A Safety and Pharmacology Study of Atezolizumab (MPDL3280A) Administered With Obinutuzumab or Tazemetostat in Participants With Relapsed/Refractory Follicular Lymphoma and Diffuse Large B-cell Lymphoma

Sponsor

Hoffmann-La Roche (Industry)

Overall Status

Completed

CT.gov ID

NCT02220842

Collaborator

(none)

Enrollment

Locations

Arms

61.1

Actual Duration (Months)

6.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This open-label, multicenter, global study is designed to assess the safety, tolerability, preliminary efficacy, and pharmacokinetics of intravenous atezolizumab (MPDL3280A) and obinutuzumab in participants with refractory or relapsed follicular lymphoma (FL) or atezolizumab and obinutuzumab or tazemetostat administered in participants with refractory or relapsed diffuse large B-cell lymphoma (DLBCL). The anticipated duration of this study is approximately 4.5 years.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma	Drug: Atezolizumab Drug: Obinutuzumab Drug: Tazemetostat	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

96 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase Ib Study of the Safety and Pharmacology of Atezolizumab Administered With Obinutuzumab in Patients With Relapsed/Refractory Follicular Lymphoma or Atezolizumab Administered With Obinutuzumab or Tazemetostat in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Actual Study Start Date :

Dec 18, 2014

Actual Primary Completion Date :

Jan 21, 2020

Actual Study Completion Date :

Jan 21, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1 Cohort A (Safety Evaluation):Atezolizumab + Obinutuzumab Relapsed/refractory FL and DLBCL participants will receive obinutuzumab alone on Days 1, 8, and 15 of Cycle 1 (Cycle length = 21 days), followed by atezolizumab and obinutuzumab on Day 1 of Cycles 2-8, and then atezolizumab alone on Day 1 of Cycle 9 and every cycle thereafter until unacceptable toxicities or disease progression.	Drug: Atezolizumab During safety evaluation stage, atezolizumab will be administered as 1200 milligrams (mg) intravenous (IV) infusion. During expansion stage, atezolizumab will be administered as either 1200 mg IV infusion or at dose decided from safety evaluation stage. Other Names: Tecentriq Drug: Obinutuzumab During safety evaluation stage, obinutuzumab will be administered as 1000 mg IV infusion. During expansion stage, obinutuzumab will be administered as either 1000 mg IV infusion or at dose decided from safety evaluation stage.
Experimental: Arm 1 Cohort B (Expansion): Atezolizumab + Obinutuzumab Relapsed/refractory FL participants will receive atezolizumab and obinutuzumab as per schedule and dose decided from the safety evaluation stage, until unacceptable toxicities or disease progression.	Drug: Atezolizumab During safety evaluation stage, atezolizumab will be administered as 1200 milligrams (mg) intravenous (IV) infusion. During expansion stage, atezolizumab will be administered as either 1200 mg IV infusion or at dose decided from safety evaluation stage. Other Names: Tecentriq Drug: Obinutuzumab During safety evaluation stage, obinutuzumab will be administered as 1000 mg IV infusion. During expansion stage, obinutuzumab will be administered as either 1000 mg IV infusion or at dose decided from safety evaluation stage.
Experimental: Arm 1 Cohort C (Expansion): Atezolizumab + Obinutuzumab Relapsed/refractory DLBCL participants will receive atezolizumab and obinutuzumab as per schedule and dose decided from the safety evaluation stage, until unacceptable toxicities or disease progression.	Drug: Atezolizumab During safety evaluation stage, atezolizumab will be administered as 1200 milligrams (mg) intravenous (IV) infusion. During expansion stage, atezolizumab will be administered as either 1200 mg IV infusion or at dose decided from safety evaluation stage. Other Names: Tecentriq Drug: Tazemetostat Tazemetostat 800 mg will be administered orally, twice daily, on Days 1 to 21. Other Names: EPZ6438
Experimental: Arm 2 Cohort D (Safety Evaluation):Atezolizumab + Tazemetostat Relapsed/refractory DLBCL participants will receive atezolizumab (on Day 1) and tazemetostat (on Days 1-21) of each 21-day cycle until unacceptable toxicities or disease progression.	Drug: Atezolizumab During safety evaluation stage, atezolizumab will be administered as 1200 milligrams (mg) intravenous (IV) infusion. During expansion stage, atezolizumab will be administered as either 1200 mg IV infusion or at dose decided from safety evaluation stage. Other Names: Tecentriq Drug: Tazemetostat Tazemetostat 800 mg will be administered orally, twice daily, on Days 1 to 21. Other Names: EPZ6438
Experimental: Arm 2 Cohort E (Expansion): Atezolizumab + Tazemetostat Relapsed/refractory DLBCL participants will receive atezolizumab and tazemetostat as per schedule and dose decided from the safety evaluation stage, until unacceptable toxicities or disease progression.	Drug: Atezolizumab During safety evaluation stage, atezolizumab will be administered as 1200 milligrams (mg) intravenous (IV) infusion. During expansion stage, atezolizumab will be administered as either 1200 mg IV infusion or at dose decided from safety evaluation stage. Other Names: Tecentriq Drug: Tazemetostat Tazemetostat 800 mg will be administered orally, twice daily, on Days 1 to 21. Other Names: EPZ6438

