Triple Therapy for Central Nervous System Lymphoma

Recruiting at 2 trial locations

Overseen By Lakshmi Nayak, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Dana-Farber Cancer Institute

Must not be taking: Warfarin, Anticoagulants, Immunosuppressants, others

Disqualifiers: Autoimmune disease, Cardiovascular disease, Diabetes, 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

Compensation: Varies

Number of Visits: 3

37 Participants Needed

Trial Summary

What is the purpose of this trial?

This research study is evaluating a combination therapy of 3 drugs as possible treatments for recurrent primary central nervous system lymphoma (PCNSL). The three drugs being used in the study are: * Pembrolizumab (MK3475) * Ibrutinib * Rituximab (or biosimilar)

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you must discontinue any medications that are moderate or strong inhibitors or inducers of CYP3A4/5 two weeks before starting the study treatment. Additionally, enzyme-inducing antiepileptic drugs need to be switched to a non-inducing alternative two weeks prior to the trial.

What data supports the effectiveness of the drugs Ibrutinib, Imbruvica, Pembrolizumab, KEYTRUDA, MK-3475, Rituximab, Rituxan, Riabni, Ruxience, Truxima for treating central nervous system lymphoma?

Research shows that Ibrutinib, when used alone or in combination with other drugs like rituximab, has shown positive responses in treating central nervous system lymphoma, with some patients experiencing sustained remission. Additionally, rituximab has been associated with improved survival in aggressive B cell CNS lymphoma. ^{1 2 3 4 5}

Is the triple therapy for CNS lymphoma generally safe in humans?

The treatments involved in the triple therapy, such as Pembrolizumab (also known as KEYTRUDA), have been studied for safety in various conditions. Pembrolizumab has shown acceptable safety in patients with Hodgkin lymphoma, though it can cause immune-related side effects, including neurological symptoms. In another study, Pembrolizumab had manageable safety in patients with myelodysplastic syndromes, with some experiencing treatment-related adverse events. ^{6 7 8 9 10}

What makes the triple drug therapy for CNS lymphoma unique?

The triple drug therapy for CNS lymphoma is unique because it combines ibrutinib, pembrolizumab, and rituximab, which target different aspects of the cancer cells and immune system. Ibrutinib crosses the blood-brain barrier to inhibit a specific protein in cancer cells, pembrolizumab helps the immune system recognize and attack cancer cells, and rituximab targets a protein on the surface of cancer cells, making this combination potentially more effective than traditional treatments. ^{1 2 4 5 11}

Research Team

Lakshmi Nayak

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

This trial is for adults with recurrent primary central nervous system lymphoma (PCNSL) who've had at least one prior CNS-directed therapy. They should be in good physical condition (ECOG 0-1), have a life expectancy over three months, and recovered from previous treatments to ≤ Grade 1 toxicity. Participants must understand and consent to the study's procedures, agree to use effective contraception, and not have certain health conditions or recent treatments that could interfere.

Inclusion Criteria

My brain lymphoma has returned or didn't respond to initial treatments, confirmed by MRI or CSF tests.

Participant must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, and other requirements of the study

I am fully active or restricted in physically strenuous activity but can do light work.

Exclusion Criteria

Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial

I do not have serious heart problems like recent heart attacks or uncontrolled heart failure.

I have a history of Hepatitis B or active Hepatitis C.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase Ib Treatment

Participants receive dose escalation of Pembrolizumab, Ibrutinib, and Rituximab to determine safety and appropriate dosing

6 weeks

Weekly visits for Rituximab administration

Phase II Treatment

Participants receive Pembrolizumab, Ibrutinib, and Rituximab at the pre-determined dosage level established in Phase Ib

Up to 24 months

Pembrolizumab every 3 weeks, Rituximab weekly for 4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 3 months for life

Treatment Details

Interventions

• Ibrutinib
• Pembrolizumab
• Rituximab

Trial Overview The study tests a combination of three drugs: Pembrolizumab, Ibrutinib, and Rituximab as potential treatments for PCNSL. The goal is to evaluate their effectiveness together in patients who have seen their cancer return after initial treatment.

Participant Groups

Group I: Pembrolizumab + Ibrutinib + Rituximab Experimental Treatment 3 Interventions

Phase 1b Dose escalation will occur using a standard 3+3 dose-escalation approach, beginning at dose level I (560 mg daily) and potentially escalating to dose level 2 (840mg) with rules for escalation and de-escalation. * Ibrutinib: orally 2x daily * Pembrolizumab: 200 mg intravenously every 3 weeks * Rituximab/biosimilar: 375mg/m\^2 intravenously once per week for 4 weeks (4 total doses). Phase 2 Participants will receive Pembrolizumab, Rituximab and Ibrutinib at the pre-determined dosage level established in Phase 1b. * Ibrutinib: orally maximum tolerated dose from phase 1 daily (560 mg or 840mg) * Pembrolizumab: 200 mg intravenously every 3 weeks * Rituximab/biosimilar: 375 mg/m\^2 intravenously once per week for 4 weeks (4 total doses).

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?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

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]

In a retrospective study of 120 patients with aggressive B cell central nervous system lymphoma, the addition of rituximab to high-dose methotrexate-based chemotherapy was associated with improved overall survival, suggesting it may enhance treatment efficacy.

