Ibrutinib + Chemotherapy for CNS Lymphoma

Recruiting at 15 trial locations

Overseen By Ingo Mellinghoff, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Warfarin, CYP3A inhibitors

Disqualifiers: Active malignancy, HIV, Hepatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

109 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether adding ibrutinib (Imbruvica, a type of targeted therapy) to a standard chemotherapy mix can improve treatment for specific types of brain lymphoma, including newly diagnosed or recurring primary central nervous system lymphoma (PCNSL) and recurring secondary central nervous system lymphoma (SCNSL). The researchers aim to determine if this combination can increase the complete response rate, meaning more patients might have no detectable cancer after treatment. This trial may suit those who have had prior treatment for CNS lymphoma but still need more effective options. As a Phase 1/Phase 2 trial, the research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to early-stage advancements in treatment.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that ibrutinib has been studied for safety in treating central nervous system lymphoma (CNSL). One study found that ibrutinib can improve response rates, but its overall effect on survival remains uncertain. This indicates promise, but more research is needed to understand its long-term effects.

For safety, a meta-analysis, which combines results from several studies, examined ibrutinib’s effectiveness and safety for CNSL. This type of analysis provides a clearer picture by pooling data. Initial findings suggest that while ibrutinib is generally well-tolerated, some side effects may occur. However, the specific side effects and their frequency can vary.

In early trial phases, researchers are still learning about a treatment's safety. These trials aim to determine the right dose and monitor for serious side effects. If ibrutinib is further along in trials, earlier studies likely found it reasonably safe for humans, but the exact risks may still be under investigation.

Overall, those considering joining a trial involving ibrutinib should know it has shown potential in some studies, but understanding its full safety profile is still ongoing. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Ibrutinib is unique because it targets B-cell receptor signaling, which is a crucial pathway in the survival and growth of lymphoma cells, specifically in central nervous system (CNS) lymphoma. Unlike standard chemotherapy treatments, which often have a broad and non-specific approach, ibrutinib offers a more targeted attack against cancer cells. This precision not only holds promise for increased effectiveness but also potentially reduces side effects compared to traditional chemotherapy. Researchers are excited about ibrutinib because it represents a new mechanism of action that could improve outcomes for patients with refractory or recurrent CNS lymphoma, who have limited treatment options.

What evidence suggests that this trial's treatments could be effective for CNS lymphoma?

Research has shown that ibrutinib holds promise for treating central nervous system lymphoma (CNSL). In studies, it has helped shrink or even eliminate the cancer in some patients. Ibrutinib effectively reaches the brain, which is crucial for treating CNSL. In this trial, participants in different arms will receive ibrutinib combined with chemotherapy drugs like rituximab and methotrexate. This combination has shown potential, especially for newly diagnosed patients. Overall, early evidence suggests that ibrutinib could be a helpful addition to traditional chemotherapy for CNS lymphoma. ^{1 5 6 7 8}

Who Is on the Research Team?

Christian Grommes, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

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.

Absolute neutrophil count (ANC) ≥ 0.75 x 109/L

My scans show my brain tumor is growing, or my spinal fluid test confirms lymphoma.

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Ibrutinib

Trial Overview 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.

How Is the Trial Designed?

Group I: Arm D: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL Experimental Treatment 4 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 SCNSL Experimental Treatment 3 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 SCNSL Experimental Treatment 3 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 SCNSL Experimental Treatment 3 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

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Pharmacyclics LLC.

Industry Sponsor

Trials

114

Recruited

13,800+

Dr. Maky Zanganeh

Pharmacyclics LLC.

Chief Executive Officer

Degree from Louis Pasteur University in Strasbourg, France; MBA from Schiller International University in France

Dr. Ellie Im

Pharmacyclics LLC.

Chief Medical Officer

MD from an unspecified institution

Janssen Biotech, Inc.

Industry Sponsor

Trials

30

Recruited

18,800+

Published Research Related to This Trial

Tyrosine kinase inhibitors (TKIs) show promise in treating brain metastases in stage IV non-small-cell lung cancer (NSCLC) patients with specific mutations, as standard chemotherapy cannot effectively penetrate the blood-brain barrier.

