Clinical Trials /

Nivolumab and Ibrutinib in Treating Patients With Relapsed or Refractory Central Nervous System Lymphoma

NCT03770416

Description:

This phase II trial studies the side effects and how well nivolumab and ibrutinib works in treating patients with central nervous system lymphoma that has come back or does not respond to treatment. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Ibrutinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving nivolumab and ibrutinib may work better in treating patients with central nervous system lymphoma.

Related Conditions:
  • Central Nervous System Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab and Ibrutinib in Treating Patients With Relapsed or Refractory Central Nervous System Lymphoma
  • Official Title: Nivolumab and Ibrutinib for Relapsed or Refractory Central Nervous System Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 2018-0510
  • SECONDARY ID: NCI-2018-02181
  • SECONDARY ID: 2018-0510
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03770416

Conditions

  • Central Nervous System B-Cell Non-Hodgkin Lymphoma
  • Recurrent Central Nervous System Lymphoma
  • Refractory Central Nervous System Lymphoma

Interventions

DrugSynonymsArms
IbrutinibBTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765Cohort A
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoCohort A

Purpose

This phase II trial studies the side effects and how well nivolumab and ibrutinib works in treating patients with central nervous system lymphoma that has come back or does not respond to treatment. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Ibrutinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving nivolumab and ibrutinib may work better in treating patients with central nervous system lymphoma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Determine the overall response rate of nivolumab and ibrutinib in central nervous system
      (CNS) lymphoma.

      SECONDARY OBJECTIVES:

      I. Determine the overall response rate of 4 weeks of ibrutinib single agent in CNS lymphoma.

      II. Determine the complete response rate of nivolumab and ibrutinib in CNS lymphoma.

      III. Determine the 1-year progression free and overall survival outcomes in CNS lymphoma.

      IV. Safety and toxicity of nivolumab and ibrutinib.

      EXPLORATORY OBJECTIVES:

      I. Assess activation of T cells in peripheral blood and cerebrospinal fluid. II. Assess the
      cytokine profile from microglial cells in cerebrospinal fluid. III. Correlate features of
      peripheral blood T cell activation with toxicities. IV. Correlate features of peripheral
      blood T cell activation with response and progression free survival (PFS).

      V. Correlate baseline tumor characteristics with response and PFS. VI. Evaluate the ability
      of minimal residual disease testing to monitor response and differentiate from pseudo
      progression.

      OUTLINE: Patients are assigned to 1 of 2 cohorts.

      COHORT A: Patients receive ibrutinib orally (PO) daily on days 1-28. Beginning course 1,
      patients also receive nivolumab intravenously (IV) over 1 hour on days 1 and 15. Treatment
      repeats every 28 days for up to 6 courses in the absence of disease progression or
      unacceptable toxicity.

      COHORT B: Patients receive ibrutinib PO daily on days 1-28 and nivolumab IV over 1 hour on
      days 1 and 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease
      progression or unacceptable toxicity.

      Patients who achieve at least a partial response after 6 courses may continue therapy for up
      to 2 years.

      After completion of study treatment, patients are followed up within 3-4 weeks and then every
      3 months for 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort AExperimentalPatients receive ibrutinib PO daily on days 1-28. Beginning course 1, patients also receive nivolumab IV over 1 hour on days 1 and 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients who achieve at least a partial response after 6 courses may continue therapy for up to 2 years.
  • Ibrutinib
  • Nivolumab
Cohort BExperimentalPatients receive ibrutinib PO daily on days 1-28 and nivolumab IV over 1 hour on days 1 and 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients who achieve at least a partial response after 6 courses may continue therapy for up to 2 years.
  • Ibrutinib
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Relapsed refractory central nervous system lymphoma, pathology confirmed B cell
             lymphoma either by biopsy or by cerebrospinal fluid (CSF) review. Patient must
             previously have had one line of systemic therapy for CNS lymphoma

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN). For patients with Gilbert's
             disease, total bilirubin up to =< 3 x ULN is allowed provided normal direct bilirubin

          -  Serum creatinine =< 1.5 x ULN

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN

          -  Females of childbearing potential must have a negative serum or urine beta human
             chorionic gonadotrophin (beta-hCG) pregnancy test result within 24 hours prior to the
             first dose of treatment and must agree to use a highly effective contraception method
             during the study and for 23 weeks following the last dose of the study drugs. Females
             of non- childbearing potential are those who are postmenopausal greater than 1 year or
             who have had a bilateral tubal ligation or hysterectomy. Males who have partners of
             childbearing potential must agree to use an effective contraceptive method during the
             study and for 31 weeks following the last dose of study drugs. Men must agree not to
             donate sperm during and for 3 months after the last dose of study drug. Women who are
             pregnant or breastfeeding are ineligible for this study

          -  Patients or their legally authorized representative must provide written informed
             consent

          -  Absolute neutrophil count (ANC) >= 1000/mm^3 independent of growth factor support