Outcome Measures

Primary Outcome Measures

Percentage of Participants With Dose Limiting Toxicities (DLTs) [21 days (for Arm 1: Days 1 to 21 to Cycle 2; for Arm 2: Days 1 to 21 of Cycle 1, cycle length = 21 days)]
Recommended Phase 2 Dose (RP2D) of Atezolizumab [21 days (for Arm 1: Days 1 to 21 to Cycle 2; for Arm 2: Days 1 to 21 of Cycle 1, cycle length = 21 days)]

Secondary Outcome Measures

Obinutuzumab Minimum Serum Concentration (Cmin) [Preinfusion (hour 0) on Day 1, 8, 15 of Cycle 1, Day 1 of Cycles 2, 3, 4, 6, 8, every 8 cycles thereafter up to treatment discontinuation, 120 days after treatment discontinuation (treatment discontinuation=up to approx 57 weeks) (Cycle=21 days)]
Percentage of Participants With Adverse Events (AEs) Graded According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) [Baseline up to approximately 4.5 years]
Percentage of Participants With Anti-therapeutic Antibody Response to Atezolizumab and Obinutuzumab [Baseline up to approximately 4.5 years]
Atezolizumab Maximum Serum Concentration (Cmax) [Preinfusion (hour 0) on Day 1 of Cycle 1 up to approx 57 weeks (detailed timeframe is provided in outcome description section)]
Arm 1: preinfusion (hour 0) on Day 1 of Cycle 1, 30 minutes post end of atezolizumab infusion (infusion over 30-60 minutes) on Day 1 of Cycle 2, preinfusion on Day 1 of Cycles 3, 4, 6, 8, and every 8 cycles thereafter up to treatment discontinuation, 120 days after treatment discontinuation (treatment discontinuation=up to approx 57 weeks), additionally preinfusion on Day 1 of Cycle 9; Arm 2: preinfusion (hour 0) and 30 minutes post end of atezolizumab infusion (infusion over 30-60 minutes) on Day 1 of Cycles 1 and 3, preinfusion on Day 1 of Cycles 2, 8, every 8 cycles thereafter up to treatment discontinuation, 120 days after treatment discontinuation (treatment discontinuation=up to approx 57 weeks) (Cycle=21 days)
Atezolizumab Minimum Serum Concentration (Cmin) [Preinfusion (hour 0) on Day 1 of Cycle 1 up to approx 57 weeks (detailed timeframe is provided in outcome description section)]
Arm 1: preinfusion (hour 0) on Day 1 of Cycles 1, 3, 4, 6, 8, and every 8 cycles thereafter up to treatment discontinuation, 120 days after treatment discontinuation (treatment discontinuation=up to approx 57 weeks), pre-infusion on Day 1 of Cycle 9; Arm 2: preinfusion (hour 0) on Day 1 of Cycles 1, 2, 3, 8, every 8 cycles thereafter up to treatment discontinuation, 120 days after treatment discontinuation (treatment discontinuation=up to approx 57 weeks) (Cycle = 21 days)
Obinutuzumab Maximum Serum Concentration (Cmax) [Arm 1: Preinfusion (hour 0) on Day 1 of Cycle 1 up to approx 57 weeks (detailed timeframe is provided in outcome description section)]
Arm 1: preinfusion (hour 0) on Day 1, 4-hour post start of infusion on Day 2, preinfusion (hour 0) and 4-hour post start of infusion on Day 8, 15 of Cycle 1, Day 1 of Cycles 2, 3, 4, 6, 8, every 8 cycles thereafter up to treatment discontinuation, 120 days after treatment discontinuation (treatment discontinuation=up to approx 57 weeks) (Cycle=21 days)
Percentage of Participants With Best Overall Response According to Lugano Classification [Cycle 3 Day 15 (Cycle 4 Day 15 for Arm 1) up to progression of disease, death, or withdrawal of consent, whichever occurs first (up to approximately 4.5 years) (Cycle=21 days)]
Percentage of Participants With Objective Response (Complete Response or Partial Response) According to Lugano Classification [Cycle 3 Day 15 (Cycle 4 Day 15 for Arm 1) up to progression of disease, death, or withdrawal of consent, whichever occurs first (up to approximately 4.5 years) (Cycle=21 days)]
Progression Free Survival (PFS) According to Lugano Classification [Cycle 3 Day 15 (Cycle 4 Day 15 for Arm 1) up to progression of disease, death, or withdrawal of consent, whichever occurs first (up to approximately 4.5 years) (Cycle=21 days)]
Overall Survival (OS) [Baseline until death due to any cause (up to approximately 4.5 years)]
Duration of Objective Response (DOR) According to Lugano Classification [From first documented complete or partial response up to progression of disease, death, or withdrawal of consent, whichever occurs first (up to approximately 4.5 years)]
Tazemetostat Plasma Concentrations [Arm 2: predose (hour 0) on Day 1 of Cycles 1, 2, 3, 4, 8, every 8 cycles thereafter up to Cycle 17; 1, 2, 4 hours post dose on Day 1 of Cycles 1 and 3; additionally (in Cohort E only) 0.5, 6, 8 hours post dose on Cycle 3 Day 1 (Cycle=21 days)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically documented, CD20-positive, relapsed or refractory (defined as having relapsed within 6 months to the previous treatment) FL or DLBCL (including primary mediastinal large B-cell lymphoma [PMLBCL])
Bone marrow biopsy at screening (unless it was performed within 3 months prior to screening)
Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
Life expectancy greater than or equal to (>=) 12 weeks
Has a QT interval corrected by Fridericia's formula (QTcF) less than or equal to (<=) 480 milliseconds (msec)
At least one bi-dimensionally measurable nodal lesion >1.5 cm in its longest diameter by computed tomography (CT) scan or MRI, as defined by the Lugano Classification
Adequate hematologic and end-organ function
Archival tumor tissue
For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 90 days after the last dose of atezolizumab or 18 months after the last dose of obinutuzumab, whichever is longer
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm

