Clinical trial NCT01889797: Phase II Randomized Trial Comparing GA101 and Rituximab in Untreated Low Tumor Burden Indolent Non-Hodgkin's Lymphoma
Official title: Phase II Randomized Trial Comparing GA101 (Obinutuzumab) and Rituximab in Patients With Previously Untreated Low Tumor Burden Indolent Non-Hodgkin's Lymphoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Indolent Non-Hodgkin's Lymphoma
Keywords: Untreated Non-Hodgkin's Lymphoma
Low Tumor Burden Non-Hodgkin's Lymphoma
NHL
Indolent
Rituximab
Rituxan
GA101
Obinutuzumab
Lead sponsor: PrECOG, LLC.
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
First posted: 2013-06-28
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Complete Response (CR) Rate
timeFrame: 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 outcomes:
measure: PET Response Rate
timeFrame: Re-staging (week 12, 13 or 14)
measure: Overall Response Rate
timeFrame: Baseline and Re-staging (week 12, 13 or 14)
measure: Progression Free Survival (PFS)
timeFrame: Percent of participants alive and progression-free at 1 year
Other outcomes:
Locations:
city: Mobile
country: United States
facility: University of South Alabama
state: Alabama
city: Greenbrae
country: United States
facility: Marin Cancer Care
state: California
city: Savannah
country: United States
facility: St. Joseph's/Candler Health System
state: Georgia
city: Decatur
country: United States
facility: Decatur Memorial Hospital
state: Illinois
city: Urbana
country: United States
facility: Carle Cancer Center
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Sioux City
country: United States
facility: Siouxland Hematology Oncology Associates
state: Iowa
city: New Orleans
country: United States
facility: Ochsner Cancer Institute
state: Louisiana
city: Baltimore
country: United States
facility: Greater Baltimore Medical Center
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: St. Joseph Mercy Health System
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: St. Louis Park
country: United States
facility: Metro MN CCOP
state: Minnesota
city: Omaha
country: United States
facility: Missouri Valley Cancer Consortium
state: Nebraska
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Canton
country: United States
facility: Aultman Hospital
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals Case Medical Center
state: Ohio
city: Toledo
country: United States
facility: Toledo Community Oncology Program
state: Ohio
city: Danville
country: United States
facility: Geisinger Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: West Reading
country: United States
facility: Reading Hospital
state: Pennsylvania
city: Williamsport
country: United States
facility: Susquehanna Health Cancer Center
state: Pennsylvania
city: Charlottesburg
country: United States
facility: University of Virginia
state: Virginia
city: Charleston
country: United States
facility: Charleston Area Medical Center (CAMC)
state: West Virginia
city: La Crosse
country: United States
facility: Gundersen Health System
state: Wisconsin
city: Madison
country: United States
facility: Dean Clinic
state: Wisconsin
city: Waukesha
country: United States
facility: ProHealth Care, Inc.
state: Wisconsin
city: Wauwatosa
country: United States
facility: Aurora Health Care
state: Wisconsin
Study officials:
affiliation: Mayo Clinic in Minnesota
name: Stephen Ansell, MD
role: STUDY_CHAIR
References:
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. doi: 10.1200/JCO.2002.08.674.
citation: 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.
citation: Mossner E, Brunker P, Moser S, Puntener U, Schmidt C, Herter S, Grau R, Gerdes C, Nopora A, van Puijenbroek E, Ferrara C, Sondermann P, Jager C, Strein P, Fertig G, Friess T, Schull C, Bauer S, Dal Porto J, Del Nagro C, Dabbagh K, Dyer MJ, Poppema S, Klein C, Umana 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.
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.
citation: 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.