NE Oncology Issue – February 2014

Offner F, et al. iwCLL 2013:4.29

Background

Ofatumumab is currently approved for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab. In vitro experiments with ofatumumab and bendamustine have shown synergistic anti-tumour activity when both agents are used together compared with the individual agents used alone. Study OMB115991 was designed to investigate the safety and efficacy of ofatumumab plus bendamustine in two populations: patients with untreated CLL who were unfit for fludarabine-based therapy and patients with relapsed CLL.1

Study design

  • Study OMB115991 was a phase II, open-label, single-arm, multicentre study.
  • The primary outcome was overall response rate (ORR) as determined by investigator evaluation, according to the 2008 National Cancer Institute Working Group guidelines.
  • Secondary outcomes included complete response (CR) rate, safety, and tolerability.
  • Patients received pre-medications of acetaminophen (1,000 mg or equivalent), an antihistamine (50 mg diphenhydramine or equivalent), and a glucocorticoid (equivalent to 50 mg prednisolone) prior to ofatumumab therapy.
  • Patients received monthly intravenous infusions of ofatumumab (cycle 1: 300 mg on day 1 and 1,000 mg on day 8; cycles 2-6: 1,000 mg on day 1 every 28 days) in combination with bendamustine on days 1 and 2, every 28 days for up to six cycles.
  • Patients with previously untreated CLL received an initial bendamustine dose of 90 mg/m2. Patients with relapsed CLL received an initial dose of 70 mg/m2.
    • A dose reduction of bendamustine, but not ofatumumab, was required for toxicity. Previously untreated patients required a bendamustine dose reduction to 60 mg/m2 and relapsed patients required a reduction to 50 mg/m2.
  • Patients were evaluated for response and safety at the start of each cycle of treatment and at every three-month follow-up visit until progression, or until three years after the last dose of study treatment.

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Key findings

Patient characteristics

  • The study enrolled a total of 97 patients: 44 patients with previously untreated CLL and 53 patients with relapsed CLL.
  • The median ages of patients in the previously untreated and relapsed groups were 62.5 and 68.0 years, respectively.
  • Patients in the relapsed group had received a median of one prior therapy.
  • Disease characteristics for each group were as follows (previously
    untreated/relapsed):

    • Modified high-risk Rai stage: 32%/57%;
    • Binet stage C: 27%/47%;
    • Median serum β2-microglobulin (mg/L): 3.6/4.8;
    • Median lymphocyte count (GI/L): 67.6/50.0;
    • 17p deletion: 5%/12%;
    • 11q deletion: 18%/29%;
    • Immunoglobulin heavy chain variable region (IgHV) unmutated: 66%/72%;
    • Zeta-chain-associated protein kinase 70 (ZAP70) positive: 82%/85%;
  • The majority of patients completed all six treatment cycles (previously untreated: 89%; relapsed: 85%).

Efficacy

  • Investigator-assessed ORRs were 95% (CR = 43%) in the previously untreated population and 74% (CR = 11%) in the relapsed population. (Table 1)
    • By computed tomography evaluation, ORR was 82% (CR = 27%) in the previously untreated population and 70% (CR = 9%) in the relapsed population.
  • For the patients who had an investigator-assessed CR and had minimal residual disease (MRD) analysis performed, MRD negativity was 56% for the previously untreated population and 0% for the relapsed population.
  • The median time to response was 0.95 months for both groups.
  • As of the data cutoff (Feb. 28, 2013), the following end points of duration of response, progression-free survival (PFS), time to progression, overall survival (OS), and time to next therapy were not yet mature.

Safety

  • Adverse events (AEs) classified as grade ≥3 included neutropenia (previously untreated group: n = 16 and relapsed group: n = 29), rash (previously untreated group: n = 2), and thrombocytopenia (relapsed group: n = 4). (Table 2)
  • No deaths occurred in the previously untreated group, and four deaths occurred in the relapsed group, two of which were considered by the investigators to be possibly related to study treatment:
    • One patient died of pneumonia and hemolytic anemia 15 days after the latest dose of study treatment;
    • One patient died of sepsis four days after the latest dose of study treatment.
  • The most frequently reported infections were upper respiratory tract infections (20% of previously untreated patients and 15% of relapsed patients), and lower respiratory tract infections (16% of previously untreated patients and 19% of relapsed patients).
  • Grade ≥3 infections occurred in 11% and 15% of previously untreated and relapsed patients, respectively.
  • In the relapsed group, three patients had serious AEs of infection that were fatal.
  • Infusion reactions occurred in 68% of previously untreated patients and 60% of relapsed patients. Infusion reactions occurred primarily during cycles 1 and 2 and were generally considered mild to moderate. (Figures 1 & 2)
  • Grade ≥3 infusion reactions occurred in 11% of previously
    untreated patients and 8% of relapsed patients. (Figures 1 & 2)

