, arsenic trioxide and gemtuzumab ozogamicin in patients with previously untreated highrisk acute promyelocytic leukemia Study Chair: D. DeAngelo

CLOSED 10502—Dose escalation and phase II study of bortezomib (IND #58443, NSC #681239) added to standard daunorubicin and cytarabine therapy for patients with previously untreated acute myeloid leukemia age 60-75 years Study Chair: E. Attar 10001—A phase II trial of sequential chemotherapy, imatinib mesylate (Gleevec, STI571) (NSC #716051, IND #61135), and transplantation for adults with newly diagnosed Ph+ acute lymphoblastic leukemia by the CALGB and SWOG Study Chair: M. Wetzler CTSU—E1A06: Melphalan, prednisone, and thalidomide or lenalidomide in treating patients with newly diagnosed multiple myeloma Study Chair: A. Chanan-Khan

LYMPHOMA COMMITTEE OPENED 50604—Phase II trial of response-adapted chemotherapy based on positron emission tomography for non-bulky stage I and II Hodgkin lymphoma Study Chair: D. Straus 50801—Phase II trial of response-adapted chemotherapy based on positron emission tomography (PET) for bulky stage I and II classical Hodgkin lymphoma (HL) Study Chair: A. LaCasce 50803—Phase II trial of rituximab + lenalidomide in previously untreated follicular non-Hodgkin’s lymphoma (NHL) Study Chair: R. Elstrom

CLOSED 50403—A randomized phase II trial of maintenance vs consolidation bortezomib therapy following aggressive chemo-immunotherapy and autologous stem cell transplant for previously untreated mantle cell lymphoma Study Chair: L. Kaplan

RESPIRATORY COMMITTEE OPENED CTSU—S0819: A randomized, phase III study comparing carboplatin/ paclitaxel or carboplatin/paclitaxel/bevacizumab with or without concurrent cetuximab in patients with advanced non-small cell lung cancer (NSCLC) Study Chair: M. Perry 30901—Randomized, phase II study of maintenance pemetrexed versus observation for patients with malignant pleural mesothelioma without progression after first-line chemotherapy Study Chair: A. Dudek 150809—Multi-analyte blood test validation for NSCLC Study Chair: J. Borgia

TRANSPLANT COMMITTEE OPENED CTSU—BMTCTN 0702: A trial of single autologous transplant with or without consolidation therapy versus tandem autologous transplant with lenalidomide maintenance for patients with multiple myeloma Study Chair: P. McCarthy 100601—Reduced-intensity allogenic hematopoietic cell transplantation as second transplantation for patients with disease relapse or myelodysplasia after prior autologous transplantation Study Chair: A. Bashey 100801—Phase II study of the addition azacytidine (NSC #102816) to reduced-intensity conditioning allogenic transplantation for myelodysplasia (MDS) and older patients with AML Study Chair: R. Vij


Cancer and Leukemia Group B Newsletter

CANCER IN THE ELDERLY continued from page 1 opportunities for developing clinical trials focused on cancer in the elderly.” The Working Group gave way to the Cancer in the Elderly Committee in 2002 after its initial success in developing clinical trials focused on older patients. Such trials included a PET Committee study of paclitaxel pharmacology in older patients (CALGB 9762), a phase III lymphoma trial evaluating the role of a unique antitumor antibody when added to chemotherapy and growth factors in patients 65 years and older (CALGB 9793), and a trial exploring the barriers to entry into clinical trials of older women with both earlyand late-stage breast cancer (CALGB 9670). Under the committee’s leadership, the CALGB received funding from the National Institute of Aging (NIA) and the National Cancer Institute (NCI) for studies on cancer in the elderly. Following the barriers to participation in clinical trials study (a study considered unique for a cooperative group because it addressed the issues of barriers to enrollment rather than treatment outcome), the committee conducted and published a randomized trial of an educational intervention designed to enhance accrual of older individuals to CALGB studies (360001). Flash-forward 15 years. CALGB has become a leader in studies of older patients with cancer – an important and largely understudied segment of the cancer patient population, according to Dr. Cohen, Director of the Center for the Study of Aging and Human Development at Duke University. In a seminal trial, it was established that breast radiation can be safely omitted in women age 70 and older with clinical node-negative, ER-positive breast cancer who receive adjuvant tamoxifen (CALGB 9343). This trial was followed with the largest study of adjuvant chemotherapy ever conducted in women age 65 or older with early stage breast cancer (CALGB 49907). The results clearly show that adjuvant capecitabine is inferior treatment compared to conventional adjuvant chemotherapy, particularly for women with ER-negative tumors. Quality of life, medication adherence and biological studies that are embedded in this study should yield extraordinarily rich data. A prospective registry study, coupled with CALGB 49907, has enrolled more than 1,500 women 65 or older with early-stage breast cancer (CALGB 369901). Considered a “patterns of care” study, CALGB 369901 will provide valuable insights into the management and outcomes of older breast cancer patients outside the clinical trials setting.

