Novel anti-CD20 monoclonal antibody ofatumumab demonstrates anti-tumour responses in patients with relapsed/refractory B-cell chronic lymphocytic leukaemia

Phase I/II study published in Blood

Data from a Phase I/II study of the novel antiCD20 monoclonal antibody, ofatumumab (formerly HuMax-CD20) in patients with relapsed or refractory B-cell chronic lymphocytic leukaemia (CLL) demonstrate anti-tumour responses in half of the patients treated in one of the three cohorts.[1] The study is published in the February issue of the journal Blood. Ofatumumab is being co-developed by GlaxoSmithKline (GSK) and Genmab A/S and has not received regulatory approval in any market for any indication at this time.

“Almost all patients with CLL experience disease progression after initial therapy, and currently there are limited therapeutic options for this group,” said Professor Bertrand Coiffier, Head of Haematology Department, Centre Hospitalier Universitaire de Lyon, France and lead investigator in the trial. “These early clinical data on ofatumumab are encouraging, with responses seen in half of the patients treated in the highest cohort.”

Ofatumumab is a unique investigational monoclonal antibody (MAb) that targets a distinct antibody binding site (the small loop epitope) of the CD20 molecule on the cell membrane of B cells.[2] This is a different binding site from approved antiCD20 monoclonal antibodies and it is closer to the cell membrane.[3] The CD20 molecule is a key target in CLL therapy because it is expressed in most cancers affecting the B cell.[4]

“CLL is a common but very serious form of leukaemia. Any hope for an effective new therapy may bring promise to those affected by the disease,” said Paolo Paoletti, MD, Senior Vice President, Oncology Medicine Development Centre, GSK. “We are very excited by these data and the potential that ofatumumab has shown to date in treating patients with relapsed or refractory CLL.”

CLL is the most common type of leukaemia and one of the most common malignant lymphoid diseases in the western world.[5] Globally, leukaemia, in all of its forms, accounts for approximately 300,000 new cases each year (2.8% of all new cancer cases) and 222,000 deaths.[6]

Efficacy results1
The primary efficacy endpoint of this study was objective tumour response over the period from screening to week 19. Fifty percent (95% Confidence Interval:30-70%) of patients (N=27) in cohort C experienced remission. Specifically, 12 of these patients had partial remission and one patient had a nodular partial remission. In the study, four weeks after beginning treatment, 62% of patients (N=32) obtained objective response as evaluated by physical examination and peripheral blood. On average, patients achieved an average progression-free survival of 106 days and an average time to next treatment of one year.

Safety Results1
Of the 33 patients enrolled in the study, 32 received four infusions as per the study protocol. One patient withdrew because of a serious adverse event (SAE) the day after the first infusion (cytolytic hepatitis, Grade 3). Twenty seven patients experienced 246 adverse events (AEs) of which 92% were mild (Grade 1-2: transient rigors, pyrexia, fatigue, rash, and increased sweating) and 61% were assessed as related to treatment. Ten of the AEs (reported by nine patients) were serious and included neutropenia, sinusitis, cytolytic hepatitis and infectious interstitial lung disease.

Infections were reported in 51% of patients, with the most frequently observed infection being nasopharyngitis (common cold) and all but one patient recovered within a month. The majority of the infections were Grade 1 or 2. Grade 3 adverse events were herpes zoster (SAE), nasopharyngitis, and pneumonia (SAE); one SAE was fatal (infectious interstitial lung disease).

Study Design1
The study was an international, multi-centre, open-label, dose escalating Phase I/II trial with the primary objective of evaluating the safety and efficacy of ofatumumab in patients with refractory or relapsed CLL. Thirty three CLL patients were divided into three cohorts of 3 (A), 3 (B), and 27 (C) and received four, once-weekly infusions of ofatumumab at the following doses: A 1x100mg + 3x500mg; B 1x300mg + 3x1000mg and C 1x500mg + 3x2000mg. The primary efficacy variable was objective tumour response over the period from screening to week 19 and was reported according to the National Cancer Institute (NCI) Working Group (WG) 1988 and 1996 criteria as complete remission (CR), nodular partial remission (nPR), partial remission (PR), progressive disease (PD), stable disease (SD), and non-evaluable patients (NE). Overall tumour response was assessed on data from physical examinations and evaluation of the peripheral blood and bone marrow as defined by the NCI WG Guidelines in CLL.[7],[8]
References

[1] Coiffier, B., Lepretre, S., Pedersen, M.L., et al. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia. A Phase I-II study. Blood 2007; 111/3/1094

[2] GSK data on file

[3] Teeling, J,L., Mackus, W,J., et al. The Biological Activity of Human CD20 Monoclonal Antibodies Is Linked to Unique Epitopes on CD20. J Immunol 2006; 177: 362-371

[4] Glennie, M,J., French, R,R., et al. Mechanisms of killing by anti-CD20 monoclonal antibodies. Molecular Immunology, 2007;44 (16):3823-3837

[5] Shanafelt TD., Byrd JC., et al. Narrative review: initial management of newly diagnosed, early-stage chronic lymphocytic leukemia. Ann Intern Med. 2006 Sep 19;145(6):435-47.

[6] Parkin, D. M., Bray F., et al. Global Cancer Statistics, 2002. CA Cancer J Clin 2005; 55:74-108

[7] Cheson, B.D., Bennett, J.M., Rai, K.R., et al. Guidelines for clinical protocols for chronic lymphocytic leukemia: recommendations of the National Cancer Institute-sponsored working group. Am J Hematol. 1988;29:152-163.

[8] Cheson, B. D., Bennett, J.M., Grever, M., et al. National Cancer Institute-Sponsored Working Group Guidelines For Chronic Lymphocytic Leukemia - Revised Guidelines For Diagnosis and Treatment. Blood. 1996;87:4990-4997.
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