This phase I/II trial studies the side effects and best dose of lenalidomide when given in combination with rituximab and nivolumab and how well they work in treating participants with non-germinal center type diffuse large B cell lymphoma or primary central nervous system lymphoma that has come back or isn't responding to treatment. Monoclonal antibodies, such as rituximab and nivolumab, may interfere with ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as lenalidomide, 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. Giving rituximab, lenalidomide, and nivolumab may work better in treating participants with diffuse large B cell lymphoma.
PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose and toxicity profile of lenalidomide in combination with standard doses of rituximab and nivolumab in relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) (non-germinal center B cell \[non-GCB\]) and in primary central nervous system (CNS) lymphoma (PCNSL) (Phase I). II. Evaluate the efficacy of lenalidomide in combination with standard doses of rituximab and nivolumab in R/R non-GCB type DLBCL and PCNSL (Phase II). SECONDARY OBJECTIVES: I. To assess the safety and tolerability of nivolumab when combined with lenalidomide and rituximab. II. To determine the time to progression (complete response, partial response or stable disease), progression free survival (PFS) and overall survival (OS). III. To evaluate the difference in overall response rate between those with and without programmed cell death ligand 1 (PD-L1) protein expression in tumor (subgroup analysis). IV. To evaluate the difference in overall response rate between those with and without MYD88 mutation in tumor (subgroup analysis). EXPLORATORY OBJECTIVES: I. To perform PD-L1, PD-1 expression on tumor cells by immunohistochemistry including double staining for PAX-5 and PD-L1 and CD68 and PD-L1, CD3/CD4/CD8 for T cell infiltration, CD68 for tumor associated macrophages. II. To assess for presence of MYD88 L265 mutation by allele specific polymerase chain reaction (PCR) in tumor tissue and /or cerebrospinal fluid (CSF) (where lumbar puncture is clinically performed). III. To perform fluorescence in situ hybridization (FISH) for 9p24.1/ PD-L1/PD-L2 locus. IV. To evaluate MYD88 PCR on CSF (where available). V. To perform gene expression panel for tumor immune response in tumor samples (prioritizing cases in which a second serial biopsy is available). OUTLINE: This is a phase I, dose-escalation study of lenalidomide followed by a phase II study. Participants receive nivolumab intravenously (IV) over 60 minutes on days 1 and 15, rituximab IV on day 1, and lenalidomide orally (PO) once daily (QD) on days 1-21. Treatment repeats every 28 days for up to of 8 courses in the absence of disease progression or unacceptable toxicity. Patients with partial response (PR) or stable disease at the end of 8 cycles will be offered lenalidomide and nivolumab maintenance for up to 12 courses. After completion of study treatment, participants are followed up every 3 months for 2 years and then every 6 months until year 4.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
6
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States
Dose limiting toxicity (DLT) (Phase I)
The maximum-tolerated dose (MTD) is the highest dose at which no more than one dose limiting toxicities are observed among 6 subjects. The MTD of lenalidomide in combination with standard doses of rituximab and nivolumab will be determined from 3+3 design.
Time frame: At the end of cycle 2 (each cycle is 28 days)
Overall response rate (complete response, partial response, or stable disease) (Phase II)
Parametric tests such as t-test or the non-parametric statistical methods such as Wilcoxon rank sum will be used to compare differences in the means for endpoints of interest between response and non-response groups.
Time frame: At the end of cycle 8 (each cycle is 28 days)
Time to progression (complete response, partial response, or stable disease)
Parametric tests such as t-test or the non-parametric statistical methods such as Wilcoxon rank sum will be used to compare differences in the means for endpoints of interest between response and non-response groups.
Time frame: Up to 4 years
Progression free survival
Survival curves will be calculated from the Kaplan-Meier method. The median PFS with 95% confidence will be reported. Cox regression will be applied to assess the association between PFS/OS.
Time frame: From the time of enrollment in the study until progression, relapse, or death, assessed up to 4 years
Overall survival
Survival curves will be calculated from the Kaplan-Meier method. The median OS with 95% confidence will be reported. Cox regression will be applied to assess the association between progression free survival/overall survival
Time frame: From the time of enrollment in the study until death, assessed up to 4 years
Incidence of adverse events per national Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.03
Data from all subjects who receive any protocol therapy will be included in the safety analyses.
Time frame: Up to 30 days after treatment
Difference in overall response rate between those with and without programmed cell death ligand 1 (PD-L1) protein expression in tumor (subgroup analysis)
Parametric tests such as t-test or the non-parametric statistical methods such as Wilcoxon rank sum will be used to compare differences in the means for endpoints of interest between response and non-response groups.
Time frame: Up to 4 years
Difference in overall response rate between those with and without MYD88 mutation in tumor (subgroup analysis)
Parametric tests such as t-test or the non-parametric statistical methods such as Wilcoxon rank sum will be used to compare differences in the means for endpoints of interest between response and non-response groups.
Time frame: Up to 4 years
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