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

Indolent Non-Hodgkin's Lymphoma Clinical Trial

— PrE0401  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01889797
• Other study ID #: PrE0401
• Secondary ID: BO25454
• Status: Completed
• Phase: Phase 2
• First received: June 26, 2013
• Last updated: August 3, 2016
• Start date: December 2013
• Est. completion date: August 2016

Study information

• Verified date: August 2016
• Source: PrECOG, LLC.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 32
• Est. completion date: August 2016
• Est. primary completion date: April 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Indolent Non-Hodgkin's Lymphoma
• Lymphoma
• Lymphoma, Non-Hodgkin

Intervention

Biological:
• Arm A: Rituximab
Rituximab 375 mg/m² IV x 4 weekly doses.
• Arm B: GA101
GA101 1,000 mg (flat dose) IV x 4 weekly doses.

Locations

Country	Name	City	State
United States	St. Joseph Mercy Health System	Ann Arbor	Michigan
United States	Greater Baltimore Medical Center	Baltimore	Maryland
United States	Tufts Medical Center	Boston	Massachusetts
United States	Montefiore Medical Center	Bronx	New York
United States	Aultman Hospital	Canton	Ohio
United States	Charleston Area Medical Center (CAMC)	Charleston	West Virginia
United States	University of Virginia	Charlottesburg	Virginia
United States	University Hospitals Case Medical Center	Cleveland	Ohio
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Marin Cancer Care	Greenbrae	California
United States	Indiana University	Indianapolis	Indiana
United States	Gundersen Health System	La Crosse	Wisconsin
United States	Dean Clinic	Madison	Wisconsin
United States	University of South Alabama	Mobile	Alabama
United States	Ochsner Cancer Institute	New Orleans	Louisiana
United States	Missouri Valley Cancer Consortium	Omaha	Nebraska
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Mayo Clinic	Rochester	Minnesota
United States	St. Joseph's/Candler Health System	Savannah	Georgia
United States	Siouxland Hematology Oncology Associates	Sioux City	Iowa
United States	Metro MN CCOP	St. Louis Park	Minnesota
United States	Toledo Community Oncology Program	Toledo	Ohio
United States	Carle Cancer Center	Urbana	Illinois
United States	ProHealth Care, Inc.	Waukesha	Wisconsin
United States	Aurora Health Care	Wauwatosa	Wisconsin
United States	Reading Hospital	West Reading	Pennsylvania
United States	Susquehanna Health Cancer Center	Williamsport	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
PrECOG, LLC.	Genentech, Inc.

Country where clinical trial is conducted

United States, 

References & Publications (5)

Beers SA, Chan CH, French RR, Cragg MS, Glennie MJ. CD20 as a target for therapeutic type I and II monoclonal antibodies. Semin Hematol. 2010 Apr;47(2):107-14. doi: 10.1053/j.seminhematol.2010.01.001. Review. — View Citation

Hainsworth JD, Litchy S, Burris HA 3rd, Scullin DC Jr, Corso SW, Yardley DA, Morrissey L, Greco FA. Rituximab as first-line and maintenance therapy for patients with indolent non-hodgkin's lymphoma. J Clin Oncol. 2002 Oct 15;20(20):4261-7. — View Citation

Mössner E, Brünker P, Moser S, Püntener U, Schmidt C, Herter S, Grau R, Gerdes C, Nopora A, van Puijenbroek E, Ferrara C, Sondermann P, Jäger C, Strein P, Fertig G, Friess T, Schüll C, Bauer S, Dal Porto J, Del Nagro C, Dabbagh K, Dyer MJ, Poppema S, Klein C, Umaña P. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood. 2010 Jun 3;115(22):4393-402. doi: 10.1182/blood-2009-06-225979. Epub 2010 Mar 1. — View Citation

Salles GA, et al. Efficacy and Safety of Obinutuzumab (GA101) Monotherapy in Relapsed/Refractory Indolent Non-Hodgkin's Lymphoma: Results from a Phase I/II Study (BO20999) American Society of Hematology Annual meeting 2011 Abstract 268.

Sehn LH, Goy A, Offner FC, Martinelli G, Caballero MD, Gadeberg O, Baetz T, Zelenetz AD, Gaidano G, Fayad LE, Buckstein R, Friedberg JW, Crump M, Jaksic B, Zinzani PL, Padmanabhan Iyer S, Sahin D, Chai A, Fingerle-Rowson G, Press OW. Randomized Phase II Trial Comparing Obinutuzumab (GA101) With Rituximab in Patients With Relapsed CD20+ Indolent B-Cell Non-Hodgkin Lymphoma: Final Analysis of the GAUSS Study. J Clin Oncol. 2015 Oct 20;33(30):3467-74. doi: 10.1200/JCO.2014.59.2139. Epub 2015 Aug 17. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Cytokine Profile	Descriptive statistics of changes, such as malignant B-cells, will be reported.	Baseline and Re-Staging (week 12, 13 or 14)	No
Other	Bank Biospecimens for Retrospective Examination	To bank biospecimens for retrospective examination of FcGammaR (FcRIIIA) polymorphisms and correlation with responses to antibody therapy and GA101.	Baseline and Re-Staging (week 12, 13 or 14)	No
Other	Bank Biospecimens for Future Assessment	To bank biospecimens for future assessment of biomarkers of prognosis and/or response.	Baseline and Re-Staging (week 12, 13 or 14)	No
Primary	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	No
Secondary	PET Response Rate	PET response rate [PET-documented CR + Partial Response (PR)] based on PET scan results.	Re-staging (week 12, 13 or 14)	No
Secondary	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.	Baseline and Re-staging (week 12, 13 or 14)	No
Secondary	Time to Next Treatment	Next treatment is defined as any monoclonal antibody treatment, immunological therapy (such as vaccines), chemotherapy, radiotherapy, or radioimmunotherapy.	Every 3 months for 2 years, then every 6 months for up to 4 years	No
Secondary	Progression Free Survival (PFS)	CT scan every 6 months until progression. Compare PFS in each treatment arm.	Every 3 months for 2 years, then every 6 months for up to 4 years	No
Secondary	Number of Participants with Adverse Events as a Measure of Safety and Tolerability	Adverse event rates, exposure and laboratory data by treatment arm.	Weekly x 4 weeks and Re-Staging (week 12, 13 or 14)	Yes