This phase I trial tests the safety, side effects, best dose and effectiveness of lenalidomide when added to nivolumab and the usual drugs (rituximab and methotrexate) in patients with primary central nervous system (CNS) lymphoma. Lenalidomide may stop or slow primary CNS lymphoma by blocking the growth of new blood vessels necessary for tumor growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of cancer cells to grow and spread. Rituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Methotrexate is frequently combined with other chemotherapy agents to improve response. This study may help increase the understanding of lenalidomide and nivolumab use in primary CNS lymphoma treatment. In addition, it may help researchers see whether the control of CNS lymphoma can be extended by using these study drugs as maintenance (prolonged therapy) after control is achieved with the initial chemotherapy regimen (induction).
PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose (MTD) of lenalidomide when given in combination with high dose-methotrexate (HD-MTX) and rituximab, with or without nivolumab, as induction treatment of primary CNS lymphoma. II. Determine the proportion of patients who are able to stay on maintenance therapy with lenalidomide and/or nivolumab for 6 months after induction treatment of primary CNS lymphoma. SECONDARY OBJECTIVES: I. To evaluate the overall response rate (ORR) of the combination of methotrexate, rituximab, lenalidomide, nivolumab. II. To evaluate the effect of the treatment regimen and lenalidomide / nivolumab maintenance on progression free survival (PFS). III. To evaluate the effect of the treatment regimen and lenalidomide / nivolumab maintenance on overall survival (OS). EXPLORATORY OBJECTIVES: I. To analyze tumor tissue and cerebrospinal fluid (CSF) for gene expression profiles, and to correlate these profiles with treatment outcomes. II. To determine whether CSF proteome and metabolome are predictors of outcomes (prognostic marker). III. To assess response to therapy and minimal residual disease via MRI-based metrics and minimal residual disease of blood and CSF. IV. To evaluate the relationship between neurocognitive deficits and tumor and brain volumetrics, as assessed by magnetic resonance imaging (MRI) and tumor metabolism. OUTLINE: This is a dose-escalation study of lenalidomide. INDUCTION: Patients receive rituximab intravenously (IV) on day 1, methotrexate IV over 2 hours or orally (PO) on day 2, lenalidomide PO daily on days 5-9, and nivolumab IV over 30 minutes on day 14. (In dose level IV that includes nivolumab, the doses of rituximab for cycles 2-6 may be given on the same day as nivolumab for the previous cycle). Treatment repeats every 14 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve complete response, partial response, or stable disease proceed to maintenance therapy. MAINTENANCE: Within 6 weeks after the last dose of lenalidomide in induction therapy, patients receive lenalidomide PO daily on days 1-21, and nivolumab IV over 30 minutes on day 1. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo magnetic resonance imaging (MRI) throughout the trial, computed tomography (CT) and positron emission tomography (PET)/CT during screening, and lumbar puncture at the end of the 6th cycle of induction, and after 6 months of maintenance. Patients may also undergo bone marrow aspirate and biopsy, testicular ultrasound and/or echocardiogram (ECHO) during screening. After completion of study treatment, patients are followed up every 3 months for 2 years, then every 6 months for up to 2 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
47
Undergo bone marrow aspirate and biopsy
Undergo CT and PET/CT
Undergo ECHO
Given PO
Undergo lumbar puncture
Undergo MRI
Given IV or PO
Given IV
Undergo PET/CT
Given IV
Undergo testicular ultrasound
Cedars Sinai Medical Center
Los Angeles, California, United States
RECRUITINGUCSF Medical Center-Parnassus
San Francisco, California, United States
RECRUITINGUM Sylvester Comprehensive Cancer Center at Coral Gables
Coral Gables, Florida, United States
RECRUITINGUM Sylvester Comprehensive Cancer Center at Deerfield Beach
Deerfield Beach, Florida, United States
Maximum tolerated dose
Defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients). The number and severity of all adverse events will be tabulated and summarized in this patient population both overall and by dose level according to the Common Terminology Criteria for Adverse Events (CTCAE) Cancer Therapy Evaluation Program version 5.0 criteria. The grade 3+ adverse events will also be described and summarized in a similar fashion. This will provide an indication of the level of tolerance for this treatment combination in this patient group.
Time frame: During the first 14-day cycle of treatment
Proportion of evaluable patients who are able to stay on maintenance therapy
The proportion of evaluable patients who meet the criteria for maintenance feasibility, along with the 95% exact binomial confidence interval, will be provided.
Time frame: Up to 6 months
Overall response
Will be estimated by the number of patients with the objective status of complete response, unconfirmed complete response, or partial response divided by the total number of evaluable patients. The overall response rate with an exact binomial 95% confidence interval will be provided and will be analyzed at the end of induction therapy and again after all therapy (induction and maintenance).
Time frame: Up to 5 years
Progression free survival (PFS)
The distribution of progression-free survival will be estimated using the method of Kaplan-Meier (Kaplan-Meier, 1958). PFS time from start of maintenance therapy will also be reported in a similar fashion as the PFS time starting from induction therapy.
Time frame: Time from start of induction treatment to progression or death due to any cause
Overall Survival (OS)
The distribution of overall survival will be estimated using the method of Kaplan-Meier (Kaplan-Meier, 1958). OS time from start of maintenance therapy will also be reported in a similar fashion as the OS time starting from induction therapy.
Time frame: Time from start of induction treatment to death due to any cause
Incidence of adverse events
Toxicity will be measured by the CTCAE version 5.0. The maximum grade, frequency, and severity for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration and analyzed descriptively.
Time frame: Up to 5 years
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University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, United States
RECRUITINGUM Sylvester Comprehensive Cancer Center at Kendall
Miami, Florida, United States
RECRUITINGUniversity of Miami Sylvester Comprehensive Cancer Center at Sole Mia
North Miami, Florida, United States
RECRUITINGUM Sylvester Comprehensive Cancer Center at Plantation
Plantation, Florida, United States
RECRUITINGUI Health Care Mission Cancer and Blood - Ankeny Clinic
Ankeny, Iowa, United States
RECRUITINGSaint Anthony Regional Hospital
Carroll, Iowa, United States
RECRUITING...and 44 more locations