Ibrutinib + Chemotherapy for CNS Lymphoma
Recruiting in Palo Alto (17 mi)
+15 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Memorial Sloan Kettering Cancer Center
Must not be taking: Warfarin, CYP3A inhibitors
Disqualifiers: Active malignancy, HIV, Hepatitis, others
No Placebo Group
Breakthrough Therapy
Approved in 4 Jurisdictions
Trial Summary
What is the purpose of this trial?The purpose of this study is to test any good or bad effects of the study drug called of ibrutinib (also known as Imbruvica™). At this stage of this trial, the study is investigating whether Ibrutinib can be incorporated into the established first-line chemotherapy regimen rituximab, methotrexate, vincristine, and procarbazine (R-VMP) in order to further refine the first-line induction therapy for PCNSL, as observed by a superior CRR (complete response rate) (ARM D RECRUITING ONLY)
Do I have to stop taking my current medications for the trial?
The trial requires that you stop taking certain medications before starting the study drug. Specifically, you must stop using warfarin or similar anticoagulants at least seven days prior, and any drugs that affect the P450/CYP3A enzyme at least two weeks prior. Additionally, you must stop systemic immunosuppressant therapy at least 28 days before the first dose.
What data supports the effectiveness of the drug Ibrutinib in treating CNS Lymphoma?
Research shows that Ibrutinib, when used alone or with chemotherapy, can significantly reduce tumors in patients with central nervous system lymphoma. In one study, 94% of patients showed tumor reductions with Ibrutinib alone, and 86% achieved complete remission when combined with chemotherapy.
12345Is the combination of Ibrutinib and chemotherapy safe for treating CNS lymphoma?
Ibrutinib, when used alone or with chemotherapy for CNS lymphoma, has shown some safety concerns, particularly an increased risk of aspergillosis (a type of fungal infection) due to its effect on the immune system. However, it has been generally well-tolerated in some patients, with one case showing good tolerance and sustained remission.
12367How does the drug ibrutinib differ from other treatments for CNS lymphoma?
Ibrutinib is unique because it is a Bruton's tyrosine kinase inhibitor, which means it works by blocking a specific protein that helps cancer cells grow. This mechanism is different from standard chemotherapy, which often cannot cross the blood-brain barrier to reach the central nervous system effectively.
89101112Eligibility Criteria
This trial is for adults with primary or secondary central nervous system lymphoma who have had at least one prior CNS therapy (except for some newly diagnosed cases). They must understand the study and consent, have a certain level of physical function, adequate organ function, agree to use effective birth control, and not be pregnant. Exclusions include uncontrolled infections, certain drug interactions, severe heart conditions, inability to swallow capsules, among others.Inclusion Criteria
My bilirubin levels are within the normal range, or slightly elevated due to Gilbert Syndrome.
I am 18 years old or older.
Absolute neutrophil count (ANC) ≥ 0.75 x 109/L
+20 more
Exclusion Criteria
I have had a stem cell transplant from a donor.
I am not using other cancer drugs except for approved supportive care.
I've had recent cancer treatment or am still experiencing side effects.
+22 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive 4 cycles of therapy with Methotrexate, Rituximab, Vincristine, Procarbazine, and Ibrutinib. Ibrutinib is dosed at 560 mg daily, with a safety lead-in of 6 patients.
16 weeks
Multiple visits for each cycle
Follow-up
Participants are monitored for safety and effectiveness after treatment, with progression-free survival assessed.
2 years
Dose Escalation
Establish the maximum-tolerated dose (MTD) of ibrutinib as a single agent and in combination with high-dose Methotrexate (HD-MTX).
1 year
Participant Groups
The trial tests Ibrutinib's effectiveness when added to an established chemotherapy regimen (rituximab + high-dose methotrexate + procarbazine) in patients with central nervous system lymphoma. It aims to improve complete response rates by refining first-line induction therapy.
4Treatment groups
Experimental Treatment
Group I: Arm D: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSLExperimental Treatment4 Interventions
THIS IS ONLY ARM RECRUITING In Arm D, patients will be treated with 4 cycles of therapy. Methotrexate (3.5 g/m2) will be given at Dday 1 and Dday 15 of each cycle. Rituximab (500 mg/m2) will be given at Dday 0 and Dday 15 of each cycle. Vincristine (1.4mg/m2) will be given at Dday 1 and 15 of cycle 1 and 2 only. Procarbazine (100mg/m2) will be given of Day 1 of each cycle. Ibrutinib will be dosed at 560 mg daily. Arm D will have a safety lead-in of 6 patients. If more than 1 of 6 subjects develop a dose limiting toxicity (DLT) within the first 28 days of therapy (cycle 1), ibrutinib will be reduced to 420 mg daily dosing, and 6 additional patients will be enrolled. If more than 1 of 6 subjects develop a DLT, additional enrollment will be stopped.
