Testing the Addition of an Immunotherapy Agent, Atezolizumab, When Given With the Usual Chemo-Immunotherapy Drug Combination (Rituximab plus Gemcitabine and Oxaliplatin) for Relapsed/Refractory (That has Come Back or not Responded to Treatment) Transformed Diffuse Large B-Cell Lymphoma
18 Years and older, Male and Female
10126 (primary)
PHI-96
10126
NCI-2017-01957
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.
Objectives
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 by multispectral immunofluorescence, including density of CD8+ cells and cytotoxic lymphocyte (CTL):regulatory T cell (Treg) ratio.
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.
Eligibility
- 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
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (however, patients with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN (AST and/or ALT =< 5 x ULN for patients with liver involvement)
- Alkaline phosphatase =< 2.5 x ULN (=< 5 x ULN for patients with documented liver involvement or bone metastases)
- Creatinine clearance >= 30 mL/min/1.73 m^2 by Cockcroft-Gault
- International normalized ratio (INR) and partial thromboplastin time (aPTT) =< 1.5 x ULN (this applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation, such as low-molecular-weight heparin or warfarin, should be on a stable dose)
- Administration of atezolizumab may have an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-lethality; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 5 months (150 days) after the last dose of study agent; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
- Ability to understand and the willingness to sign a written informed consent document
- Patients positive for human immunodeficiency virus (HIV) are allowed on study, but HIV-positive patients must have:
* A stable regimen of highly active anti-retroviral therapy (HAART)
* No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections
* A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard polymerase chain reaction (PCR)-based tests
Treatment Sites in Georgia
1125 Troupe Street
Augusta, GA 30904
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