A Study of Obinutuzumab [RO5072759 (GA101)] in Combination With CHOP Chemotherapy in Patients With Previously Untreated Advanced Diffuse Large B-Cell Lymphoma (GATHER)

A Phase II, Open-Label, Multicenter Study of Efficacy, Safety, and Biomarkers in Patients With Previously Untreated Advanced Diffuse Large B-Cell Lymphoma Treated With GA101 (RO5072759) in Combination With CHOP Chemotherapy

This open-label, multicenter study will evaluate the efficacy and safety of obinutuzumab [RO5072759 (GA101)] in combination with CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone) chemotherapy in patients with advanced diffuse large B-cell lymphoma. Patients will receive 8 cycles of obinutuzumab (1000 mg intravenously on Day 1 of each 21-day cycle, during Cycle 1 obinutuzumab will also be infused on Days 8 and 15) in combination with CHOP chemotherapy on Day 1 of cycles 1 to 6. A substudy will investigate the drug-drug interaction of obinutuzumab with CHOP chemotherapy agents. For the substudy, an additional cohort of approximately 15 patients are planned to be enrolled at a subset of investigational sites.

Study Overview

• Status: Completed
• Conditions: Lymphoma, B-Cell
• Intervention / Treatment: Drug: obinutuzumab; Drug: cyclophosphamide; Drug: doxorubicin; Drug: prednisone; Drug: vincristine

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-3300
      • University of Alabama at Birmingham
  • California
    • Encinitas, California, United States, 92024
      • cCare
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Cancer Center Department of Hematology
    • Denver, Colorado, United States, 80218
      • Rocky Mountain Cancer Ctr - Denver (Williams)
  • Connecticut
    • Norwalk, Connecticut, United States, 06856
      • Norwalk Hospital
  • Florida
    • Fort Myers, Florida, United States, 33901-8101
      • Florida Cancer Specialists; Department of Oncology
    • Saint Petersburg, Florida, United States, 33719
      • Florida Cancer Specialists; Saint Petersburg
  • Georgia
    • Marietta, Georgia, United States, 30060
      • Northwest Georgia Oncology Centers PC - Marietta
  • Idaho
    • Coeur d'Alene, Idaho, United States, 83814
      • Kootenai Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University; Robert H. Lurie Comp Can Ctr
    • Peoria, Illinois, United States, 61615-7828
      • Onc Hem Assoc of Central IL
  • Iowa
    • Ames, Iowa, United States, 50010
      • McFarland Clinic
  • Kentucky
    • Louisville, Kentucky, United States, 40245
      • Jewish Cancer Care
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Medical School
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0934
      • University of Michigan
  • Montana
    • Missoula, Montana, United States, 59802
      • MT Cancer Inst Fndtn; MT Can Spec
  • Nevada
    • Las Vegas, Nevada, United States, 89128
      • Comprehensive Cancer Centers of Nevada
  • New Jersey
    • Basking Ridge, New Jersey, United States, 07920
      • MSKCC at Basking Ridge
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New Mexico
    • Farmington, New Mexico, United States, 87401
      • San Juan Oncology Associates
  • New York
    • Commack, New York, United States, 11725
      • Memorial Sloan-Kettering; Cancer Center
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • Rockville Centre, New York, United States, 11570
      • MSKCC at Mercy Med Ctr
    • Sleepy Hollow, New York, United States, 10591
      • MSKCC at Sleepy Hollow
  • North Carolina
    • High Point, North Carolina, United States, 27262
      • Emerywood Hematology and Onc
  • Oregon
    • Springfield, Oregon, United States, 97477
      • Willamette Valley Cancer Insitute and Research Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of SC (MUSC)
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • SCRI-Tennessee Oncology
  • Texas
    • Fort Worth, Texas, United States, 76177
      • Onc & Hem Assoc; USO Cent Pharm
    • Houston, Texas, United States, 77030
      • Methodist Hospital Research Institute
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center Department of Lymphoma & Myeloma
    • San Antonio, Texas, United States, 78229
      • Cancer Therapy & Research Center
    • Tyler, Texas, United States, 75702
      • USO - Tyler Cancer Ctr
  • Virginia
    • Roanoke, Virginia, United States, 24014
      • Blue Ridge Cancer Care - Roanoke
  • Washington
    • Spokane, Washington, United States, 99208
      • Medical Oncology Associates
    • Vancouver, Washington, United States, 98684
      • Northwest Cancer Specialists - Vancouver
    • Yakima, Washington, United States, 98902
      • Yakima Valley Memorial Hospital/North Star Lodge
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54311
      • Aurora Bay Care Medical Center

