A Pilot Phase I Study of Atezolizumab (MPDL3280A) in Combination With Immunogenic Chemotherapy (Gemcitabine-Oxaliplatin) and Rituximab for Transformed Diffuse Large B-Cell Lymphoma
Overview
- Phase
- Phase 1
- Intervention
- Computed Tomography
- Conditions
- Recurrent Diffuse Large B-Cell Lymphoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 24
- Locations
- 4
- Primary Endpoint
- Incidence of adverse events
- Status
- Active, Not Recruiting
- Last Updated
- 19 days ago
Overview
Brief Summary
This pilot phase I trial studies the side effects of atezolizumab, gemcitabine, oxaliplatin, and rituximab and to see how well they work in treating patients with transformed diffuse large B-cell lymphoma that has come back (relapsed) or does not respond to treatment (refractory). Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as gemcitabine and oxaliplatin, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Giving atezolizumab, gemcitabine, oxaliplatin, and rituximab may work better in treating patients with transformed diffuse large B-cell lymphoma.
Detailed Description
PRIMARY OBJECTIVES: I. Assess the safety and toxicity of atezolizumab in combination with immunogenic chemotherapy (gemcitabine plus oxaliplatin) with rituximab (R-GEMOX-ATEZO) in patients with relapsed or refractory (rel/ref) transformed diffuse large B-cell lymphoma (DLBCL), including determination of the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of R-GEMOX-ATEZO. II. Evaluate on-treatment changes in density of and proximity between immune cell subsets in the tumor microenvironment after immunogenic chemotherapy alone and R-GEMOX-ATEZO. SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity. II. Evaluate genomic (e.g. gene expression profiles, whole exome sequencing) characteristics of patients with rel/ref transformed DLBCL treated with R-GEMOX-ATEZO. OUTLINE: INDUCTION PHASE: Patients receive rituximab intravenously (IV), gemcitabine IV, and oxaliplatin IV every 2 weeks. Starting cycle 2, patients also receive atezolizumab IV over 30-60 minutes every 2 weeks. Treatment repeats every 14 days of cycle 1 and every 28 days for up to 4 cycles in the absence of disease progression or unaccepted toxicity. Patients also undergo computed tomography (CT), positron emission tomography (PET)-CT, magnetic resonance imaging (MRI), bone marrow biopsy, collection of blood samples, and tumor biopsy throughout induction phase. MAINTENANCE PHASE: Patients receive rituximab IV and atezolizumab over 30-60 minutes IV on day 1. Cycles repeat every 3 weeks in the absence of disease progression or unaccepted toxicity. Patients also undergo CT, PET-CT, MRI, bone marrow biopsy, and collection of blood samples throughout maintenance phase. After completion of study treatment, patients are followed up at 30 days and then every 6 months for up to 1 year.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have histologically confirmed transformed diffuse large B-cell lymphoma (DLBCL), including histologic transformation from any indolent lymphoma (e.g. follicular or marginal zone lymphoma) or Richter transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)
- •Patients must have measurable disease by CT or PET scan, with one or more sites of disease \>= 1.5 cm in longest dimension
- •Relapsed or refractory disease after at least 1 prior regimen, defined using the 2014 Lugano classification
- •Age \>= 18 years. Because no dosing or adverse event data are currently available on the use of atezolizumab in patients \<18 years of age, children are excluded from this study, but will be eligible for future pediatric trials
- •Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
- •Life expectancy of greater than 3 months
- •Leukocytes \>= 2,500/mcL, unless documented bone marrow involvement by lymphoma
- •Absolute neutrophil count \>= 1,000/mcL, unless documented bone marrow involvement by lymphoma
- •Platelets \>= 75,000/mcL, unless documented bone marrow involvement by lymphoma
- •Hemoglobin \>= 8 g/dL, unless documented bone marrow involvement by lymphoma
Exclusion Criteria
- •Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation
- •Patients who have previously received gemcitabine plus oxaliplatin therapy
- •Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events (other than alopecia) due to agents administered more than 2 weeks earlier; however, the following therapies are allowed:
- •Hormone-replacement therapy or oral contraceptives
- •Herbal therapy \> 1 week prior to cycle 1, day 1 (herbal therapy intended as anticancer therapy must be discontinued at least 1 week prior to cycle 1, day 1)
- •Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents
- •Patients who have received prior treatment with anti-CTLA-4 may be enrolled, provided the following requirements are met:
- •Minimum of 12 weeks from the first dose of anti-CTLA-4 and \> 6 weeks from the last dose
- •No history of severe immune-related adverse effects from anti-CTLA-4 (National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] version 5.0)
- •Treatment with any other investigational agent within 3 weeks prior to cycle 1, day 1
Arms & Interventions
Treatment (rituximab, gemcitabine, oxaliplatin, atezolizumab)
INDUCTION PHASE: Patients receive rituximab IV, gemcitabine IV, and oxaliplatin IV every 2 weeks. Starting cycle 2, patients also receive atezolizumab IV over 30-60 minutes every 2 weeks. Treatment repeats every 14 days of cycle 1 and every 28 days for up to 4 cycles in the absence of disease progression or unaccepted toxicity. Patients also undergo CT, PET-CT, MRI, bone marrow biopsy, collection of blood samples, and tumor biopsy throughout induction phase. MAINTENANCE PHASE: Patients receive rituximab IV and atezolizumab IV over 30-60 minutes on day 1. Cycles repeat every 3 weeks in the absence of disease progression or unaccepted toxicity. Patients also undergo CT, PET-CT, MRI, bone marrow biopsy, and collection of blood samples throughout maintenance phase.
