Clinical Trials /

Rituximab, Lenalidomide, and Nivolumab in Treating Participants With Relapsed or Refractory Non-Germinal Center Type Diffuse Large B Cell Lymphoma or Primary Central Nervous System Lymphoma

NCT03558750

Description:

This phase I/II trial studies the side effects and best dose of lenalidomide when given in combination with rituximab and nivolumab and how well they work in treating participants with non-germinal center type diffuse large B cell lymphoma or primary central nervous system lymphoma that has come back or isn't responding to treatment. Monoclonal antibodies, such as rituximab and nivolumab, may interfere with ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as lenalidomide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving rituximab, lenalidomide, and nivolumab may work better in treating participants with diffuse large B cell lymphoma.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Primary Central Nervous System Lymphoma
Recruiting Status:

Terminated

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Rituximab, Lenalidomide, and Nivolumab in Treating Participants With Relapsed or Refractory Non-Germinal Center Type Diffuse Large B Cell Lymphoma or Primary Central Nervous System Lymphoma
  • Official Title: Combination of Rituximab, Lenalidomide and Nivolumab for Relapsed/ Refractory Non-germinal Center (Non-GCB) Type Diffuse Large B Cell Lymphoma (DLBCL) Including Primary Central Nervous System Lymphoma (PCNSL): A Phase 1/2 Trial

Clinical Trial IDs

  • ORG STUDY ID: VICC PCL 1758
  • SECONDARY ID: NCI-2018-01092
  • NCT ID: NCT03558750

Conditions

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

Interventions

DrugSynonymsArms
NivolumabTreatment (nivolumab, rituximab, lenalidomide)
RituximabTreatment (nivolumab, rituximab, lenalidomide)
LenalidomideTreatment (nivolumab, rituximab, lenalidomide)

Purpose

This phase I/II trial studies the side effects and best dose of lenalidomide when given in combination with rituximab and nivolumab and how well they work in treating participants with non-germinal center type diffuse large B cell lymphoma or primary central nervous system lymphoma that has come back or isn't responding to treatment. Monoclonal antibodies, such as rituximab and nivolumab, may interfere with ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as lenalidomide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving rituximab, lenalidomide, and nivolumab may work better in treating participants with diffuse large B cell lymphoma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Determine the maximum tolerated dose and toxicity profile of lenalidomide in combination
      with standard doses of rituximab and nivolumab in relapsed/refractory (R/R) diffuse large B
      cell lymphoma (DLBCL) (non-germinal center B cell [non-GCB]) and in primary central nervous
      system (CNS) lymphoma (PCNSL) (Phase I).

      II. Evaluate the efficacy of lenalidomide in combination with standard doses of rituximab and
      nivolumab in R/R non-GCB type DLBCL and PCNSL (Phase II).

      SECONDARY OBJECTIVES:

      I. To assess the safety and tolerability of nivolumab when combined with lenalidomide and
      rituximab.

      II. To determine the time to progression (complete response, partial response or stable
      disease), progression free survival (PFS) and overall survival (OS).

      III. To evaluate the difference in overall response rate between those with and without
      programmed cell death ligand 1 (PD-L1) protein expression in tumor (subgroup analysis).

      IV. To evaluate the difference in overall response rate between those with and without MYD88
      mutation in tumor (subgroup analysis).

      EXPLORATORY OBJECTIVES:

      I. To perform PD-L1, PD-1 expression on tumor cells by immunohistochemistry including double
      staining for PAX-5 and PD-L1 and CD68 and PD-L1, CD3/CD4/CD8 for T cell infiltration, CD68
      for tumor associated macrophages.

      II. To assess for presence of MYD88 L265 mutation by allele specific polymerase chain
      reaction (PCR) in tumor tissue and /or cerebrospinal fluid (CSF) (where lumbar puncture is
      clinically performed).

      III. To perform fluorescence in situ hybridization (FISH) for 9p24.1/ PD-L1/PD-L2 locus.

      IV. To evaluate MYD88 PCR on CSF (where available). V. To perform gene expression panel for
      tumor immune response in tumor samples (prioritizing cases in which a second serial biopsy is
      available).

      OUTLINE: This is a phase I, dose-escalation study of lenalidomide followed by a phase II
      study.

      Participants receive nivolumab intravenously (IV) over 60 minutes on days 1 and 15, rituximab
      IV on day 1, and lenalidomide orally (PO) once daily (QD) on days 1-21. Treatment repeats
      every 28 days for up to of 8 courses in the absence of disease progression or unacceptable
      toxicity. Patients with partial response (PR) or stable disease at the end of 8 cycles will
      be offered lenalidomide and nivolumab maintenance for up to 12 courses.

