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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Indolent Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Biological: Arm A: Rituximab
* Biological: Arm B: GA101


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Registration: Patients having both diffuse and follicular architectural elements will be considered eligible if the histology is predominantly follicular (≥ 50% of the cross-sectional area), and there is no evidence of transformation to a large cell histology. Biopsy-proven diagnosis of Grade 1 or 2 follicular non-Hodgkin's lymphoma with no evidence of transformation to large cell histology. Meet criteria for Low Tumor Burden: No nodal or extra nodal mass ≥ 7 centimeter (cm) <3 nodal masses >3 cm in diameter No systemic symptoms or B symptoms No splenomegaly >16 cm by CT scan No risk of compression of a vital organ. No leukemic phase with >5000/mm³ circulating lymphocytes. No cytopenias defined as: Platelets <100,000/mm³ Hemoglobin (Hgb) <10 g/dL Absolute Neutrophil Count (ANC) <1500/mm³ Must have Stage III or Stage IV disease. Baseline measurements/evaluations obtained within 6 weeks of registration. Patient must have at least one objective measurable disease parameter. Age ≥ 18 years. Eastern Oncology Cooperative Group Performance Status 0-1. Must not have received investigational agents within 30 days of registration. Signed Institutional Review Board (IRB)-approved informed consent. Willing to provide blood samples for research purposes. Women must not be pregnant or breastfeeding. Women of childbearing potential and sexually active males must use an accepted and effective method of contraception. No prior chemotherapy, radiotherapy or immunotherapy for lymphoma. No prior treatment with cytotoxic drugs or rituximab for a previous cancer or another condition (e.g. rheumatoid arthritis) or prior use of an anti-CD20 antibody. No prior use of any monoclonal antibody within 3 months of randomization. No history of severe allergic/anaphylactic reactions to humanized/murine monoclonal antibodies or known sensitivity/allergy to murine products. No history of prior malignancy except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for at least 2 years and did not require treatment with cytotoxic drugs or rituximab. No major surgery within 4 weeks prior to randomization, other than for diagnosis. Must be Human Immunodeficiency Virus (HIV) negative. Have adequate organ function without growth factor and/or transfusion support within ≤ 2 weeks prior to registration: ANC ≥ 1500/mm³ Hgb ≥ 10 g/dL Platelets ≥ 100,000/mm³ Serum Creatinine ≤ 2x Upper Limit Normal (ULN) Total Bilirubin ≤ 2x ULN AST (aspartate aminotransferase)/ALT (alanine aminotransferase) ≤ 5x ULN PTT (Partial Thromboplastin Time) or aPTT (activated Partial Thromboplastin Time) >1.5x the ULN in the absence of a lupus anticoagulant INR (International Normalized Ratio) >1.5x the ULN in the absence of therapeutic anticoagulation No active, uncontrolled infections (afebrile for ≥ 48 hours off antibiotics). Must not receive immunization with attenuated live vaccines within 28 days prior to registration or during the study period. Must be tested for hepatitis B surface antigen (HBsAg) and total hepatitis B core antibody (anti-HBc) within 2 weeks of registration. Patients who are chronic carriers of HBsAg and anti-HBc are excluded. Must be tested for hepatitis C antibody within 2 week of registration. If this test is positive, patients are excluded unless a hepatitis C virus ribonucleic acid (HCV RNA) is negative. No evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (i.e., severe arrhythmia, myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A: Rituximab<br>Rituximab 375 mg/m² IV weekly for 4 weeks. | Biological: Arm A: Rituximab<br>* Rituximab 375 mg/m² IV x 4 weekly doses.<br>* Other names: NSC# 687451;|
| Experimental: Arm B: GA101<br>GA101 1,000 mg IV weekly for 4 weeks. | Biological: Arm B: GA101<br>* GA101 1,000 mg (flat dose) IV x 4 weekly doses.<br>* Other names: huMAB<CD20>;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) Rate | 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. | Re-staging (week 12, 13 or 14) and during follow-up if physician feels patient is subsequently in CR for up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PET Response Rate | PET response rate [PET-documented CR + Partial Response (PR)] based on PET scan results. Patients with unevaluable disease were included in the denominator. | Re-staging (week 12, 13 or 14) | 
| Overall Response Rate | 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. | Baseline and Re-staging (week 12, 13 or 14) | 
| Progression Free Survival (PFS) | 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. | Percent of participants alive and progression-free at 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Untreated Non-Hodgkin's Lymphoma, Low Tumor Burden Non-Hodgkin's Lymphoma, NHL, Indolent, Rituximab, Rituxan, GA101, Obinutuzumab