Key factors predicting better survival included younger age (≤60 years), good performance status, normal lactate dehydrogenase levels, and receiving treatment after 2004, highlighting the importance of these variables in patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab is associated with improved survival for aggressive B cell CNS lymphoma. Gregory, G., Arumugaswamy, A., Leung, T., et al.[2022]

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 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]

Primary central nervous system lymphomas are aggressive cancers that respond well to high-dose methotrexate-based chemotherapy, with recent studies showing that the MATRix regimen (methotrexate, cytarabine, thiotepa, and rituximab) significantly improves overall survival.

Despite treatment advancements, patients face risks of neurotoxicity and other side effects, highlighting the need for a balance between intensifying therapy and managing these adverse effects, as well as the exploration of targeted therapies for refractory cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapy of primary CNS lymphoma: role of intensity, radiation, and novel agents. Ferreri, AJM.[2018]

In the KEYNOTE-087 study, pembrolizumab demonstrated a 69% overall response rate in patients with relapsed/refractory classical Hodgkin lymphoma, indicating its efficacy as a treatment option.

Health-related quality of life assessments showed significant improvements in overall health and functional scores among 206 patients at 12 and 24 weeks, suggesting that pembrolizumab not only helps in treating the disease but also enhances patients' quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes in KEYNOTE-087, a phase 2 study of pembrolizumab in patients with classical Hodgkin lymphoma. von Tresckow, B., Fanale, M., Ardeshna, KM., et al.[2020]

Pembrolizumab, a PD-1 inhibitor used in cancer treatment, has been linked to a rare but serious immune-related adverse event called inflammatory myeloradiculitis, marking the first reported case associated with this medication.

The study reviews other similar cases of myelitis related to immune checkpoint inhibitors, providing insights into their characteristics, treatment options, and outcomes, which can help guide future management of such adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inflammatory Myeloradiculitis Secondary to Pembrolizumab: A Case Report and Literature Review. Vickers, ML., Seidl, B., Bigby, K., et al.[2020]

In a phase 1b study involving 28 patients with myelodysplastic syndromes (MDS) resistant to hypomethylating agents, pembrolizumab demonstrated manageable safety, with 36% experiencing treatment-related adverse events, but no patients achieved a complete or partial response.

Despite the lack of significant tumor response, 19% of patients showed a complete response in bone marrow, and the median overall survival was 6 months, indicating some clinical activity in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for myelodysplastic syndromes after failure of hypomethylating agents in the phase 1b KEYNOTE-013 study. Garcia-Manero, G., Ribrag, V., Zhang, Y., et al.[2022]

In a Phase II study involving 18 patients with leptomeningeal disease, the combination of ipilimumab and nivolumab showed promising efficacy, with 44% of patients alive at three months, surpassing the expected 18%.

The treatment had an acceptable safety profile, although one-third of patients experienced significant adverse events, including two cases leading to treatment discontinuation due to hepatitis and colitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis. Brastianos, PK., Strickland, MR., Lee, EQ., et al.[2021]

An adolescent with refractory Hodgkin lymphoma treated with the PD1 inhibitor nivolumab developed serious immune-related neurological adverse events, including Hashimoto thyroiditis and posterior reversible encephalopathy syndrome, highlighting potential risks associated with this treatment.

The patient responded well to a combination of intravenous steroids, immunoglobulin, and plasma exchange, leading to full recovery, suggesting that timely intervention can effectively manage severe immune-related reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune-related Neurological Symptoms in an Adolescent Patient Receiving the Checkpoint Inhibitor Nivolumab. Tchapyjnikov, D., Borst, AJ.[2018]

Ibrutinib, an irreversible inhibitor of Bruton tyrosine kinase, shows a high rate of durable responses in patients with primary central nervous system lymphoma and secondary diffuse large B-cell lymphoma, indicating its efficacy in treating these challenging conditions.

Mutations in the CD79B protein and activation of the MTOR pathway were linked to reduced effectiveness of ibrutinib, but combining it with PIK3CA and PIK3CD inhibitors in preclinical studies demonstrated potential to overcome this resistance, suggesting new avenues for targeted therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spotlight on Ibrutinib in PCNSL: Adding Another Feather to Its Cap. Lakshmanan, A., Byrd, JC.[2021]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Successful Consolidation/Maintenance Therapy with Single Agent Ibrutinib for Primary CNS Lymphoma after Initial Induction Therapy. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Rituximab is associated with improved survival for aggressive B cell CNS lymphoma. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Ibrutinib in PCNSL: The Curious Cases of Clinical Responses and Aspergillosis. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

Therapy of primary CNS lymphoma: role of intensity, radiation, and novel agents. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes in KEYNOTE-087, a phase 2 study of pembrolizumab in patients with classical Hodgkin lymphoma. [2020]

7. United States pubmed.ncbi.nlm.nih.gov

Inflammatory Myeloradiculitis Secondary to Pembrolizumab: A Case Report and Literature Review. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Pembrolizumab for myelodysplastic syndromes after failure of hypomethylating agents in the phase 1b KEYNOTE-013 study. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Immune-related Neurological Symptoms in an Adolescent Patient Receiving the Checkpoint Inhibitor Nivolumab. [2018]

11. United States pubmed.ncbi.nlm.nih.gov

Spotlight on Ibrutinib in PCNSL: Adding Another Feather to Its Cap. [2021]