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

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

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.

Study Overview

• Status: Completed
• Conditions: Lymphoma
• Intervention / Treatment: Drug: Atezolizumab; Drug: Obinutuzumab; Drug: Tazemetostat

• Study Type: Interventional
• Enrollment (Actual): 96
• Phase: Phase 1

Contacts and Locations

Study Locations

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

• 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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Outcome Measure	Measure Description	Time Frame
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)	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)	Preinfusion (hour 0) on Day 1 of Cycle 1 up to approx 57 weeks (detailed timeframe is provided in outcome description section)
Atezolizumab Minimum Serum Concentration (Cmin)	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)	Preinfusion (hour 0) on Day 1 of Cycle 1 up to approx 57 weeks (detailed timeframe is provided in outcome description section)
Obinutuzumab Maximum Serum Concentration (Cmax)	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)	Arm 1: Preinfusion (hour 0) on Day 1 of Cycle 1 up to approx 57 weeks (detailed timeframe is provided in outcome description section)
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)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Palomba ML, Cartron G, Popplewell L, Ribrag V, Westin J, Huw LY, Agarwal S, Shivhare M, Hong WJ, Raval A, Chang AC, Penuel E, Morschhauser F. Combination of Atezolizumab and Tazemetostat in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Results From a Phase Ib Study. Clin Lymphoma Myeloma Leuk. 2022 Jul;22(7):504-512. doi: 10.1016/j.clml.2021.12.014. Epub 2021 Dec 24.
• Palomba ML, Till BG, Park SI, Morschhauser F, Cartron G, Marks R, Shivhare M, Hong WJ, Raval A, Chang AC, Penuel E, Popplewell LL. Combination of Atezolizumab and Obinutuzumab in Patients with Relapsed/Refractory Follicular Lymphoma and Diffuse Large B-Cell Lymphoma: Results from a Phase 1b Study. Clin Lymphoma Myeloma Leuk. 2022 Jul;22(7):e443-e451. doi: 10.1016/j.clml.2021.12.010. Epub 2021 Dec 24.

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2014
• Primary Completion (Actual): January 21, 2020
• Study Completion (Actual): January 21, 2020

Study Registration Dates

• First Submitted: August 7, 2014
• First Submitted That Met QC Criteria: August 19, 2014
• First Posted (Estimate): August 20, 2014

Study Record Updates

• Last Update Posted (Actual): January 27, 2020
• Last Update Submitted That Met QC Criteria: January 22, 2020
• Last Verified: January 1, 2020

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, B-Cell; Lymphoma; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Antineoplastic Agents; Antineoplastic Agents, Immunological; Obinutuzumab; Atezolizumab
• Other Study ID Numbers: GO29383; 2014-001812-21 (EudraCT Number)