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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

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ClinicalTrials.gov Identifier: NCT02220842
Recruitment Status : Completed
First Posted : August 20, 2014
Last Update Posted : January 27, 2020
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

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

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Study Type : Interventional  (Clinical Trial)
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 : December 18, 2014
Actual Primary Completion Date : January 21, 2020
Actual Study Completion Date : January 21, 2020


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 Name: 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 Name: 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 Name: Tecentriq

Drug: Tazemetostat
Tazemetostat 800 mg will be administered orally, twice daily, on Days 1 to 21.
Other Name: 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 Name: Tecentriq

Drug: Tazemetostat
Tazemetostat 800 mg will be administered orally, twice daily, on Days 1 to 21.
Other Name: 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 Name: Tecentriq

Drug: Tazemetostat
Tazemetostat 800 mg will be administered orally, twice daily, on Days 1 to 21.
Other Name: EPZ6438




Primary Outcome Measures :
  1. Percentage of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: 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) ]
  2. Recommended Phase 2 Dose (RP2D) of Atezolizumab [ Time Frame: 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 :
  1. Obinutuzumab Minimum Serum Concentration (Cmin) [ Time Frame: 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) ]
  2. 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) [ Time Frame: Baseline up to approximately 4.5 years ]
  3. Percentage of Participants With Anti-therapeutic Antibody Response to Atezolizumab and Obinutuzumab [ Time Frame: Baseline up to approximately 4.5 years ]
  4. Atezolizumab Maximum Serum Concentration (Cmax) [ Time Frame: 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)

  5. Atezolizumab Minimum Serum Concentration (Cmin) [ Time Frame: 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)

  6. Obinutuzumab Maximum Serum Concentration (Cmax) [ Time Frame: 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)

  7. Percentage of Participants With Best Overall Response According to Lugano Classification [ Time Frame: 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) ]
  8. Percentage of Participants With Objective Response (Complete Response or Partial Response) According to Lugano Classification [ Time Frame: 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) ]
  9. Progression Free Survival (PFS) According to Lugano Classification [ Time Frame: 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) ]
  10. Overall Survival (OS) [ Time Frame: Baseline until death due to any cause (up to approximately 4.5 years) ]
  11. Duration of Objective Response (DOR) According to Lugano Classification [ Time Frame: 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) ]
  12. Tazemetostat Plasma Concentrations [ Time Frame: 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) ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02220842


Locations
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United States, California
City of Hope National Medical Center
Duarte, California, United States, 91010
United States, Indiana
Fort Wayne Neurological Center
Fort Wayne, Indiana, United States, 46805
United States, New Jersey
Hackensack University Medical Center
Hackensack, New Jersey, United States, 07601
United States, New York
Sloan Kettering Cancer Center
New York, New York, United States, 10065-6007
United States, North Carolina
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States, 27599
United States, Texas
MD Anderson Cancer Center
Houston, Texas, United States, 77030
United States, Washington
UW- Fred Hutchinson Cancer Center
Seattle, Washington, United States, 98109
France
Hopital Claude Huriez - CHU Lille; Service des maladies du sang
Lille, France, 59037
Hopital Saint Eloi
Montpellier, France, 34295
Hôpital Saint-Louis
Paris, France, 75475
Centre Hospitalier Lyon Sud
Pierre Benite, France, 69495
Institut Gustave Roussy
Villejuif, France, 94805
Germany
Universitaetsklinikum Freiburg
Freiburg, Germany, 79106
Italy
Azienda Ospedaliera Città della Salute e della Scienza di Torino
Torino, Piemonte, Italy, 10126
United Kingdom
Barts Hospital
London, United Kingdom, E1 2EF
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche
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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT02220842    
Other Study ID Numbers: GO29383
2014-001812-21 ( EudraCT Number )
First Posted: August 20, 2014    Key Record Dates
Last Update Posted: January 27, 2020
Last Verified: January 2020
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Follicular
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Atezolizumab
Obinutuzumab
Antineoplastic Agents
Antineoplastic Agents, Immunological