Testing the Addition of Lenalidomide and Nivolumab to the Usual Treatment for Primary CNS Lymphoma

Study Purpose

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).

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years and Over
Gender	All

More Inclusion & Exclusion Criteria

Inclusion Criteria:

- Histologically proven primary CNS diffuse large b-cell lymphoma confirmed by one of the following: - Brain biopsy or resection.

- Cerebrospinal fluid.

- Vitreous fluid.

- No prior organ transplantation to exclude post-transplant lymphoproliferative disorders.

- No prior chemotherapy or radiation therapy for lymphoma.

- No prior allogeneic stem cell transplantation.

- Use of systemic corticosteroids (dexamethasone up to 24 mg/day or equivalent) for disease control or improvement of performance status to be tapered as fast as clinically safe after initiation of therapy is permissible.

- Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown and an agent that has known genotoxic, mutagenic and teratogenic effects.

Therefore, female of childbearing potential (FCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) =< 7 days prior to registration.

- Age >= 18 years.

- Karnofsky performance scale (KPS) >= 40 (>= 50 for patients older than 60 unless related to lymphoma on investigator's opinion) - Absolute neutrophil count (ANC) >= 1,500/mm^3.

- Platelet count >= 100,000/mm^3.

- Calculated creatinine clearance >= 50 mL/min by Cockcroft-Gault formula.

- Total Bilirubin =< 1.5 x upper limit of normal (ULN) - Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN) - No evidence of non-Hodgkin's lymphoma (NHL) outside CNS.

- No prior history of NHL.

- No history of autoimmune disorder.

Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded. These include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as Systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease. Patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible. Patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible.

- Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event) - Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (except short course of systemic corticosteroids for disease control or improvement of performance status or other immunosuppressive medications within 14 days prior to registration.

Inhaled or topical steroids and adrenal replacement doses < 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if < 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted.

- Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study.

- No prior or concurrent malignancies with exception of surgically cured carcinoma in situ (CIS) of the uterus, carcinoma of the skin without evidence of disease for >= 5 years.

- No concurrent malignancy requiring active therapy.

- No untreated hepatitis C virus (HCV) infection with detectable HCV viral load.

- No untreated chronic hepatitis B virus (HBV) infection with detectable HBV viral load.

- No untreated human immunodeficiency virus (HIV) infection or with detectable viral load or with CD4+T-cell count of less than 500/mm^3.

- No history of HIV infection and evidence of Epstein Barr virus (EBV)-related primary central nervous system lymphoma (PCNSL) - Inability to tolerate anticoagulation with acetylsalicylic acid, warfarin, or direct oral anticoagulants.

- No other investigational agent.

- No history of severe hypersensitivity reaction to any monoclonal antibody.

- No history of allergic reactions attributed to compounds of similar chemical or biologic composition to or other agents used in study.

- Sulfonamide drugs, trimethoprim, salicylates, nonsteroidal anti-inflammatory drugs, penicillin, vitamin C, ciprofloxacin, and proton pump inhibitors should be held at least 48 hours prior to methotrexate administration

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT04609046
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 1
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	National Cancer Institute (NCI)
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Alvaro J Alencar
Principal Investigator Affiliation	Alliance for Clinical Trials in Oncology
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	NIH
Overall Status	Recruiting
Countries	United States
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System

Additional Details

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.

Arms & Interventions

Arms

Experimental: Treatment (rituximab, methotrexate, lenalidomide, nivolumab)

INDUCTION: Patients receive rituximab IV on day 1, methotrexate IV over 2 hours or 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 MRI, CT, PET/CT, lumbar puncture, bone marrow aspirate and biopsy, testicular ultrasound and ECHO. (See Detailed Description)

Interventions

Procedure: - Bone Marrow Aspiration and Biopsy

Undergo bone marrow aspirate and biopsy

Procedure: - Computed Tomography

Undergo CT and PET/CT

Procedure: - Echocardiography Test

Undergo ECHO

Drug: - Lenalidomide

Given PO

Procedure: - Lumbar Puncture

Undergo lumbar puncture

Procedure: - Magnetic Resonance Imaging

Undergo MRI

Drug: - Methotrexate

Given IV or PO

Biological: - Nivolumab

Given IV

Procedure: - Positron Emission Tomography

Undergo PET/CT

Biological: - Rituximab

Given IV

Procedure: - Ultrasound Imaging

Undergo testicular ultrasound

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

Cedars Sinai Medical Center, Los Angeles 5368361, California 5332921

Status

Recruiting

Address

Cedars Sinai Medical Center

Los Angeles 5368361, California 5332921, 90048

Site Contact

Site Public Contact

310-423-8965

UCSF Medical Center-Parnassus, San Francisco 5391959, California 5332921

Status

Recruiting

Address

UCSF Medical Center-Parnassus

San Francisco 5391959, California 5332921, 94143

Site Contact

Site Public Contact

877-827-3222

Coral Gables 4151871, Florida 4155751

Status

Recruiting

Address

UM Sylvester Comprehensive Cancer Center at Coral Gables

Coral Gables 4151871, Florida 4155751, 33146

Site Contact

Site Public Contact

305-243-2647

Deerfield Beach 4153071, Florida 4155751

Status

Recruiting

Address

UM Sylvester Comprehensive Cancer Center at Deerfield Beach

Deerfield Beach 4153071, Florida 4155751, 33442

Site Contact

Site Public Contact

305-243-2647

Miami 4164138, Florida 4155751

Status

Recruiting

Address

University of Miami Miller School of Medicine-Sylvester Cancer Center

Miami 4164138, Florida 4155751, 33136

Site Contact

Site Public Contact

305-243-2647

Miami 4164138, Florida 4155751

Status

Recruiting

Address

UM Sylvester Comprehensive Cancer Center at Kendall

Miami 4164138, Florida 4155751, 33176

Site Contact

Site Public Contact

305-243-2647

Plantation 4168782, Florida 4155751

Status

Recruiting

Address

UM Sylvester Comprehensive Cancer Center at Plantation

Plantation 4168782, Florida 4155751, 33324

Site Contact

Site Public Contact

305-243-2647

Iowa Methodist Medical Center, Des Moines 4853828, Iowa 4862182

Status

Recruiting

Address

Iowa Methodist Medical Center

Des Moines 4853828, Iowa 4862182, 50309

Site Contact

Site Public Contact

515-241-6727

Des Moines 4853828, Iowa 4862182

Status

Recruiting

Address

UI Health Care Mission Cancer and Blood - Des Moines Clinic

Des Moines 4853828, Iowa 4862182, 50309

Site Contact

Site Public Contact

515-241-3305

Broadlawns Medical Center, Des Moines 4853828, Iowa 4862182

Status

Recruiting

Address

Broadlawns Medical Center

Des Moines 4853828, Iowa 4862182, 50314

Site Contact

Site Public Contact

515-282-2200

Mercy Medical Center - Des Moines, Des Moines 4853828, Iowa 4862182

Status

Recruiting

Address

Mercy Medical Center - Des Moines

Des Moines 4853828, Iowa 4862182, 50314

Site Contact

Site Public Contact

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