Clinical trial NCT02220842: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Lymphoma
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2014-08-20
Enrollment: 96
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Percentage of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: 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)
measure: Recommended Phase 2 Dose (RP2D) of Atezolizumab
timeFrame: 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 outcomes:
measure: Obinutuzumab Minimum Serum Concentration (Cmin)
timeFrame: 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)
measure: 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)
timeFrame: Baseline up to approximately 4.5 years
measure: Percentage of Participants With Anti-therapeutic Antibody Response to Atezolizumab and Obinutuzumab
timeFrame: Baseline up to approximately 4.5 years
measure: Atezolizumab Maximum Serum Concentration (Cmax)
timeFrame: Preinfusion (hour 0) on Day 1 of Cycle 1 up to approx 57 weeks (detailed timeframe is provided in outcome description section)
measure: Atezolizumab Minimum Serum Concentration (Cmin)
timeFrame: Preinfusion (hour 0) on Day 1 of Cycle 1 up to approx 57 weeks (detailed timeframe is provided in outcome description section)
measure: Obinutuzumab Maximum Serum Concentration (Cmax)
timeFrame: Arm 1: Preinfusion (hour 0) on Day 1 of Cycle 1 up to approx 57 weeks (detailed timeframe is provided in outcome description section)
measure: Percentage of Participants With Best Overall Response According to Lugano Classification
timeFrame: 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)
measure: Percentage of Participants With Objective Response (Complete Response or Partial Response) According to Lugano Classification
timeFrame: 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)
measure: Progression Free Survival (PFS) According to Lugano Classification
timeFrame: 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)
measure: Overall Survival (OS)
timeFrame: Baseline until death due to any cause (up to approximately 4.5 years)
measure: Duration of Objective Response (DOR) According to Lugano Classification
timeFrame: 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)
measure: Tazemetostat Plasma Concentrations
timeFrame: 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)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Fort Wayne
country: United States
facility: Fort Wayne Neurological Center
state: Indiana
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: Sloan Kettering Cancer Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: UW- Fred Hutchinson Cancer Center
state: Washington
city: Lille
country: France
facility: Hopital Claude Huriez - CHU Lille; Service des maladies du sang
city: Montpellier
country: France
facility: Hopital Saint Eloi
city: Paris
country: France
facility: Hôpital Saint-Louis
city: Pierre Benite
country: France
facility: Centre Hospitalier Lyon Sud
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg
city: Torino
country: Italy
facility: Azienda Ospedaliera Città della Salute e della Scienza di Torino
state: Piemonte
city: London
country: United Kingdom
facility: Barts Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.