Testing the Addition of Lenalidomide and Nivolumab to the Usual Treatment for Primary CNS Lymphoma
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|ClinicalTrials.gov Identifier: NCT04609046|
Recruitment Status : Recruiting
First Posted : October 30, 2020
Last Update Posted : May 31, 2023
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|Condition or disease||Intervention/treatment||Phase|
|Central Nervous System Lymphoma Diffuse Large B-Cell Lymphoma||Drug: Lenalidomide Procedure: Magnetic Resonance Imaging Drug: Methotrexate Biological: Nivolumab Biological: Rituximab||Phase 1|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||32 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase I Trial of Methotrexate, Rituximab, Lenalidomide, and Nivolumab (Nivo-MR2) Induction Followed by Lenalidomide and Nivolumab Maintenance in Primary CNS Lymphoma|
|Actual Study Start Date :||January 15, 2021|
|Estimated Primary Completion Date :||May 31, 2024|
|Estimated Study Completion Date :||May 31, 2024|
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 5-14, 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.
Procedure: Magnetic Resonance Imaging
Given IV or PO
- Maximum tolerated dose (MTD) [ Time Frame: Up to 6 months ]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 (CTEP) 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.
- Proportion of evaluable patients who are able to stay on maintenance therapy [ Time Frame: Up to 6 months ]The proportion of evaluable patients who meet the criteria for maintenance feasibility, along with the 95% exact binomial confidence interval, will be provided.
- Overall response [ Time Frame: Up to 5 years ]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).
- Progression free survival (PFS) [ Time Frame: Time from start of induction treatment to progression or death due to any cause ]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.
- Overall Survival (OS) [ Time Frame: Time from start of induction treatment to death due to any cause ]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.
- Incidence of adverse events [ Time Frame: Up to 5 years ]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.
- Minimal residual disease (MRD) [ Time Frame: Up to 5 years ]Will estimate the proportion of patients with MRD at each time point with 95% confidence intervals. Will also use swimmer plots and other graphical analyses to visualize when MRD is detected/not detected in sequential samples relative to progression of disease.
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|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
Histologically proven primary CNS diffuse large b-cell lymphoma confirmed by one of the following:
- Brain biopsy or resection
- Cerebrospinal fluid
- Vitreous fluid
- At least one measurable, contrast-enhancing lesion in the brain (>= 1 cm in length), CSF or vitreous (intraocular lymphoma)
- 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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04609046
|Principal Investigator:||Alvaro J Alencar||Alliance for Clinical Trials in Oncology|
|Responsible Party:||National Cancer Institute (NCI)|
|Other Study ID Numbers:||
NCI-2020-08331 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
A051901 ( Other Identifier: Alliance for Clinical Trials in Oncology )
A051901 ( Other Identifier: CTEP )
U10CA180821 ( U.S. NIH Grant/Contract )
|First Posted:||October 30, 2020 Key Record Dates|
|Last Update Posted:||May 31, 2023|
|Last Verified:||March 2023|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||Yes|
|Plan Description:||NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Immune System Diseases
Antineoplastic Agents, Immunological
Physiological Effects of Drugs
Abortifacient Agents, Nonsteroidal
Reproductive Control Agents
Molecular Mechanisms of Pharmacological Action