Group II: Arm C: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSLExperimental Treatment3 Interventions
Arm C will investigate the MTD of ibrutinib in combination with HD-MTX and to determine the safety and tolerability of the ibrutinib/HD-MTX combination regimen in PCNSL and SCNSL patients. To minimize drug-drug interaction between HD-MTX and Ibrutinib, Ibrutinib will not be administered concurrently with HD-MTX.
Group III: Arm B: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSLExperimental Treatment3 Interventions
The defined MTD from Arm A will then be used in an expansion cohort to further assess toxicity and clinical activity
Group IV: Arm A: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSLExperimental Treatment3 Interventions
This is an open-label, non-randomized, single center, dose escalation, phase I/II study to establish the maximum-tolerated dose (MTD) of ibrutinib as a single agent in patients with refractory/recurrent PCNSL or refractory/recurrent SCNSL (Arm A).
Ibrutinib is already approved in European Union, United States, Canada, Japan for the following indications:
🇪🇺 Approved in European Union as Imbruvica for:
- Chronic lymphocytic leukemia
- Mantle cell lymphoma
- Waldenström's macroglobulinemia
- Marginal zone lymphoma
- Graft-versus-host disease
🇺🇸 Approved in United States as Imbruvica for:
- Chronic lymphocytic leukemia/small lymphocytic lymphoma
- Mantle cell lymphoma
- Waldenström's macroglobulinemia
- Marginal zone lymphoma
- Graft-versus-host disease
🇨🇦 Approved in Canada as Imbruvica for:
- Chronic lymphocytic leukemia
- Mantle cell lymphoma
- Waldenström's macroglobulinemia
- Marginal zone lymphoma
🇯🇵 Approved in Japan as Imbruvica for:
- Chronic lymphocytic leukemia
- Mantle cell lymphoma
- Waldenström's macroglobulinemia
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Memorial Sloan Kettering WestchesterWest Harrison, NY
Memorial Sloan Kettering Basking Ridge (Limited Protocol Activities)Basking Ridge, NJ
Memorial Sloan Kettering Monmouth (Limited Protocol Activities)Middletown, NJ
Memorial Sloan Kettering Bergen (Limited Protocol Activities)Montvale, NJ
More Trial Locations
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Who Is Running the Clinical Trial?
Memorial Sloan Kettering Cancer CenterLead Sponsor
Pharmacyclics LLC.Industry Sponsor
Janssen Biotech, Inc.Industry Sponsor
References
The outcome of ibrutinib-based regimens in relapsed/refractory central nervous system lymphoma and the potential impact of genomic variants. [2023]Relapsed/refractory (r/r) central nervous system lymphoma (CNSL) exhibits aggressive behavior and poor outcomes. As an effective bruton tyrosine kinase (BTK) inhibitor, ibrutinib yields benefits in B-cell malignancies.
Inhibition of B Cell Receptor Signaling by Ibrutinib in Primary CNS Lymphoma. [2022]Primary CNS lymphoma (PCNSL) harbors mutations that reinforce B cell receptor (BCR) signaling. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, targets BCR signaling and is particularly active in lymphomas with mutations altering the BCR subunit CD79B and MYD88. We performed a proof-of-concept phase Ib study of ibrutinib monotherapy followed by ibrutinib plus chemotherapy (DA-TEDDi-R). In 18 PCNSL patients, 94% showed tumor reductions with ibrutinib alone, including patients having PCNSL with CD79B and/or MYD88 mutations, and 86% of evaluable patients achieved complete remission with DA-TEDDi-R. Increased aspergillosis was observed with ibrutinib monotherapy and DA-TEDDi-R. Aspergillosis was linked to BTK-dependent fungal immunity in a murine model. PCNSL is highly dependent on BCR signaling, and ibrutinib appears to enhance the efficacy of chemotherapy.