Intervention: Computed Tomography
Treatment (rituximab, gemcitabine, oxaliplatin, atezolizumab)
INDUCTION PHASE: Patients receive rituximab IV, gemcitabine IV, and oxaliplatin IV every 2 weeks. Starting cycle 2, patients also receive atezolizumab IV over 30-60 minutes every 2 weeks. Treatment repeats every 14 days of cycle 1 and every 28 days for up to 4 cycles in the absence of disease progression or unaccepted toxicity. Patients also undergo CT, PET-CT, MRI, bone marrow biopsy, collection of blood samples, and tumor biopsy throughout induction phase. MAINTENANCE PHASE: Patients receive rituximab IV and atezolizumab IV over 30-60 minutes on day 1. Cycles repeat every 3 weeks in the absence of disease progression or unaccepted toxicity. Patients also undergo CT, PET-CT, MRI, bone marrow biopsy, and collection of blood samples throughout maintenance phase.
Intervention: Magnetic Resonance Imaging
Treatment (rituximab, gemcitabine, oxaliplatin, atezolizumab)
INDUCTION PHASE: Patients receive rituximab IV, gemcitabine IV, and oxaliplatin IV every 2 weeks. Starting cycle 2, patients also receive atezolizumab IV over 30-60 minutes every 2 weeks. Treatment repeats every 14 days of cycle 1 and every 28 days for up to 4 cycles in the absence of disease progression or unaccepted toxicity. Patients also undergo CT, PET-CT, MRI, bone marrow biopsy, collection of blood samples, and tumor biopsy throughout induction phase. MAINTENANCE PHASE: Patients receive rituximab IV and atezolizumab IV over 30-60 minutes on day 1. Cycles repeat every 3 weeks in the absence of disease progression or unaccepted toxicity. Patients also undergo CT, PET-CT, MRI, bone marrow biopsy, and collection of blood samples throughout maintenance phase.
Intervention: Biopsy Procedure
Treatment (rituximab, gemcitabine, oxaliplatin, atezolizumab)
INDUCTION PHASE: Patients receive rituximab IV, gemcitabine IV, and oxaliplatin IV every 2 weeks. Starting cycle 2, patients also receive atezolizumab IV over 30-60 minutes every 2 weeks. Treatment repeats every 14 days of cycle 1 and every 28 days for up to 4 cycles in the absence of disease progression or unaccepted toxicity. Patients also undergo CT, PET-CT, MRI, bone marrow biopsy, collection of blood samples, and tumor biopsy throughout induction phase. MAINTENANCE PHASE: Patients receive rituximab IV and atezolizumab IV over 30-60 minutes on day 1. Cycles repeat every 3 weeks in the absence of disease progression or unaccepted toxicity. Patients also undergo CT, PET-CT, MRI, bone marrow biopsy, and collection of blood samples throughout maintenance phase.
Intervention: Rituximab
Treatment (rituximab, gemcitabine, oxaliplatin, atezolizumab)
INDUCTION PHASE: Patients receive rituximab IV, gemcitabine IV, and oxaliplatin IV every 2 weeks. Starting cycle 2, patients also receive atezolizumab IV over 30-60 minutes every 2 weeks. Treatment repeats every 14 days of cycle 1 and every 28 days for up to 4 cycles in the absence of disease progression or unaccepted toxicity. Patients also undergo CT, PET-CT, MRI, bone marrow biopsy, collection of blood samples, and tumor biopsy throughout induction phase. MAINTENANCE PHASE: Patients receive rituximab IV and atezolizumab IV over 30-60 minutes on day 1. Cycles repeat every 3 weeks in the absence of disease progression or unaccepted toxicity. Patients also undergo CT, PET-CT, MRI, bone marrow biopsy, and collection of blood samples throughout maintenance phase.
Intervention: Oxaliplatin
Treatment (rituximab, gemcitabine, oxaliplatin, atezolizumab)
INDUCTION PHASE: Patients receive rituximab IV, gemcitabine IV, and oxaliplatin IV every 2 weeks. Starting cycle 2, patients also receive atezolizumab IV over 30-60 minutes every 2 weeks. Treatment repeats every 14 days of cycle 1 and every 28 days for up to 4 cycles in the absence of disease progression or unaccepted toxicity. Patients also undergo CT, PET-CT, MRI, bone marrow biopsy, collection of blood samples, and tumor biopsy throughout induction phase. MAINTENANCE PHASE: Patients receive rituximab IV and atezolizumab IV over 30-60 minutes on day 1. Cycles repeat every 3 weeks in the absence of disease progression or unaccepted toxicity. Patients also undergo CT, PET-CT, MRI, bone marrow biopsy, and collection of blood samples throughout maintenance phase.
