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
LONDON, PHILADELPHIA, 8 February 2008-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]
About ofatumumab
Ofatumumab is being developed for the treatment of a number of
serious conditions including chronic lymphocytic leukaemia, diffuse
large B-cell lymphoma, (the most common sub-type of
non-Hodgkin’s lymphoma in the Western world), follicular
lymphoma (the second most common sub-type of non-Hodgkin’s
lymphoma), rheumatoid arthritis and multiple sclerosis. Ofatumumab
will be studied further in ongoing clinical trials.2
GlaxoSmithKline and Genmab A/S have a worldwide agreement to co-develop ofatumumab.
GSK in oncology
GSK Oncology is dedicated to producing innovations in cancer that
will make profound differences in the lives of patients. Through
GSK’s revolutionary “bench to bedside” approach,
we are transforming the way treatments are discovered and
developed, resulting in one of the most robust pipelines in the
oncology sector. Our worldwide research in oncology includes
partnerships with more than 160 cancer centres. GSK is closing in
on cancer from all sides with a new generation of patient focused
cancer treatments in prevention, supportive care, chemotherapy, and
targeted therapies.
About GlaxoSmithKline
GlaxoSmithKline – one of the world's leading research-based
pharmaceutical and healthcare companies – is committed to
improving the quality of human life by enabling people to do more,
feel better, and live longer. For company information, visit
GlaxoSmithKline at www.gsk.com.
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References
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[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.
Posted: February 2008