      After completion of study treatment, participants are followed up every 3 months for 2 years
      and then every 6 months until year 4.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (nivolumab, rituximab, lenalidomide)ExperimentalNivolumab give by IV over 60 minutes on days 1 and 15, rituximab IV on day 1, and lenalidomide by mouth once per day on days 1-21. Repeats every 28 days for up to of 8 courses in the absence of disease progression or unacceptable toxicity. Patients with partial response or stable disease at the end of 8 cycles will be offered lenalidomide and nivolumab maintenance for up to 12 courses.
  • Lenalidomide

Eligibility Criteria

        Inclusion Criteria:

          -  Understand and voluntarily sign an informed consent form.

          -  Able to adhere to the study visit schedule and other protocol requirements in the
             opinion of the investigator

          -  Patients with histological confirmation of relapsed/refractory non-GCB type (using
             Hans algorithm) diffuse large B cell lymphoma (DLBCL) or relapsed/refractory primary
             CNS lymphoma (PCNSL) with at least one of the following characteristics:

               -  Definition of refractory disease: progression of disease based on Cheson criteria
                  for DLBCL or international primary CNS lymphoma cooperative group for PCNSL
                  either with nonresponse or progression within 3 months of prior therapy

               -  Definition of relapsed disease: progression of disease based on Cheson criteria
                  for DLBCL or International primary CNS lymphoma cooperative group for PCNSL at
                  least 3 months after prior therapy

               -  Definition of non-GCB subtype (Hans algorithm): cases will be subclassified based
                  on immunohistochemical staining with CD10, BCL-6 and MUM-1 as previously
                  described.

               -  Patients should have exhausted (or be ineligible for) approved therapies known to
                  provide clinical benefit for DLBCL or PCNSL (e.g. high dose chemotherapy with
                  autologous stem cell transplant, chimeric antigen receptor-transduced [CAR-T]
                  therapy, etc.).

          -  Eastern Cooperative Oncology Group (ECOG) performance status of =< 2 at study entry.

          -  Absolute neutrophil count >= 1000/mm^3 within 45 days prior to initiation of therapy.
             (Patients with documented marrow involvement (with lymphoma) or hypersplenism
             secondary to involvement of the spleen by lymphoma at the time of randomization are
             not required to meet the parameter).

          -  Platelet count >= 75K /mm^3 within 45 days prior to initiation of therapy. (Patients
             with documented marrow involvement (with lymphoma) or hypersplenism secondary to
             involvement of the spleen by lymphoma at the time of randomization are not required to
             meet the parameter).

          -  Serum creatinine =< 2.0 mg/dL or creatinine clearance of > 40 ml/min within 45 days
             prior to initiation of therapy. (Patients with documented marrow involvement (with
             lymphoma) or hypersplenism secondary to involvement of the spleen by lymphoma at the
             time of randomization are not required to meet the parameter).

          -  Total bilirubin =< 1.5 mg/dL within 45 days prior to initiation of therapy. (Patients
             with documented marrow involvement (with lymphoma) or hypersplenism secondary to
             involvement of the spleen by lymphoma at the time of randomization are not required to
             meet the parameter).

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2 x
             upper limit of normal (ULN) within 45 days prior to initiation of therapy. (Patients
             with documented marrow involvement (with lymphoma) or hypersplenism secondary to
             involvement of the spleen by lymphoma at the time of randomization are not required to
             meet the parameter).

          -  Disease free of prior malignancies for >= 3 years with exception of currently treated
             basal cell or squamous cell carcinoma of the skin, or carcinoma "in situ" of the
             cervix or breast.

          -  All study participants must be registered into the mandatory Revlimid Risk Evaluation
             and Mitigation Strategies (REMS) program, and be willing and able to comply with the
             requirements of the Revlimid REMS program. program, and be willing and able to comply
             with the requirements of the Revlimid REMS program.

             * Females of childbearing potential (FCBP) must have a negative serum or urine
             pregnancy test with a sensitivity of at least 50 mIU/mL within 10-14 days and again
             within 24 hours prior to prescribing lenalidomide for cycle 1 (prescriptions must be
             filled within 7 days as required by the Revlimid REMS program) and must either commit
             to continued abstinence from heterosexual intercourse or begin TWO acceptable methods
             of birth control, one highly effective method and one additional effective method AT
             THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also
             agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual
             contact with a FCBP even if they have had a successful vasectomy.

             ** A female of childbearing potential is a sexually mature female who: 1) has not
             undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally
             postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in
             the preceding 24 consecutive months).

          -  Able to take aspirin (81 or 325 mg) daily or for thromboprophylaxis with lenalidomide.

        Exclusion Criteria:

          -  Any serious medical condition, laboratory abnormality, or psychiatric illness that
             would prevent the subject from signing the informed consent.

          -  Pregnant or breast feeding females (lactating females must agree not to breast feed
             while taking lenalidomide).

          -  Any condition, including the presence of laboratory abnormalities, which places the
             subject at unacceptable risk if he/she were to participate in the study or confounds
             the ability to interpret data from the study.

          -  Use of any other experimental drug or therapy within 28 days of baseline.

          -  Known hypersensitivity to thalidomide.

          -  Known prior development of erythema nodosum if characterized by a desquamating rash
             while taking thalidomide or similar drugs.