Successful Consolidation/Maintenance Therapy with Single Agent Ibrutinib for Primary CNS Lymphoma after Initial Induction Therapy. [2022]Primary central nervous system lymphoma (PCNSL) is a rare and aggressive disease that originates from lymphocytes and develops in the central nervous system. There is no standard consolidation/maintenance therapy for PCNSL. While there exists a variety of options, the high chance of inferior outcomes for elderly patients and the risk of neurotoxicity requires exploration of alternative options for consolidation/maintenance therapy for PCNSL in the elderly population with CNS lymphoma. We treated one 77-year-old patient with single agent ibrutinib, a Bruton's tyrosine kinase inhibitor that crosses the blood-brain-barrier, as consolidation/maintenance therapy after induction therapy with high-dose methotrexate (HD-MTX) and rituximab plus temozolomide. This treatment resulted in good tolerance, further resolution of a small residue lymphoma, and sustained remission. The patient has completed one year of consolidation/maintenance therapy and is currently under clinical and imaging surveillance. She has survived 27 months without recurrence since diagnosis. This case shows the potential effectiveness of single agent ibrutinib as consolidation/maintenance therapy for PCNSL after induction therapy. More cases are needed to confirm the findings.
Efficacy and Safety of Ibrutinib in Central Nervous System Lymphoma: A PRISMA-Compliant Single-Arm Meta-Analysis. [2022]Central nervous system lymphoma (CNSL) is an aggressive lymphoma. Studies investigating primary CNSL determined that the Bruton tyrosine kinase (BTK) played an important role in pathogenesis. Ibrutinib, an oral BTK inhibitor, is a new treatment strategy for CNSL. The purpose of this meta-analysis was to clarify the effectiveness and safety of ibrutinib in the treatment of CNSL.
Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma. [2021]Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK) and has shown single-agent activity in recurrent/refractory central nervous system (CNS) lymphoma. Clinical responses are often transient or incomplete, suggesting a need for a combination therapy approach. We conducted a phase 1b clinical trial to explore the sequential combination of ibrutinib (560 or 840 mg daily dosing) with high-dose methotrexate (HD-MTX) and rituximab in patients with CNS lymphoma (CNSL). HD-MTX was given at 3.5 g/m2 every 2 weeks for a total of 8 doses (4 cycles; 1 cycle = 28 days). Ibrutinib was held on days of HD-MTX infusion and resumed 5 days after HD-MTX infusion or after HD-MTX clearance. Single-agent daily ibrutinib was administered continuously after completion of induction therapy until disease progression, intolerable toxicity, or death. We also explored next-generation sequencing of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) before and during treatment. The combination of ibrutinib, HD-MTX, and rituximab was tolerated with an acceptable safety profile (no grade 5 events, 3 grade 4 events). No dose-limiting toxicity was observed. Eleven of 15 patients proceeded to maintenance ibrutinib after completing 4 cycles of the ibrutinib/HD-MTX/rituximab combination. Clinical responses occurred in 12 of 15 patients (80%). Sustained tumor responses were associated with clearance of ctDNA from the CSF. This trial was registered at www.clinicaltrials.gov as #NCT02315326.
Rituximab-Lenalidomide-Ibrutinib Combination for Relapsed/Refractory Primary CNS Lymphoma: A Case Series of the LOC Network. [2021]Label="BACKGROUND AND OBJECTIVES">To evaluate the efficacy and tolerance of the association rituximab-lenalidomide-ibrutinib (R2I) in relapsed/refractory (R/R) primary CNS lymphoma (PCNSL).
Ibrutinib in PCNSL: The Curious Cases of Clinical Responses and Aspergillosis. [2018]In this issue of Cancer Cell, Lionakis et al. demonstrate that the combination of temozolomide, etoposide, doxorubicin, dexamethasone, rituximab, and the Bruton tyrosine kinase (BTK) inhibitor ibrutinib induced frequent responses in patients with primary central nervous system lymphoma but was associated with significant toxicity, including pulmonary and cerebral aspergillosis infections.
Rituximab and ibrutinib in the treatment of Waldenström's macroglobulinemia. [2021]The Bruton's tyrosine kinase inhibitor ibrutinib represents a highly effective single substance in the treatment of Waldenström's macroglobulinemia. Ibrutinib monotherapy is a valid therapeutic option either in the relapsed or refractory setting or in patients first line, particulary when they are ineligible for chemotherapy. However, the treatment success depends on the genotype. Recent data suggest that ibrutinib in combination with rituximab may partially overcome this genotype dependency.