Immunotherapy is becoming a standard treatment for NSCLC, and there is increasing interest in its effectiveness against brain metastases, offering new hope for patients with this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain metastases in non-small-cell lung cancer: are tyrosine kinase inhibitors and checkpoint inhibitors now viable options? Abdallah, SM., Wong, A.[2023]

Ibrutinib, a BTK inhibitor, shows a promising overall response rate of 69% in treating central nervous system lymphoma (CNSL) based on a meta-analysis of 8 studies involving 162 patients.

The treatment is generally well tolerated, with common adverse effects being cytopenia and infections, but further randomized-controlled trials are needed to better understand its efficacy and safety compared to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Ibrutinib in Central Nervous System Lymphoma: A PRISMA-Compliant Single-Arm Meta-Analysis. Lv, L., Sun, X., Wu, Y., et al.[2022]

In a phase Ib study involving 18 patients with primary CNS lymphoma (PCNSL), 94% experienced tumor reductions with ibrutinib monotherapy, highlighting its efficacy, especially in patients with specific mutations (CD79B and MYD88) that enhance B cell receptor signaling.

While ibrutinib showed promising results in reducing tumors and enhancing chemotherapy effectiveness, there was an increased risk of aspergillosis, a fungal infection, indicating a potential safety concern linked to impaired fungal immunity due to BTK inhibition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of B Cell Receptor Signaling by Ibrutinib in Primary CNS Lymphoma. Lionakis, MS., Dunleavy, K., Roschewski, M., et al.[2022]

Ibrutinib is an effective treatment for Waldenström's macroglobulinemia, serving as a valid option for both relapsed/refractory cases and first-line therapy, especially for patients who cannot undergo chemotherapy.

Combining ibrutinib with rituximab may help improve treatment outcomes by reducing the dependency on specific genotypes, suggesting a potential strategy for enhancing efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab and ibrutinib in the treatment of Waldenström's macroglobulinemia. Grunenberg, A., Buske, C.[2021]

The combination of rituximab, lenalidomide, and ibrutinib (R2I) showed a high response rate in 14 patients with relapsed/refractory primary CNS lymphoma, with 4 achieving complete response and 4 achieving partial response within a median of 2.5 months.

R2I was generally well-tolerated, with manageable toxicity leading to discontinuation in only 3 patients, and no deaths related to toxicity, indicating its potential as a treatment option for patients who have failed conventional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab-Lenalidomide-Ibrutinib Combination for Relapsed/Refractory Primary CNS Lymphoma: A Case Series of the LOC Network. Houillier, C., Chabrot, CM., Moles-Moreau, MP., et al.[2021]

A combination treatment of temozolomide, etoposide, doxorubicin, dexamethasone, rituximab, and the BTK inhibitor ibrutinib showed promising responses in patients with primary central nervous system lymphoma.

However, this treatment regimen was linked to significant toxicity, including serious infections like pulmonary and cerebral aspergillosis, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib in PCNSL: The Curious Cases of Clinical Responses and Aspergillosis. Grommes, C., Younes, A.[2018]

Ibrutinib treatment showed a high overall response rate of 75% in patients with relapsed/refractory primary central nervous system lymphoma (PCNSL), with a median progression-free survival of 4 months, indicating its efficacy in this aggressive cancer type.

Genomic analysis revealed that patients with simpler genetic variants and lower tumor mutation burdens (TMB) responded better to ibrutinib, suggesting that genomic profiling could help predict treatment outcomes and tailor therapies for CNS lymphoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The outcome of ibrutinib-based regimens in relapsed/refractory central nervous system lymphoma and the potential impact of genomic variants. Wang, S., Zhu, Y., Qian, X., et al.[2023]

In a study of 556 patients with untreated EGFR-mutated advanced non-small-cell lung cancer, osimertinib demonstrated significantly better central nervous system (CNS) progression-free survival compared to standard EGFR tyrosine kinase inhibitors, with a hazard ratio of 0.48, indicating a reduced risk of CNS progression.

Osimertinib also showed higher CNS objective response rates, with 91% in patients with measurable CNS lesions, compared to 68% for standard EGFR-TKIs, suggesting that osimertinib is more effective in controlling CNS metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Reungwetwattana, T., Nakagawa, K., Cho, BC., et al.[2019]

Erlotinib and its metabolite OSI-420 have limited penetration into the brain due to the action of the Abcg2 efflux transporter, with brain penetration ratios significantly higher in knockout mice lacking this transporter.