Participation Criteria

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:

• Adult patients, ≥18 years of age
• Previously untreated cluster of differentiation antigen 20 (CD20)-positive diffuse large B-cell lymphoma
• Ann Arbour Stage III/IV and bulky II (mass >10 cm)
• At least one bi-dimensionally measurable lesion defined as >1.5 cm in its largest dimension by CT scan
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
• Left ventricular ejection fraction ≥50%
• Adequate hematologic function

Exclusion Criteria:

• Transformed lymphoma (follicular IIIB) if previously treated with chemotherapy or immunotherapy
• Prior therapy for diffuse large B-cell lymphoma except for nodal biopsy or local irradiation
• Central nervous system (CNS) lymphoma, primary mediastinal large cell lymphoma, primary cutaneous lymphoma, primary effusion lymphoma
• Patients who received cytotoxic drugs or rituximab as part of their treatment for another condition (e.g. rheumatoid arthritis) or prior use of an anti-CD20 antibody
• Chemotherapy or other investigational therapy within 28 days prior to the start of Cycle 1
• Contraindication to any of the individual components of CHOP, including prior receipt of anthracyclines
• History of severe allergic or anaphylactic reactions to monoclonal antibody therapy
• History of other malignancy, except for curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix, or malignancy treated with or without curative intent and in remission without treatment for ≥2 years prior to enrolment
• Positive for hepatitis B, hepatitis C, human immunodeficiency virus (HIV) or human T-cell leukemia virus (HTLV-1) infection
• Pregnant or lactating women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: obinutuzumab + CHOP; Participants received 1000 mg obinutuzumab intravenously on Day 1 of each 21-day cycle for 8 cycles; during Cycle 1 administration also on Days 8 and 15. Participants also received standard CHOP therapy (cyclophosphamide, doxorubicin, vincristine and prednisone) for 6 cycles.