The CALGB Cancer in the Elderly Committee has also led the way in studies of drug pharmacology and tolerance in older patients and in the development of a novel brief geriatric assessment instrument to facilitate the clinical evaluation of older individuals (CALGB 360401). Both Drs. Cohen and Muss agree that cancer in the elderly is “a major problem confronting all heath care providers and will become an even more pressing problem as the population continues to age.” They also agree that the CALGB is well recognized and positioned as a significant force in advancing issues of concern regarding treatment of cancer in the elderly.

NIH, FDA to Collaborate on Fasttracking Innovations to the Public The U.S. Food and Drug Administration and the National Institutes of Health recently unveiled an initiative designed to accelerate the process from scientific breakthrough to the availability of new, innovative medical therapies for patients. The initiative involves two interrelated scientific disciplines: translational science, the shaping of basic scientific discoveries into treatments; and regulatory science, the development and use of new tools, standards and approaches to more efficiently develop products and to more effectively evaluate product safety, efficacy and quality. Both disciplines are needed to turn biomedical discoveries into products that benefit people. As part of the effort, the agencies will establish a Joint NIH-FDA Leadership Council to spearhead collaborative work on important public health issues. The Joint Leadership Council will work together to help ensure that regulatory considerations form an integral component of biomedical research planning, and that the latest science is integrated into the regulatory review process. In addition, the NIH and the FDA have jointly issued a Request for Applications, making $6.75 million dollars available over three years for work in regulatory science. The research supported through this initiative should add to the scientific knowledge base by providing new methods, models or technologies that will inform the scientific and regulatory community about better approaches to evaluating safety and efficacy in medical product development.

Summer 2010


SUPPORT The following organizations provided support to Cancer and Leukemia Group B research and educational programs in 2010. Abbott Laboratories Amgen, Inc. Breast Cancer Research Foundation Bristol-Myers Squibb Oncology Eisai, Inc.

Genentech BioOncology Millennium Pharmaceuticals Network for Good Novartis Oncology OSI Pharmaceuticals

Otsuka Pharmaceuticals Pfizer, Inc. Sanofi-Aventis Sigma-Tau Pharmaceuticals

2010 Cancer and Leukemia Group B Meetings

Fall Committee Meeting* September 23-25 Hilton Chicago Oâ&#x20AC;&#x2122;Hare Airport Chicago, IL * Closed meetings open to Cadre members of committee or invited guests.

Fall Group Meeting November 11-13 The Intercontinental Miami Miami, FL

support cancer research give to the

Cancer and Leukemia Group B Foundation The Cancer and Leukemia Group B Foundation, a nonprofit, tax-exempt foundation that raises funds to help the Cancer and Leukemia Group B (CALGB) answer important cancer research questions through large-scale clinical trials. CALGB is a cooperative group comprising 25 of the nation’s most prestigious medical centers, 200-plus affiliated institutions and 3,000 medical oncologists and specialists working together to reduce morbidity and mortality from cancer by developing new strategies for the early detection, treatment and prevention of cancer. By supporting CALGB clinical trials and laboratory research through the CALGB Foundation, you can help find new ways to prevent, treat and cure many types of cancer, including leukemia and lymphoma, and cancers of the breast, prostate, lung and GI tract. Gifts to the Foundation may be designated according to your wishes, and are tax-deductible to the extent permitted by law. Here are some recent initiatives supported by the CALGB Foundation: • New chemotherapy treatments for breast, prostate, lung and colorectal cancer. • New surgical techniques for breast and colon cancer. • Genetic studies of breast cancer risk. • Molecular determinants of response to therapy for breast, colorectal and lung cancers, and leukemia. • Research that improves the quality of life for cancer patients and their caregivers. Yes! I want to support the Cancer and Leukemia Group B. Enclosed is my/our contribution of $ ___________ to support the research of the Cancer and Leukemia Group B. ❒ In Memory of ____________________________________

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Quarterly CALGB Newsletter, Summer 2010