Neoplasms

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Rare Diseases

Lymphoma

Lymphoma, Non-Hodgkin

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

All Drugs and Chemicals

Antineoplastic Agents

Antirheumatic Agents

Antibodies

Antibodies, Monoclonal

Obinutuzumab

Rituximab

Immunoglobulins

Antineoplastic Agents, Immunological

Immunologic Factors

Rituximab 375 mg/m² IV weekly for 4 weeks.

Rituximab 375 mg/m² IV x 4 weekly doses.

Arm A: Rituximab

GA101 1,000 mg (flat dose) IV x 4 weekly doses.

Arm B: GA101

Stephen Ansell, MD

Patients with previously untreated low tumor burden indolent Non-Hodgkin's Lymphoma (NHL) will receive either rituximab or GA101 weekly for 4 weeks followed by re-staging to determine response.

Rituximab, an anti-CD20 chimeric antibody, was approved by the United States Food and Drug Administration in 1998 for the treatment of patients with relapsed low-grade B-cell lymphomas. Clinically, four weekly doses of rituximab have proven to be well tolerated and effective in previously untreated as well as relapsed patients with low-grade lymphoma.

GA101 is an anti-CD20 humanized and glyco-engineered monoclonal antibody. GA101 has been shown to have increased antibody-dependent cellular cytotoxicity (ADCC) and direct cell-death induction compared to Rituximab. It is possible that GA101 may have greater efficacy than rituximab.

PrE0401 Sub-Study Evaluation of Corrected QT (QTc) Interval and Pharmacokinetic Parameters in Patients Participating in GA101 (Obinutuzumab)

Approximately twenty-five patients randomized to GA101 may participate in the sub-study. Electrocardiograms and blood samples will be obtained.

According to the American Cancer Society, it is estimated that approximately 70,800 individuals will be diagnosed with non-Hodgkin's lymphoma (NHL) and over 18,990 men and women will die of the disease in 2014. 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 cells.

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.

Phase II Randomized Trial Comparing GA101 and Rituximab in Untreated Low Tumor Burden Indolent Non-Hodgkin's Lymphoma

Phase II Randomized Trial Comparing GA101 (Obinutuzumab) and Rituximab in Patients With Previously Untreated Low Tumor Burden Indolent Non-Hodgkin's Lymphoma

Positron Emission Tomography (PET)-documented CR rates after induction therapy (weekly treatment x 4 weeks with GA101 or rituximab)

Definitions for clinical response are modified from the Revised Response Criteria for Malignant Lymphoma (Cheson BD, et al. Revised Response Criteria for Malignant Lymphoma. J Clin Oncol 2007; 25(5): 579-86). Lymph node measurements were taken from CT, CT portion of the PET/CT, or MRI scans where applicable. CR is defined as complete disappearance of all evidence of disease; PR as a \>50% decrease in the sum of the products of the maximal perpendicular diameters of measured lesions (SPD) and no new sites; SD as failure to attain CR/PR or PD; and PD as any new lesion \>1.5cm in any axis or ≥50% increase in previously involved sites.

PET response rate \[PET-documented CR + Partial Response (PR)\] based on PET scan results. Patients with unevaluable disease were included in the denominator.

Overall response rate (CR + PR by Cheson criteria) at re-staging (including bone marrow biopsy if CR suspected) by PET and Neck, Chest, Abdomen and Pelvic Computed Tomography (CT) scan. Patients with unevaluable disease were included in the denominator.

CT scan every 3 months for 2 years, then every 6 months until progression. Compare PFS in each treatment arm.

Progressive disease (PD) was defined using Cheson criteria as described in the Primary Outcome section above. Progression-free survival (PFS) was defined as the time from start of treatment to the documentation of PD or death, whichever occurs first. Patients alive and without PD were censored at the date of last disease assessment.

Genentech, Inc.

PrECOG, LLC.

Adverse events were assessed weekly, prior to and during administration of study drug.

Rituximab 375 mg/m² IV weekly for 4 weeks.

Arm A: Rituximab: Rituximab 375 mg/m² IV x 4 weekly doses.

GA101 1,000 mg IV weekly for 4 weeks.

Arm B: GA101: GA101 1,000 mg (flat dose) IV x 4 weekly doses.

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

PS 0

PS 1

The ECOG performance status (PS) measures how a disease impacts a patient's daily living abilities. It describes a patient's level of functioning in terms of their ability to care for themselves, daily \& physical abilities. The PS score ranges from 0 to 5. A PS score of 0 indicates that a patient is fully active \& able to carry out all pre-disease performance without restriction; 1 indicates that a patient is restricted in performance; 2 indicates ambulatory; \& at the extreme, 5 indicates a patient is deceased. High score indicates the disease has a higher negative impact on living abilities.

ECOG Performance Status

Stage III (1)

Stage III (2)

Stage IV

The Ann Arbor staging is used to describe the extent of non-Hodgkin lymphoma (NHL) in adults. There are 4 levels of the Ann Arbor staging system. Stage I means the lymphoma is only in 1 lymph node area or lymphoid organ; II indicates 2 or more groups of lymph nodes on the same side of the diaphragm; III indicates disease is present in lymph node areas on both sides of the diaphragm and may have spread to other organs; and IV shows that disease has spread outside the lymph system and also to the bone marrow, liver, brain, spinal cord or lungs. Higher grades are considered as worse.

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