Phase II Randomized Trial Comparing GA101 (Obinutuzumab) and Rituximab in Patients With Previously Untreated Low Tumor Burden Indolent Non-Hodgkin's Lymphoma
According to the American Cancer Society, it is estimated that approximately 66,000
individuals were diagnosed with non-Hodgkin's lymphoma (NHL) and over 19,000 men and women
died of the disease in 2010. The survival rates for patients with indolent NHL remained
unchanged from the 1950s through the early 1990s, but recent evidence suggests that outcomes
are improving. Indolent NHL is a particular challenge because it is an incurable disease
requiring multiple treatments; yet relatively long survivals elevate the importance of
quality of life associated with treatment.
Agents such as rituximab are active in patients with a low burden of disease and result in
high response rates and durable remissions for most patients. However, the optimal
therapeutic approach to patients with low-grade lymphoma with a low disease burden is
controversial as conventional chemotherapy also results in high rates of response.
Regardless of whether patients receive immunotherapy, chemotherapy, or a combination
thereof, they unfortunately exhibit a continuing pattern of disease relapse and the median
survival for newly diagnosed patients is between 7-10 years.
Rituximab and GA101 both target the CD20 antigen. The CD20 antigen is located on the surface
of normal and malignant B-cell lymphocytes. An attractive feature of this target is that
CD20 is not on hematopoietic stem cells, nor is it expressed in any great extent on other
normal body tissues.
Studies in vitro have shown that rituximab predominantly induces antibody dependent cellular
cytotoxicity (ADCC), but also binds complement and directly induces apoptosis in lymphoma
GA101 shows increased ADCC related to an improved binding of the GA101 to the different
allotypes expressed by natural killer cells and monocytes. It also has increased direct
cell-death related to an elbow hinge amino acid exchange and Type II binding of the CD20
epitope. The safety of GA101 in NHL so far appears to be similar to that observed with
rituximab in patients with NHL, except for a higher incidence of infusion-related reactions.
Depletion of malignant B-cells using anti-CD20 monoclonal antibodies has an acceptable
safety profile, particularly in patients with low-grade B-cell lymphomas with a low disease
burden. To determine whether treatment with GA101 results in better outcomes than that seen
with rituximab and to determine which anti-CD20 antibody to utilize in future studies, we
will conduct a randomized Phase II trial of rituximab and GA101 in patients with previously
untreated low-grade lymphoma. Patients will receive either rituximab or GA101 weekly for 4
weeks followed by re-staging. The endpoints of the study will be the Complete Response (CR),
Overall Response Rate (ORR), time to next treatment, progression free survival (PFS), and
safety of each treatment arm.
PrE0401 Sub-Study Evaluation of Corrected QT (QTc) Interval and Pharmacokinetic Parameters
in Patients Participating in GA101 (Obinutuzumab)
Patients randomized to GA101 and who consent to the sub-study will have electrocardiograms
obtained pre and post Week 1 and Week 4 to investigate the effect of GA101 on QTc interval.
Pharmacokinetic blood samples will also be done to evaluate serum concentrations of GA101 at
the same time-points.
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Complete Response (CR) Rate
Positron Emission Tomography (PET)-documented CR rates after induction therapy (weekly treatment x 4 weeks with GA101 or rituximab)
Re-staging (week 12, 13 or 14) and during follow-up if physician feels patient is subsequently in CR for up to 4 years
Stephen Ansell, MD
Mayo Clinic in Minnesota
United States: Food and Drug Administration