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

NCT03770416 | Completed Phase 2 FDA Drug

• 2 other identifiers: 2018-0510NCI-2018-02181
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• ORR

  At 4 weeks of ibrutinib single agent

• Progression free survival (PFS)

  From study entry to objective disease progression or death from any cause, assessed at 1 year

• Overall survival

  From study entry to death, assessed at 1 year

• Incidence of adverse events (AEs)

  Baseline up to 30 days after the last dose of study drug

Other Outcomes (3)

• T cells activation in peripheral blood and cerebrospinal fluid

  Baseline up to 2 years

• Cytokine profile from microglial cells in cerebrospinal fluid

  Baseline up to 2 years

• Tumor characteristics

  Baseline up to 2 years

Study Arms (2)

Cohort A

EXPERIMENTAL

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.

Drug: Ibrutinib; Biological: Nivolumab

Cohort B

EXPERIMENTAL

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.

Drug: Ibrutinib; Biological: Nivolumab

Interventions

Ibrutinib DRUG

Given PO

Also known as: BTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765

Cohort A; Cohort B

Nivolumab BIOLOGICAL

Given IV

Also known as: BMS-936558, MDX-1106, NIVO, ONO-4538, Opdivo

Cohort A; Cohort B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Age 18 years or older
• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2
• 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
• 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.
• Patients or their legally authorized representative must provide written informed consent.
• Hematology values must be within the following limits:
• Absolute neutrophil count (ANC) 1000/mm3 independent of growth factor support
• Platelets 100,000/mm3 or 50,000/mm3 if bone marrow involvement independent of transfusion support in either situation
• Creatinine clearance (CrCl) \> 30 ml/min

You may not qualify if:

• 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 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 PFT in a clinically significant manner.
• 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.
• Patients with uncontrolled active infection (viral, bacterial, and fungal) are not eligible.
• Active current hepatitis B or C infection/reactivation as measured by DNA/RNA quantification, or known seropositivity for HIV.
• Patient is pregnant or breast-feeding.

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Chihara D, Steiner RE, Nair R, Feng L, Ahmed S, Strati P, Malpica L, Griffith DP, Mathew SA, Montinez W, Masand G, Samaniego F, Rodriguez MA, Hagemeister FB, Fayad LE, Iyer SP, Nastoupil LJ, Neelapu SS, Flowers CR, Westin JR. Phase 2 trial of ibrutinib and nivolumab in patients with relapsed CNS lymphomas. Blood Adv. 2025 Apr 8;9(7):1485-1491. doi: 10.1182/bloodadvances.2024014635.

  PMID: 39908461 DERIVED

Related Links

• M D Anderson Cancer Center

MeSH Terms

Interventions

ibrutinib; Nivolumab

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Jason Westin, MD

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 4, 2018
• First Posted: December 10, 2018
• Study Start: February 15, 2019
• Primary Completion: February 10, 2025
• Study Completion: February 10, 2025
• Last Updated: February 28, 2025

Record last verified: 2025-02

Locations

US (1)