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

Nivolumab and Ibrutinib for Relapsed or Refractory Central Nervous System Lymphoma

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.

Study Overview

• Status: Completed
• Conditions: Refractory Central Nervous System Lymphoma; Central Nervous System B-Cell Non-Hodgkin Lymphoma; Recurrent Central Nervous System Lymphoma
• Intervention / Treatment: Biological: Nivolumab; Drug: Ibrutinib

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.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Relapsed refractory central nervous system lymphoma, pathology confirmed B cell lymphoma either by biopsy or by CSF review. Patient must previously have had at least one line of systemic therapy for CNS lymphoma.
2. Age 18 years or older
3. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2

4. Patients must have adequate renal and hepatic function

   • 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
   • ALT and AST ≤3 x ULN
5. Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotrophin (β-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.
6. Patients or their legally authorized representative must provide written informed consent.

7. Hematology values must be within the following limits:

   1. Absolute neutrophil count (ANC) 1000/mm3 independent of growth factor support
   2. Platelets 100,000/mm3 or 50,000/mm3 if bone marrow involvement independent of transfusion support in either situation
8. Creatinine clearance (CrCl) > 30 ml/min

Exclusion Criteria:

1. 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
2. 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.
3. 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.
4. History of stroke or cerebral hemorrhage within 6 months of enrollment.
5. Patients who have uncontrolled hypertension (defined as sustained systolic blood pressure ≥ 160 mmHg or diastolic ≥ 100 mmHg)
6. Prior history of BTK inhibitor or PD1 inhibitor prior to start of trial.
7. Active, uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia requiring steroid therapy.
8. 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).
9. 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 GVHD for at least 30 days before cycle 1 day 1.
10. Patients with organ allografts (such as renal transplant) are excluded.
11. History of biopsy proven interstitial lung disease or pneumonitis which has impacted PFT in a clinically significant manner.
12. Patients who are on high dose steroids (>10mg daily of prednisone or equivalent) or immune suppression medications. Note: Patients on high-dose steroids (doses >10mg/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.
13. Patients with uncontrolled active infection (viral, bacterial, and fungal) are not eligible.
14. Active current hepatitis B or C infection/reactivation as measured by DNA/RNA quantification, or known seropositivity for HIV.
15. Patient is pregnant or breast-feeding.
16. Malabsorption syndrome or other condition that precludes enteral route of administration.
17. Concomitant use of warfarin or other Vitamin K antagonists.
18. Requires chronic treatment with a strong cytochrome P450 (CYP) 3A inhibitor (see Appendix 3).
19. 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.
20. Vaccinated with live, attenuated vaccines within 4 weeks of enrollment.
21. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A; Patients 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.	Biological: Nivolumab; Given IV; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo; Drug: Ibrutinib; Given PO; Other Names: PCI-32765; Imbruvica; BTK Inhibitor PCI-32765; CRA-032765
Experimental: 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.	Biological: Nivolumab; Given IV; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo; Drug: Ibrutinib; Given PO; Other Names: PCI-32765; Imbruvica; BTK Inhibitor PCI-32765; CRA-032765

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR)	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.	Up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR	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.	At 4 weeks of ibrutinib single agent
Progression free survival (PFS)	Will be estimated using the method of Kaplan and Meier.	From study entry to objective disease progression or death from any cause, assessed at 1 year
Overall survival	Will be estimated using the method of Kaplan and Meier.	From study entry to death, assessed at 1 year
Incidence of adverse events (AEs)	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.	Baseline up to 30 days after the last dose of study drug

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
T cells activation in peripheral blood and cerebrospinal fluid	Descriptive statistics including plots, mean, median and standard deviations will be used to summarize data. T-test and analysis of variance (ANOVA) will be used to compare outcome measures across patient characteristics. Dunnett's and Tukey's test that properly adjust for multiplicity in multiple tests will be implemented. Pair-wise comparisons will be performed using pre- and post-therapy samples from each patient. The chi-square (c2) test or Fisher's exact test will be used to test the association between two categorical variables such as disease state and performance status. Both univariate and multivariate logistic regressions will be performed to model prognostic factors.	Baseline up to 2 years
Cytokine profile from microglial cells in cerebrospinal fluid	Descriptive statistics including plots, mean, median and standard deviations will be used to summarize data. T-test and ANOVA will be used to compare outcome measures across patient characteristics. Dunnett's and Tukey's test that properly adjust for multiplicity in multiple tests will be implemented. Pair-wise comparisons will be performed using pre- and post-therapy samples from each patient. The chi-square (c2) test or Fisher's exact test will be used to test the association between two categorical variables such as disease state and performance status. Both univariate and multivariate logistic regressions will be performed to model prognostic factors.	Baseline up to 2 years
Tumor characteristics	Correlation baseline tumor characteristics with response and PFS will be calculated. Pair-wise comparisons will be performed using pre- and post-therapy samples from each patient. The chi-square (c2) test or Fisher's exact test will be used to test the association between two categorical variables such as disease state and performance status.	Baseline up to 2 years

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Jason Westin, MD, M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• M D Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): February 15, 2019
• Primary Completion (Actual): February 10, 2025
• Study Completion (Actual): February 10, 2025

Study Registration Dates

• First Submitted: December 4, 2018
• First Submitted That Met QC Criteria: December 6, 2018
• First Posted (Actual): December 10, 2018

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 26, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Tyrosine Kinase Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Nivolumab; Ibrutinib
• Other Study ID Numbers: 2018-0510 (Other Identifier: M D Anderson Cancer Center); NCI-2018-02181 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No