Exclusion Criteria:

Known central nervous system lymphoma, leptomeningeal lymphoma, or histologic evidence of transformation from an indolent lymphoma to a high-grade or DLBCL
Grade 3b FL, small lymphocytic lymphoma (SLL), or Waldenström's macroglobulinemia (WM) or other lymphoma subtypes except as stated in the inclusion criteria
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently); participants with indwelling catheters are eligible
Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab
History of severe allergic or anaphylactic reactions to monoclonal antibody therapy
Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homolog 2 (EZH2)
Regular treatment with corticosteroids within the 2 or 4 weeks prior to the start of Cycle 1, unless administered for indications other than non-Hodgkin's lymphoma at a dose equivalent to < 30 mg/day prednisone/prednisolone
Pregnant and lactating women
History of autoimmune disease
Participants with history of confirmed progressive multifocal leukoencephalopathy (PML)
Participants with prior allogeneic bone marrow transplantation or prior solid organ transplantation
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis per chest CT scan at screening. History of radiation pneumonitis in the radiation field (fibrosis) is allowed
Positive test for Human Immunodeficiency Virus (HIV)
History of chronic hepatitis B infection or positive test results for active or chronic hepatitis B or hepatitis C
Significant cardiovascular disease, such as cardiac disease (New York Heart Association Class II or greater), myocardial infarction within the previous 3 months, unstable arrhythmias, or unstable angina
Hypersensitivity or prior treatment with obinutuzumab
Fludarabine or Campath within 12 months prior to study entry
Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
Treatment with systemic immunostimulatory agents (including but not limited to interferon, interleukin-2) within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to Cycle 1, Day 1
Treatment with systemic immunosuppressive medications, including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (anti-TNF) agents within 2 weeks prior to Cycle 1, Day 1; inhaled corticosteroids and mineralocorticoids are allowed
Participants with active tuberculosis (TB) will be excluded from the clinical trial

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope National Medical Center	Duarte	California	United States	91010
2	Fort Wayne Neurological Center	Fort Wayne	Indiana	United States	46805
3	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
4	Sloan Kettering Cancer Center	New York	New York	United States	10065-6007
5	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27599
6	MD Anderson Cancer Center	Houston	Texas	United States	77030
7	UW- Fred Hutchinson Cancer Center	Seattle	Washington	United States	98109
8	Hopital Claude Huriez - CHU Lille; Service des maladies du sang	Lille		France	59037
9	Hopital Saint Eloi	Montpellier		France	34295
10	Hôpital Saint-Louis	Paris		France	75475
11	Centre Hospitalier Lyon Sud	Pierre Benite		France	69495
12	Institut Gustave Roussy	Villejuif		France	94805
13	Universitaetsklinikum Freiburg	Freiburg		Germany	79106
14	Azienda Ospedaliera Città della Salute e della Scienza di Torino	Torino	Piemonte	Italy	10126
15	Barts Hospital	London		United Kingdom	E1 2EF