Phase II Randomized Trial Comparing GA101 and Rituximab in Untreated Low Tumor Burden Indolent Non-Hodgkin's Lymphoma (PrE0401)

March 23, 2017 updated by: PrECOG, LLC.

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

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

32

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Alabama
      • Mobile, Alabama, United States, 36604
        • University of South Alabama
    • California
      • Greenbrae, California, United States, 94904
        • Marin Cancer Care
    • Georgia
      • Savannah, Georgia, United States, 31405
        • St. Joseph's/Candler Health System
    • Illinois
      • Decatur, Illinois, United States, 62526
        • Decatur Memorial Hospital
      • Urbana, Illinois, United States, 61801
        • Carle Cancer Center
    • Indiana
      • Indianapolis, Indiana, United States, 46202
        • Indiana University
    • Iowa
      • Sioux City, Iowa, United States, 51101
        • Siouxland Hematology Oncology Associates
    • Louisiana
      • New Orleans, Louisiana, United States, 70121
        • Ochsner Cancer Institute
    • Maryland
      • Baltimore, Maryland, United States, 21204
        • Greater Baltimore Medical Center
    • Massachusetts
      • Boston, Massachusetts, United States, 02111
        • Tufts Medical Center
    • Michigan
      • Ann Arbor, Michigan, United States, 48106
        • St. Joseph Mercy Health System
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Mayo Clinic
      • St. Louis Park, Minnesota, United States, 55416
        • Metro MN CCOP
    • Nebraska
      • Omaha, Nebraska, United States, 68106
        • Missouri Valley Cancer Consortium
    • New York
      • Bronx, New York, United States, 10467
        • Montefiore Medical Center
    • Ohio
      • Canton, Ohio, United States, 44710
        • Aultman Hospital
      • Cleveland, Ohio, United States, 44106
        • University Hospitals Case Medical Center
      • Toledo, Ohio, United States, 43617
        • Toledo Community Oncology Program
    • Pennsylvania
      • Danville, Pennsylvania, United States, 17822
        • Geisinger Medical Center
      • Philadelphia, Pennsylvania, United States, 19111
        • Fox Chase Cancer Center
      • West Reading, Pennsylvania, United States, 19611
        • Reading Hospital
      • Williamsport, Pennsylvania, United States, 17701
        • Susquehanna Health Cancer Center
    • Virginia
      • Charlottesburg, Virginia, United States, 22908
        • University of Virginia
    • West Virginia
      • Charleston, West Virginia, United States, 25304
        • Charleston Area Medical Center (CAMC)
    • Wisconsin
      • La Crosse, Wisconsin, United States, 54601
        • Gundersen Health System
      • Madison, Wisconsin, United States, 53717
        • Dean Clinic
      • Waukesha, Wisconsin, United States, 53188
        • ProHealth Care, Inc.
      • Wauwatosa, Wisconsin, United States, 53266
        • Aurora Health Care

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Arm A: Rituximab
Rituximab 375 mg/m² IV weekly for 4 weeks.
Biological: Arm A: Rituximab
Rituximab 375 mg/m² IV x 4 weekly doses.
Other Names:
  • Rituxan
  • IDEC-C2B8
  • Chimeric anti-CD20 monoclonal antibody
  • NSC# 687451
Experimental: Arm B: GA101
GA101 1,000 mg IV weekly for 4 weeks.
Biological: Arm B: GA101
GA101 1,000 mg (flat dose) IV x 4 weekly doses.
Other Names:
  • RO5072759
  • Obinutuzumab
  • huMAB

What is the study measuring?

Primary Outcome Measures

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

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
Time Frame: Re-staging (week 12, 13 or 14)
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
Time Frame: Baseline and Re-staging (week 12, 13 or 14)
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)
Time Frame: Percent of participants alive and progression-free at 1 year

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

PrECOG, LLC.

Collaborators

Genentech, Inc.

Investigators

  • Study Chair: Stephen Ansell, MD, Mayo Clinic in Minnesota

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 2013

Primary Completion (Actual)

April 1, 2016

Study Completion (Actual)

August 1, 2016

Study Registration Dates

First Submitted

June 26, 2013

First Submitted That Met QC Criteria

June 26, 2013

First Posted (Estimate)

June 28, 2013

Study Record Updates

Last Update Posted (Actual)

May 5, 2017

Last Update Submitted That Met QC Criteria

March 23, 2017

Last Verified

March 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PrE0401
  • BO25454 (Other Grant/Funding Number: Genentech)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

IPD Plan Description

Data is proprietary.

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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