CNS Response to Osimertinib Versus Standard Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients With Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. [2019]Purpose We report CNS efficacy of osimertinib versus standard epidermal growth factor receptor ( EGFR) tyrosine kinase inhibitors (TKIs) in patients with untreated EGFR-mutated advanced non-small-cell lung cancer from the phase III FLAURA study. Patients and Methods Patients (N = 556) were randomly assigned to osimertinib or standard EGFR-TKIs (gefitinib or erlotinib); brain scans were not mandated unless clinically indicated. Patients with asymptomatic or stable CNS metastases were included. In patients with symptomatic CNS metastases, neurologic status was required to be stable for ≥ 2 weeks after completion of definitive therapy and corticosteroids. A preplanned subgroup analysis with CNS progression-free survival as primary objective was conducted in patients with measurable and/or nonmeasurable CNS lesions on baseline brain scan by blinded independent central neuroradiologic review. The CNS evaluable-for-response set included patients with ≥ one measurable CNS lesion. Results Of 200 patients with available brain scans at baseline, 128 (osimertinib, n = 61; standard EGFR-TKIs, n = 67) had measurable and/or nonmeasurable CNS lesions, including 41 patients (osimertinib, n = 22; standard EGFR-TKIs, n = 19) with ≥ one measurable CNS lesion. Median CNS progression-free survival in patients with measurable and/or nonmeasurable CNS lesions was not reached with osimertinib (95% CI, 16.5 months to not calculable) and 13.9 months (95% CI, 8.3 months to not calculable) with standard EGFR-TKIs (hazard ratio, 0.48; 95% CI, 0.26 to 0.86; P = .014 [nominally statistically significant]). CNS objective response rates were 91% and 68% in patients with ≥ one measurable CNS lesion (odds ratio, 4.6; 95% CI, 0.9 to 34.9; P = .066) and 66% and 43% in patients with measurable and/or nonmeasurable CNS lesions (odds ratio, 2.5; 95% CI, 1.2 to 5.2; P = .011) treated with osimertinib and standard EGFR-TKIs, respectively. Probability of experiencing a CNS progression event was consistently lower with osimertinib versus standard EGFR-TKIs. Conclusion Osimertinib has CNS efficacy in patients with untreated EGFR-mutated non-small-cell lung cancer. These results suggest a reduced risk of CNS progression with osimertinib versus standard EGFR-TKIs.
Role of ATP-binding cassette and solute carrier transporters in erlotinib CNS penetration and intracellular accumulation. [2021]To study the role of drug transporters in central nervous system (CNS) penetration and cellular accumulation of erlotinib and its metabolite, OSI-420.
Management of CNS metastases in patients with EGFR mutation-positive NSCLC. [2020]Central nervous system (CNS) metastases are a frequent and severe complication associated with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). The first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) have shown considerable efficacy in EGFR-mutated NSCLC. However, their limited potential to cross the blood-brain barrier (BBB) renders them less effective in the management of CNS metastases in NSCLC. Osimertinib, a third-generation irreversible EGFR-TKI with good potential to cross the BBB, has shown significant clinical activity and acceptable safety profile in patients with EGFR-positive NSCLC brain and leptomeningeal metastases. The progression-free survival (PFS) of up to 15.2 months in CNS metastases patients in the FLAURA trial and the CNS objective response rates (ORRs) of 54% and 43% in the AURA/AURA2 and BLOOM trials, respectively, have established the role of osimertinib in patients with NSCLC with CNS metastases. The AURA3 trial also reported a PFS of 8.5 months and overall ORR of 71%. These data have supported osimertinib to be recognized as a "preferred" first-line treatment for EGFR-positive metastatic NSCLC by the National Comprehensive Cancer Network (NCCN). With limited treatment options available, upfront administration of osimertinib in patients with NSCLC irrespective of EGFR T790M and CNS metastases may improve the overall response rate and potentially reduce the adverse effects of radiotherapy. Our review focuses on the management of EGFR-mutated NSCLC CNS metastases in the context of recent NCCN guidelines.
Brain metastases in non-small-cell lung cancer: are tyrosine kinase inhibitors and checkpoint inhibitors now viable options? [2023]Significant progress has been made in the treatment of stage iv non-small-cell lung cancer (nsclc); however, the prognosis of patients with brain metastases remains poor. Resection and radiation therapy remain standard options. This issue is an important one because 10% of patients with nsclc have brain metastases at diagnosis, and 25%-40% develop brain metastases during their disease. Standard chemotherapy does not cross the blood-brain barrier. However, there is new hope that tyrosine kinase inhibitors (tkis) used in patients with identified targetable mutations such as mutations of EGFR and rearrangements of ALK could have activity in the central nervous system (cns). Furthermore, immunotherapy is increasingly becoming a standard option for patients with nsclc, and interest about the intracranial activity of those agents is growing. This review presents current data about the cns activity of the available major tkis and immunotherapy agents.