Clinical Trials /

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

NCT04609046

Description:

This phase I trial evaluates the side effects and best dose 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).

Related Conditions:
  • Primary Central Nervous System Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of Lenalidomide and Nivolumab to the Usual Treatment for Primary CNS Lymphoma
  • Official Title: Phase I Trial of Methotrexate, Rituximab, Lenalidomide, and Nivolumab (Nivo-MR2) Induction Followed by Lenalidomide and Nivolumab Maintenance in Primary CNS Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-08331
  • SECONDARY ID: NCI-2020-08331
  • SECONDARY ID: A051901
  • SECONDARY ID: A051901
  • SECONDARY ID: U10CA180821
  • NCT ID: NCT04609046

Conditions

  • Central Nervous System Lymphoma
  • Diffuse Large B-Cell Lymphoma

Interventions

DrugSynonymsArms
LenalidomideCC-5013, CC5013, CDC 501, RevlimidTreatment (rituximab, methotrexate, lenalidomide, nivolumab)
MethotrexateAbitrexate, Alpha-Methopterin, Amethopterin, Brimexate, CL 14377, CL-14377, Emtexate, Emthexat, Emthexate, Farmitrexat, Fauldexato, Folex, Folex PFS, Lantarel, Ledertrexate, Lumexon, Maxtrex, Medsatrexate, Metex, Methoblastin, Methotrexate LPF, Methotrexate Methylaminopterin, Methotrexatum, Metotrexato, Metrotex, Mexate, Mexate-AQ, MTX, Novatrex, Rheumatrex, Texate, Tremetex, Trexeron, Trixilem, WR-19039Treatment (rituximab, methotrexate, lenalidomide, nivolumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (rituximab, methotrexate, lenalidomide, nivolumab)
RituximabABP 798, BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT-P10, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8, PF-05280586, Rituxan, Rituximab ABBS, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar GB241, Rituximab Biosimilar IBI301, Rituximab Biosimilar JHL1101, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, rituximab biosimilar TQB2303, rituximab-abbs, RTXM83, TruximaTreatment (rituximab, methotrexate, lenalidomide, nivolumab)

Purpose

This phase I trial evaluates the side effects and best dose 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).

Detailed Description

      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 5-14, and nivolumab IV over 30
      minutes on day 14. 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 5 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.

      After completion of study treatment, patients are followed up every 3 months for 2 years,
      then every 6 months for up to 3 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (rituximab, methotrexate, lenalidomide, nivolumab)ExperimentalINDUCTION: 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. 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 5 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.
  • Lenalidomide
  • Methotrexate
  • Nivolumab
  • Rituximab

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

          -  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

          -  Short course systemic corticosteroids (dexamethasone up to 24 mg/day or equivalent)
             for disease control or improvement of performance status (=< 10 days) 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

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD)
Time Frame:Up to 6 months
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Overall response
Time Frame:Up to 5 years
Safety Issue:
Description: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).
Measure:Progression free survival (PFS)
Time Frame:Time from start of induction treatment to progression or death due to any cause
Safety Issue:
Description: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.
Measure:Overall Survival (OS)
Time Frame:Time from start of induction treatment to death due to any cause
Safety Issue:
Description: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.
Measure:Incidence of adverse events
Time Frame:Up to 5 years
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

November 9, 2020