Both erlotinib and OSI-420 are substrates for specific solute carriers (OAT3 and OCT2), which facilitate their cellular uptake, suggesting potential strategies to enhance their central nervous system delivery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of ATP-binding cassette and solute carrier transporters in erlotinib CNS penetration and intracellular accumulation. Elmeliegy, MA., Carcaboso, AM., Tagen, M., et al.[2021]

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor, has shown significant clinical activity in patients with EGFR-positive non-small cell lung cancer (NSCLC) and CNS metastases, with progression-free survival rates of up to 15.2 months in the FLAURA trial.

The drug has demonstrated a strong ability to cross the blood-brain barrier, achieving objective response rates of 54% and 43% in the AURA/AURA2 and BLOOM trials, respectively, leading to its recognition as a preferred first-line treatment for EGFR-positive metastatic NSCLC by the NCCN.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of CNS metastases in patients with EGFR mutation-positive NSCLC. Shetty, V., Babu, S.[2020]

In a phase 1b clinical trial involving 15 patients with recurrent CNS lymphoma, the combination of ibrutinib, high-dose methotrexate (HD-MTX), and rituximab was well-tolerated, showing no severe toxicity and allowing 11 out of 15 patients to continue with maintenance therapy after initial treatment.

The treatment resulted in clinical responses in 80% of patients, with sustained tumor responses linked to the clearance of circulating tumor DNA (ctDNA) from cerebrospinal fluid, indicating a potential mechanism for monitoring treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma. Grommes, C., Tang, SS., Wolfe, J., et al.[2021]

A 77-year-old patient with primary central nervous system lymphoma (PCNSL) showed good tolerance and sustained remission after receiving ibrutinib as a consolidation therapy following high-dose methotrexate and rituximab plus temozolomide.

This case suggests that ibrutinib, a Bruton's tyrosine kinase inhibitor that can cross the blood-brain barrier, may be an effective option for elderly patients with PCNSL, but further studies are needed to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Consolidation/Maintenance Therapy with Single Agent Ibrutinib for Primary CNS Lymphoma after Initial Induction Therapy. Du, S., Bota, D., Kong, XT.[2022]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S1040842824003408

Efficacy and safety of ibrutinib in central nervous system ... Ibrutinib shows promising efficacy in improving partial and complete response rates in CNSL. The substantial heterogeneity observed underscores the need for ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8788490/

Ibrutinib in Refractory or Relapsing Primary Central Nervous ... Primary Central Nervous System Lymphoma (PCNSL) is a rare variant of Non-Hodgkin Lymphoma (NHL) representing 1–2% of all NHL cases.

3. tandfonline.com tandfonline.com/doi/full/10.2147/BLCTT.S360442

Long-Term Survival with Ibrutinib Therapy in Elderly ... It can cross the blood brain barrier quite well with a median CNS penetration of 43.4%, 35.1%, and 28.7% at dose levels of 560 mg, 700 mg, and ...

4. aacrjournals.org aacrjournals.org/clincancerres/article/30/18/4005/747460/A-Phase-II-Study-Assessing-Long-term-Response-to

A Phase II Study Assessing Long-term Response to Ibrutinib ... A Phase II study assessing long-term response to ibrutinib monotherapy in recurrent or refractory CNS lymphoma.

5. acsjournals.onlinelibrary.wiley.com acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.34985

A phase 2 study of ibrutinib maintenance following first‐line ... Outcomes of older patients with primary central nervous system lymphoma treated in routine clinical practice in the UK: methotrexate dose ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8280788/

Efficacy and Safety of Ibrutinib in Central Nervous System ... The purpose of this meta-analysis was to clarify the effectiveness and safety of ibrutinib in the treatment of CNSL.

7. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/6020/527681/Preliminary-Safety-and-Efficacy-of-Emavusertib-CA

Preliminary Safety and Efficacy of Emavusertib (CA-4948) in ... We present updated safety and efficacy of emavusertib in combination with ibrutinib in patients with R/R PCNSL most recently treated with BTKi regimen.

8. neurology.org neurology.org/doi/abs/10.1212/WNL.0000000000211279

Ibrutinib in Central Nervous System Lymphoma (P8-6.014) Ibrutinib shows promising efficacy in improving partial and complete response rates in CNSL, although its impact on overall survival remains inconclusive.