          -  Platelets >= 100,000/mm^3 or >= 50,000/mm^3 if bone marrow involvement independent of
             transfusion support in either situation

          -  Creatinine clearance (CrCl) > 25 ml/min

        Exclusion Criteria:

          -  History of another primary invasive malignancy that has not been definitively treated
             or in remission for at least 2 years. Patients with non-melanoma skin cancers or with
             carcinomas in situ are eligible regardless of the time from diagnosis (including
             concomitant diagnoses). If patients have another malignancy that was treated within
             the last 2 years, such patients may be enrolled if the likelihood of requiring
             systemic therapy for this other malignancy within 2 years is less than 10%, as
             determined by an expert in that particular malignancy at MD Anderson Cancer Center and
             after consultation with the principal investigator

          -  Any major surgery or wound that has not healed, radiotherapy, cytotoxic chemotherapy,
             biologic therapy, immunotherapy, immunomodulatory drugs, experimental therapy within 4
             weeks prior to the first dose of the study drugs

          -  Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias,
             congestive heart failure, or myocardial infarction within 6 months of screening, or
             any class 3 or 4 cardiac disease as defined by the New York Heart Association
             functional classification

          -  History of stroke or cerebral hemorrhage within 6 months of enrollment

          -  Patients who have uncontrolled hypertension (defined as sustained systolic blood
             pressure >= 160 mmHg or diastolic >= 100 mmHg)

          -  Prior history of BTK inhibitor or PD1 inhibitor prior to start of trial

          -  Active, uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia requiring
             steroid therapy

          -  Patients with autoimmune diseases are excluded: Patients with a history of
             inflammatory bowel disease (including Crohn's disease and ulcerative colitis) are
             excluded from this study as are patients with a history of autoimmune disease (e.g.,
             rheumatoid arthritis, systemic progressive sclerosis, systemic lupus erythematosus,
             Wegener's granulomatosis)

          -  Patients with previous allogeneic stem cell transplant (SCT) within 6 months or with
             active acute or chronic graft-versus host disease are excluded. Patients must be off
             immunosuppression for graft versus host disease (GVHD) for at least 30 days before
             cycle 1 day 1

          -  Patients with organ allografts (such as renal transplant) are excluded

          -  History of biopsy proven interstitial lung disease or pneumonitis which has impacted
             pulmonary function test (PFT) in a clinically significant manner

          -  Patients who are on high dose steroids (> 10 mg daily of prednisone or equivalent) or
             immune suppression medications

               -  Note: Patients on high-dose steroids (doses > 10 mg/day of prednisone or
                  equivalent) or immune suppression medications are eligible provided these drugs
                  are discontinued at least 3 days prior to starting on the study drugs

          -  Patients with uncontrolled active infection (viral, bacterial, and fungal) are not
             eligible

          -  Active current hepatitis B or C infection/reactivation as measured by deoxyribonucleic
             acid (DNA)/ribonucleic acid (RNA) quantification, or known seropositivity for human
             immunodeficiency virus (HIV)

          -  Patient is pregnant or breast-feeding

          -  Malabsorption syndrome or other condition that precludes enteral route of
             administration

          -  Concomitant use of warfarin or other vitamin K antagonists.

          -  Requires chronic treatment with a strong cytochrome P450 (CYP) 3A inhibitor

          -  Other severe acute or chronic medical or psychiatric condition or laboratory
             abnormality that in the opinion of the investigator may increase the risk associated
             with study participation or investigational product administration or may interfere
             with the interpretation of study results and/or would make the patient inappropriate
             for enrollment into this study

          -  Vaccinated with live, attenuated vaccines within 4 weeks of enrollment

          -  Any life-threatening illness, medical condition, or organ system dysfunction which, in
             the investigator's opinion, could compromise the subject's safety, interfere with the
             absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue
             risk
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:Up to 2 years
Safety Issue:
Description:The overall response rate and its 95% confidence interval will be estimated. Fisher's exact test will be used to evaluate the association between response and other categorical patient variables.

Secondary Outcome Measures

Measure:ORR
Time Frame:At 4 weeks of ibrutinib single agent
Safety Issue:
Description:The overall response rate and its 95% confidence interval will be estimated. Fisher's exact test will be used to evaluate the association between response and other categorical patient variables.
Measure:Progression free survival (PFS)
Time Frame:From study entry to objective disease progression or death from any cause, assessed at 1 year
Safety Issue:
Description:Will be estimated using the method of Kaplan and Meier.
Measure:Overall survival
Time Frame:From study entry to death, assessed at 1 year
Safety Issue:
Description:Will be estimated using the method of Kaplan and Meier.
Measure:Incidence of adverse events (AEs)
Time Frame:Baseline up to 30 days after the last dose of study drug
Safety Issue:
Description:AE data will be summarized by frequency tables for all patients. For the toxicity endpoint, per-treated analysis will be performed to include any patient who received the treatment regardless of the eligibility nor the duration or dose of the treatment received.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

May 16, 2019