          -  Concurrent use of other anti-cancer agents or treatments.

          -  Patients with a prior history of pulmonary toxicity due to medications (Ex: history of
             carmustine [BCNU] toxicity).

          -  Active human immunodeficiency virus (HIV) infection or infectious hepatitis, type B or
             C.

               -  Patients with a past or resolved hepatitis B virus (HBV) infection (defined as
                  the presence of hepatitis B core antibody [anti-HBc] and absence of hepatitis B
                  surface antigen [HBsAg]) may be included if HBV deoxyribonucleic acid (DNA) is
                  undetectable. If enrolled, patients must be willing to undergo monthly HBV DNA
                  testing.

               -  HIV positive patients may enroll if they meet all of the below criteria:

                    -  HIV is sensitive to antiretroviral therapy.

                    -  Must be willing to take effective antiretroviral therapy if indicated.

                    -  No history of CD4 prior to or at the time of lymphoma diagnosis < 300
                       cells/mm^3.

                    -  No history of acquired immunodeficiency syndrome (AIDS)-defining conditions.

                    -  If on antiretroviral therapy, must not be taking zidovudine or stavudine.

                    -  Must be willing to take prophylaxis for pneumocystis jiroveci pneumonia
                       (PCP) during therapy and until at least 2 months following the completion of
                       therapy or until the CD4 cells recover to over 250 cells/mm^3, whichever
                       occurs later.

          -  A diagnosis of deep vein thromboses in the preceding four weeks of study enrollment.

          -  Subjects with active interstitial pneumonitis.

          -  Patient with active, uncontrolled infections (patients must be afebrile for > 48 hours
             off antibiotics).

          -  Patient with clinically significant history of liver disease, including viral or other
             hepatitis, current alcohol abuse, or cirrhosis.

          -  Subjects with active, known or suspected autoimmune disease. Subjects with 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 are permitted
             to enroll.

          -  Evidence of significant, uncontrolled concomitant diseases that could affect
             compliance with the protocol or interpretation of results or that could increase risk
             to the patient, including renal disease that would preclude chemotherapy
             administration or pulmonary disease (including obstructive pulmonary disease and
             history of bronchospasm).

          -  Major surgery within 4 weeks prior to cycle 1, other than for diagnosis.

          -  Malabsorption syndrome or other condition that precludes oral route of administration
             of lenalidomide.

          -  Vaccinations with a live vaccine within 28 days prior to start of treatment or need
             for live vaccine at any time during study treatment.

          -  Patient must not have serious medical or psychiatric illness likely to interfere with
             participation in this clinical study in the opinion of the investigator.

          -  Inability to swallow oral medications.

          -  Subjects with New York Heart Association (NYHA) class III or IV heart failure.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:19 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting toxicity (DLT) (Phase I)
Time Frame:At the end of cycle 2 (each cycle is 28 days)
Safety Issue:
Description:The maximum-tolerated dose (MTD) is the highest dose at which no more than one dose limiting toxicities are observed among 6 subjects. The MTD of lenalidomide in combination with standard doses of rituximab and nivolumab will be determined from 3+3 design.

Secondary Outcome Measures

Measure:Time to progression (complete response, partial response, or stable disease)
Time Frame:Up to 4 years
Safety Issue:
Description:Parametric tests such as t-test or the non-parametric statistical methods such as Wilcoxon rank sum will be used to compare differences in the means for endpoints of interest between response and non-response groups.
Measure:Progression free survival
Time Frame:From the time of enrollment in the study until progression, relapse, or death, assessed up to 4 years
Safety Issue:
Description:Survival curves will be calculated from the Kaplan-Meier method. The median PFS with 95% confidence will be reported. Cox regression will be applied to assess the association between PFS/OS.
Measure:Overall survival
Time Frame:From the time of enrollment in the study until death, assessed up to 4 years
Safety Issue:
Description:Survival curves will be calculated from the Kaplan-Meier method. The median OS with 95% confidence will be reported. Cox regression will be applied to assess the association between progression free survival/overall survival
Measure:Incidence of adverse events per national Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.03
Time Frame:Up to 30 days after treatment
Safety Issue:
Description:Data from all subjects who receive any protocol therapy will be included in the safety analyses.
Measure:Difference in overall response rate between those with and without programmed cell death ligand 1 (PD-L1) protein expression in tumor (subgroup analysis)
Time Frame:Up to 4 years
Safety Issue:
Description:Parametric tests such as t-test or the non-parametric statistical methods such as Wilcoxon rank sum will be used to compare differences in the means for endpoints of interest between response and non-response groups.
Measure:Difference in overall response rate between those with and without MYD88 mutation in tumor (subgroup analysis)
Time Frame:Up to 4 years
Safety Issue:
Description:Parametric tests such as t-test or the non-parametric statistical methods such as Wilcoxon rank sum will be used to compare differences in the means for endpoints of interest between response and non-response groups.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Vanderbilt-Ingram Cancer Center

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