Intervention: Gemcitabine
Treatment (rituximab, gemcitabine, oxaliplatin, atezolizumab)
INDUCTION PHASE: Patients receive rituximab IV, gemcitabine IV, and oxaliplatin IV every 2 weeks. Starting cycle 2, patients also receive atezolizumab IV over 30-60 minutes every 2 weeks. Treatment repeats every 14 days of cycle 1 and every 28 days for up to 4 cycles in the absence of disease progression or unaccepted toxicity. Patients also undergo CT, PET-CT, MRI, bone marrow biopsy, collection of blood samples, and tumor biopsy throughout induction phase. MAINTENANCE PHASE: Patients receive rituximab IV and atezolizumab IV over 30-60 minutes on day 1. Cycles repeat every 3 weeks in the absence of disease progression or unaccepted toxicity. Patients also undergo CT, PET-CT, MRI, bone marrow biopsy, and collection of blood samples throughout maintenance phase.
Intervention: Bone Marrow Biopsy
Treatment (rituximab, gemcitabine, oxaliplatin, atezolizumab)
INDUCTION PHASE: Patients receive rituximab IV, gemcitabine IV, and oxaliplatin IV every 2 weeks. Starting cycle 2, patients also receive atezolizumab IV over 30-60 minutes every 2 weeks. Treatment repeats every 14 days of cycle 1 and every 28 days for up to 4 cycles in the absence of disease progression or unaccepted toxicity. Patients also undergo CT, PET-CT, MRI, bone marrow biopsy, collection of blood samples, and tumor biopsy throughout induction phase. MAINTENANCE PHASE: Patients receive rituximab IV and atezolizumab IV over 30-60 minutes on day 1. Cycles repeat every 3 weeks in the absence of disease progression or unaccepted toxicity. Patients also undergo CT, PET-CT, MRI, bone marrow biopsy, and collection of blood samples throughout maintenance phase.
Intervention: Atezolizumab
Treatment (rituximab, gemcitabine, oxaliplatin, atezolizumab)
INDUCTION PHASE: Patients receive rituximab IV, gemcitabine IV, and oxaliplatin IV every 2 weeks. Starting cycle 2, patients also receive atezolizumab IV over 30-60 minutes every 2 weeks. Treatment repeats every 14 days of cycle 1 and every 28 days for up to 4 cycles in the absence of disease progression or unaccepted toxicity. Patients also undergo CT, PET-CT, MRI, bone marrow biopsy, collection of blood samples, and tumor biopsy throughout induction phase. MAINTENANCE PHASE: Patients receive rituximab IV and atezolizumab IV over 30-60 minutes on day 1. Cycles repeat every 3 weeks in the absence of disease progression or unaccepted toxicity. Patients also undergo CT, PET-CT, MRI, bone marrow biopsy, and collection of blood samples throughout maintenance phase.
Intervention: Biospecimen Collection
Treatment (rituximab, gemcitabine, oxaliplatin, atezolizumab)
INDUCTION PHASE: Patients receive rituximab IV, gemcitabine IV, and oxaliplatin IV every 2 weeks. Starting cycle 2, patients also receive atezolizumab IV over 30-60 minutes every 2 weeks. Treatment repeats every 14 days of cycle 1 and every 28 days for up to 4 cycles in the absence of disease progression or unaccepted toxicity. Patients also undergo CT, PET-CT, MRI, bone marrow biopsy, collection of blood samples, and tumor biopsy throughout induction phase. MAINTENANCE PHASE: Patients receive rituximab IV and atezolizumab IV over 30-60 minutes on day 1. Cycles repeat every 3 weeks in the absence of disease progression or unaccepted toxicity. Patients also undergo CT, PET-CT, MRI, bone marrow biopsy, and collection of blood samples throughout maintenance phase.
Intervention: Positron Emission Tomography
Outcomes
Primary Outcomes
Incidence of adverse events
Time Frame: Up to course 2 (42 days)
Adverse events will be graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Observed toxicities will be summarized by dose limiting toxicity (DLT) (yes/no) as well as by type (organ affected or laboratory determination such as absolute neutrophil count), severity, cycle experienced, and attribution. All patients who begin treatment will be included in the summaries of toxicity.
Maximum tolerated dose (MTD) and recommended phase 2 dose
Time Frame: Course 2, up to 28 days
MTD and recommended phase 2 dose will be determined by DLT. Toxicities will be graded according to CTCAE criteria version 5.0. The study will use a traditional 3+3 design.
Secondary Outcomes
- Complete response rate(Up to 1 year)
- Best overall response rate (complete response + partial response)(Up to 1 year)
- Biomarker analysis(Up to 1 year)