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

NCT04609046 · National Cancer Institute (NCI)
In plain English

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Official title
Phase I Trial of Methotrexate, Rituximab, Lenalidomide, and Nivolumab (Nivo-MR2) Induction Followed by Lenalidomide and Nivolumab Maintenance in Primary CNS Lymphoma
About this study
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.
Eligibility 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
Study design
Enrollment target: 47 participants
Allocation: na
Masking: none
Age groups: adult, older_adult
Timeline
Starts: 2021-05-24
Estimated completion: 2027-04-01
Last updated: 2026-04-17
Interventions
Procedure: Bone Marrow Aspiration and BiopsyProcedure: Computed TomographyProcedure: Echocardiography TestDrug: LenalidomideProcedure: Lumbar PunctureProcedure: Magnetic Resonance ImagingDrug: MethotrexateBiological: NivolumabProcedure: Positron Emission TomographyBiological: RituximabProcedure: Ultrasound Imaging
Primary outcomes
  • Maximum tolerated dose (During the first 14-day cycle of treatment)
  • Proportion of evaluable patients who are able to stay on maintenance therapy (Up to 6 months)
Sponsor
National Cancer Institute (NCI) · nih
Contacts & investigators
InvestigatorAlvaro J Alencar · principal_investigator, Alliance for Clinical Trials in Oncology
All locations (54)
Cedars Sinai Medical CenterRecruiting
Los Angeles, California, United States
UCSF Medical Center-ParnassusRecruiting
San Francisco, California, United States
UM Sylvester Comprehensive Cancer Center at Coral GablesRecruiting
Coral Gables, Florida, United States
UM Sylvester Comprehensive Cancer Center at Deerfield BeachRecruiting
Deerfield Beach, Florida, United States
University of Miami Miller School of Medicine-Sylvester Cancer CenterRecruiting
Miami, Florida, United States
UM Sylvester Comprehensive Cancer Center at KendallRecruiting
Miami, Florida, United States
University of Miami Sylvester Comprehensive Cancer Center at Sole MiaRecruiting
North Miami, Florida, United States
UM Sylvester Comprehensive Cancer Center at PlantationRecruiting
Plantation, Florida, United States
UI Health Care Mission Cancer and Blood - Ankeny ClinicRecruiting
Ankeny, Iowa, United States
Saint Anthony Regional HospitalRecruiting
Carroll, Iowa, United States
UI Health Care Mission Cancer and Blood - West Des Moines ClinicRecruiting
Clive, Iowa, United States
Iowa Methodist Medical CenterRecruiting
Des Moines, Iowa, United States
UI Health Care Mission Cancer and Blood - Des Moines ClinicRecruiting
Des Moines, Iowa, United States
Broadlawns Medical CenterRecruiting
Des Moines, Iowa, United States
Mercy Medical Center - Des MoinesRecruiting
Des Moines, Iowa, United States
UI Health Care Mission Cancer and Blood - Laurel ClinicRecruiting
Des Moines, Iowa, United States
Iowa Lutheran HospitalSuspended
Des Moines, Iowa, United States
UI Healthcare Mission Cancer and Blood - Fort DodgeSuspended
Fort Dodge, Iowa, United States
UI Health Care Mission Cancer and Blood - Waukee ClinicRecruiting
Waukee, Iowa, United States
Methodist West HospitalSuspended
West Des Moines, Iowa, United States
LSU Health Baton Rouge-North ClinicActive Not Recruiting
Baton Rouge, Louisiana, United States
Our Lady of the Lake Physician GroupActive Not Recruiting
Baton Rouge, Louisiana, United States
MaineHealth Maine Medical Center - PortlandRecruiting
Portland, Maine, United States
MaineHealth Maine Medical Center- ScarboroughRecruiting
Scarborough, Maine, United States
MaineHealth Cancer Care and IV Therapy - South PortlandRecruiting
South Portland, Maine, United States
Hickman Cancer CenterActive Not Recruiting
Adrian, Michigan, United States
Toledo Clinic Cancer Centers-MonroeActive Not Recruiting
Monroe, Michigan, United States
Siteman Cancer Center at Saint Peters HospitalRecruiting
City of Saint Peters, Missouri, United States
Siteman Cancer Center at West County HospitalRecruiting
Creve Coeur, Missouri, United States
Washington University School of MedicineRecruiting
St Louis, Missouri, United States
Siteman Cancer Center-South CountyRecruiting
St Louis, Missouri, United States
Siteman Cancer Center at Christian HospitalRecruiting
St Louis, Missouri, United States
Overlook HospitalRecruiting
Summit, New Jersey, United States
Northwell Health/Center for Advanced MedicineRecruiting
Lake Success, New York, United States
North Shore University HospitalRecruiting
Manhasset, New York, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer CenterRecruiting
New York, New York, United States
NYP/Weill Cornell Medical CenterRecruiting
New York, New York, United States
State University of New York Upstate Medical UniversityActive Not Recruiting
Syracuse, New York, United States
UNC Lineberger Comprehensive Cancer CenterRecruiting
Chapel Hill, North Carolina, United States
Ohio State University Comprehensive Cancer CenterRecruiting
Columbus, Ohio, United States
Toledo Clinic Cancer Centers-ToledoActive Not Recruiting
Toledo, Ohio, United States
University of Oklahoma Health Sciences CenterRecruiting
Oklahoma City, Oklahoma, United States
Rhode Island HospitalRecruiting
Providence, Rhode Island, United States
Medical University of South CarolinaRecruiting
Charleston, South Carolina, United States
UT Southwestern/Simmons Cancer Center-DallasRecruiting
Dallas, Texas, United States
Huntsman Cancer Institute/University of UtahActive Not Recruiting
Salt Lake City, Utah, United States
West Virginia University HealthcareRecruiting
Morgantown, West Virginia, United States
Marshfield Medical Center-EC Cancer CenterRecruiting
Eau Claire, Wisconsin, United States
Gundersen Lutheran Medical CenterRecruiting
La Crosse, Wisconsin, United States
Marshfield Medical Center-MarshfieldRecruiting
Marshfield, Wisconsin, United States
Marshfield Medical Center - MinocquaRecruiting
Minocqua, Wisconsin, United States
Marshfield Medical Center-Rice LakeRecruiting
Rice Lake, Wisconsin, United States
Marshfield Medical Center-River Region at Stevens PointRecruiting
Stevens Point, Wisconsin, United States
Marshfield Medical Center - WestonRecruiting
Weston, Wisconsin, United States