Drug: obinutuzumab; 1000 mg intravenously on Day 1 of each 21-day cycle, 8 cycles; during Cycle 1 administration also on Days 8 and 15.; Drug: cyclophosphamide; 750 mg/m^2 intravenous (IV), Day 1 of each 21-day cycle, 6 cycles.; Drug: doxorubicin; 50 mg/m^2 IV, Day 1 of each 21-cycle, 6 cycles.; Drug: prednisone; 100 mg/day, Days 1 through 5 of each 21-day cycle, 6 cycles.; Drug: vincristine; 1.4 mg/m^2 IV, Day 1 of each 21-day cycle, 6 cycles.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Response (CR) Rate as Assessed by the Investigator at the End of Treatment	Complete response rate is defined as the percentage of participants with Complete Response (CR) according to the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007). Disease response was evaluated by the investigator using regular clinical and laboratory examinations, fluorodeoxyglucose-positron emission tomography (FDG-PET) and computed tomography (CT). CR is the disappearance of all evidence of disease.	From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days)
Overall Response Rate (ORR) as Assessed by the Investigator at the End of Treatment	Overall response rate was defined as the percentage of participants with Complete Response (CR) or Partial Response (PR) according to the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007). Disease response was evaluated by the investigator using regular clinical and laboratory examinations, FDG-PET and computed tomography (CT). CR is the disappearance of all evidence of disease. PR is at least 50% regression of measurable disease compared to tumors measured by a baseline scan and no new sites.	From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Response (CR) Rate as Assessed by the Independent Review Facility (IRF) at the End of Treatment	Complete response rate is defined as the percentage of participants with Complete Response (CR) according to the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007). Disease response was evaluated by the IRF using CT scans, PET scans and pertinent clinical information. CR is the disappearance of all evidence of disease.	From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days)
Overall Response Rate (ORR) as Assessed by the IRF at the End of Treatment	Overall response rate was defined as the percentage of participants with Complete Response (CR) or Partial Response (PR) according to the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007). Disease response was evaluated by the IRF using CT scans, PET scans and pertinent clinical information. CR is the disappearance of all evidence of disease. PR is at least 50% regression of measurable disease compared to tumors measured by a baseline scan and no new sites.	From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days)
Progression-Free Survival (PFS) as Assessed by the Investigator	PFS was defined as the time from the date of the first dose of study treatment until the date of disease progression, relapse, or death from any cause.	From the first dose of study treatment to PFS assessment (up to 64 months)
Duration of Response (DOR)	DOR is defined as first occurrence of documented response (CR or PR) until the first occurrence of relapse or progression or death of any cause. CR: disappearance of all evidence of disease. PR: at least 50% regression of measurable disease compared to tumors measured by a baseline scan and no new sites.	From the response assessment to relapse, progression, or death (up to 64 months)
Percentage of Participants With Adverse Events as a Measure of Safety	An adverse event was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug or other protocol-imposed intervention. Preexisting conditions that worsened during the study were reported as adverse events.	From the first dose of study treatment to end of study (up to 5 years 4 months)
Number of Participants With Grade 3 to 4 Infusion-Related (IRR) Adverse Events (AE) in Participants Receiving Shorter Duration Infusion (SDI)	SDI 120 is a shorter duration infusion of 120 minutes and SDI 90 is shorter duration infusion of 90 minutes. Grade 3 IRR AE: Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae. Grade 4 IRR AE: Life-threatening consequences; urgent intervention indicated.	From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days)
Pharmacokinetics (PK): Maximum Concentration Observed (Cmax) for Obinutuzumab	Blood was collected for PK Parameters. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in micrograms per milliliter (μg/mL).	Cycle 1 Day 1 pre and post dose, Days 3,5, Day 8 pre and post-dose, Day 15 pre-dose. Cycle 8 Day 1 pre and post-dose, Days 5,8,12
Pharmacokinetics: Terminal Half-Life (t1/2) for Obinutuzumab	T1/2 is the time required for the concentration of the drug to reach half of its original value. Blood was collected for PK Parameters. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in days	Cycle 1 Day 1 pre and post dose, Days 3,5, Day 8 pre and post-dose, Day 15 pre-dose. Cycle 8 Day 1 pre and post-dose, Days 5,8,12
Pharmacokinetics: Clearance (Cl) for Obinutuzumab	Cl is the volume of serum cleared of the drug per unit of time. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in milliliters/day (mL/day).	Cycle 1 Day 1 pre and post dose, Days 3,5, Day 8 pre and post-dose, Day 15 pre-dose. Cycle 8 Day 1 pre and post-dose, Days 5,8,12
Pharmacokinetics: Volume of Distribution (V) for Obinutuzumab	V is the apparent volume in which a drug is distributed in the body. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in milliliters (mL).	Cycle 1 Day 1 pre and post dose, Days 3,5, Day 8 pre and post-dose, Day 15 pre-dose. Cycle 8 Day 1 pre and post-dose, Days 5,8,12
Pharmacokinetics: Area Under the Concentration-Time Curve 7 Day (AUC7day)	Blood was collected for PK parameters. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in in day times micrograms per milliliter (day*μg/mL).	Cycle 1 Day 1 pre and post dose, Days 3,5, Day 8 pre and post-dose, Day 15 pre-dose. Cycle 8 Day 1 pre and post-dose, Days 5,8,12
Pharmacodynamics: Peripheral Blood CD19-positive B-cell Count		Up to approximately 24 months

Collaborators and Investigators

• Sponsor: Genentech, Inc.

Publications and helpful links

General Publications

• Gibiansky E, Gibiansky L, Buchheit V, Frey N, Brewster M, Fingerle-Rowson G, Jamois C. Pharmacokinetics, exposure, efficacy and safety of obinutuzumab in rituximab-refractory follicular lymphoma patients in the GADOLIN phase III study. Br J Clin Pharmacol. 2019 Sep;85(9):1935-1945. doi: 10.1111/bcp.13974. Epub 2019 Jul 12.
• Sharman JP, Forero-Torres A, Costa LJ, Flinn IW, Inhorn L, Kelly K, Bessudo A, Fayad LE, Kaminski MS, Evens AM, Flowers CR, Sahin D, Mundt KE, Sandmann T, Fingerle-Rowson G, Vignal C, Mobasher M, Zelenetz AD. Obinutuzumab plus CHOP is effective and has a tolerable safety profile in previously untreated, advanced diffuse large B-cell lymphoma: the phase II GATHER study. Leuk Lymphoma. 2019 Apr;60(4):894-903. doi: 10.1080/10428194.2018.1515940. Epub 2018 Oct 2.

Study record dates

Study Major Dates

• Study Start (Actual): August 31, 2011
• Primary Completion (Actual): December 31, 2013
• Study Completion (Actual): December 23, 2016

Study Registration Dates

• First Submitted: August 10, 2011
• First Submitted That Met QC Criteria: August 10, 2011
• First Posted (Estimate): August 11, 2011

Study Record Updates

• Last Update Posted (Actual): April 25, 2018
• Last Update Submitted That Met QC Criteria: April 24, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Cyclophosphamide; Prednisone; Doxorubicin; Vincristine; Obinutuzumab
• Other Study ID Numbers: GAO4915g