    • Two patients from the previously untreated study population were discontinued from further study treatment due to infusion reactions (delayed type hypersensitivity reaction and anaphylaxis).

Key conclusions

  • Ofatumumab in combination with bendamustine is an effective and tolerable therapy, providing high response rates and an acceptable safety profile for patients with previously untreated CLL who are unfit for fludarabine-based therapy and for patients with relapsed CLL.
  • Longer follow-up is required to determine time-to-event end points such as PFS and OS.

Reference: 1. Offner F, Panagiotidis P, Afanasyev B, et al. Ofatumumab and bendamustine combination therapy in patients with untreated and relapsed chronic lymphocytic leukemia: initial results of the phase II study OMB115991. XV iwCLL Abstracts 2013:4.29.

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Spotlight Article

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Carolyn Owen, MD

Dr. Carolyn Owen completed postgraduate training in internal medicine and hematology at the University of Ottawa and the University of British Columbia, respectively, followed by a research fellowship in molecular genetics at Barts and the London School of Medicine and Dentistry in London, UK. Her research focused on familial myelodysplasia and acute myeloid leukemia. She is currently an Assistant Professor at the Foothills Medical Centre & Tom Baker Cancer Centre, and her clinical interests are low-grade lymphoma and chronic lymphocytic leukemia. She is also the local principal investigator in Calgary for several clinical trials in these areas.

 

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Laurie H. Sehn, MD, MPH
Dr. Laurie H. Sehn is a Clinical Assistant Professor at the BC Cancer Agency and the University of British Columbia in Vancouver. She has been a medical oncologist and clinical investigator with the Lymphoma Tumour Group since 1998. Dr. Sehn has served on the Board of Directors of Lymphoma Foundation Canada (LFC) since 2002 and is currently Director of Research Fellowships for the LFC. Dr. Sehn’s research interests include all of the lymphoid cancers, with particular interest in the biology and treatment of large-cell lymphoma, the application of new imaging techniques such as PET scanning to lymphoma management, and innovative new approaches to treatment.

Canadian Perspective

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Matthew Seftel, MBChB, MPH, MRCP(U.K.), FRCPC

Dr. Seftel is a hematologist/oncologist based at Princess Margaret Hospital in Toronto. He is a member of the Leukemia Group and leads the Allogeneic Blood and Marrow Transplantation Program. He is an Associate Professor at the University of Toronto in the Division of Internal Medicine. He is actively involved in clinical trials and outcomes-based research related to hematological malignancies and blood and marrow transplantation.

Investigator Commentary

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Sunil Verma, MD, MSEd, FRCPC

Dr. Sunil Verma is a medical oncologist and the Chair of Breast Medical Oncology at the Sunnybrook Odette Cancer Centre in Toronto, Ontario. He is also an Associate Professor at the University of Toronto. Dr. Verma completed his medical degree and postgraduate training in internal medicine and medical oncology at the University of Alberta. He completed a fellowship in breast cancer at the University of Toronto and a master’s degree in medical education at the University of Southern California. Dr. Verma is internationally recognized for his educational leadership and research in breast and lung cancers. He has led and created numerous innovative educational projects in oncology and won several teaching and mentoring awards. Dr. Verma’s research interests include reducing the toxicity of systemic treatment, developing novel therapies for breast and lung cancers, and medical education. He is the principal investigator for many clinical trials in breast and lung cancers, including an international phase III trial in breast cancer, and has authored or co-authored articles appearing in publications such as the Journal of Clinical Oncology, Cancer, The Oncologist, Lancet Oncology, Lancet, and The New England Journal of Medicine.