Pembrolizumab + Chemotherapy for Central Nervous System Lymphoma

Recruiting at 1 trial location

Overseen By DFCI Clinical Trials Hotline

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Dana-Farber Cancer Institute

Must not be taking: Antiepileptics, Immunosuppressants

Disqualifiers: Autoimmune, Diabetes, Hepatitis, others

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

Compensation: Varies

Number of Visits: 1

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether the drug Pembrolizumab (an immunotherapy), combined with chemotherapy, can effectively treat primary central nervous system lymphoma, a type of brain cancer. The study aims to determine the effectiveness of this combination and whether the side effects are manageable. Individuals recently diagnosed with this form of lymphoma, confirmed by a brain biopsy, and who have not yet received any treatment may be suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to contribute to groundbreaking research.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on medications that are moderate or strong inhibitors or inducers of certain liver enzymes (CYP3A4/5), or if you are taking enzyme-inducing antiepileptic drugs, you will need to stop them 2 weeks before starting the trial.

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

Research has shown that Pembrolizumab, though not yet approved for primary central nervous system lymphoma, is generally safe for patients with other types of lymphomas. Most patients tolerate it well, and the side effects are manageable.

Methotrexate is often used to treat central nervous system lymphomas. Studies indicate it is usually safe, with side effects that patients can typically manage.

Temozolomide is used in similar conditions and is known to be well-tolerated. Research has found it has a good safety record, with patients managing the side effects well.

Rituximab has been studied in cases of central nervous system lymphoma and does not significantly increase severe side effects or treatment-related deaths.

This combination of drugs has shown promise in other studies, suggesting that while side effects exist, they are generally manageable for patients. As this is an early-stage trial, the researchers aim to explore the treatment's safety in more detail. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of pembrolizumab with chemotherapy for central nervous system lymphoma because it offers a potentially more effective approach than current treatments. Pembrolizumab is a type of immunotherapy known as a checkpoint inhibitor, which works by helping the immune system recognize and attack cancer cells. This mechanism is different from traditional chemotherapy, which directly targets cancer cells but can also harm healthy cells. By combining pembrolizumab with chemotherapy, this treatment aims to enhance the body's natural defenses against cancer while still delivering the potent effects of chemotherapy. This dual approach holds promise for improved outcomes in patients with this challenging condition.

What evidence suggests that this trial's treatments could be effective for central nervous system lymphoma?

Research has shown that Pembrolizumab, administered to participants in this trial, can help treat primary central nervous system lymphoma (PCNSL) when combined with chemotherapy. Participants will receive Methotrexate, which studies have found significantly improves survival rates. Temozolomide, another treatment in this trial, aids in managing recurrent brain lymphomas and has few side effects. Rituximab, also included in the treatment regimen, has proven effective and improves response rates in PCNSL when combined with high-dose Methotrexate. Together, these drugs may combat PCNSL by attacking cancer cells in different ways, potentially leading to better outcomes. ^{2 4 5 6 7}

Who Is on the Research Team?

Lakshmi Nayak

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for individuals with newly diagnosed primary central nervous system lymphoma. Specific eligibility criteria are not provided, but typically participants would need to meet certain health standards and have no conflicting conditions.

Inclusion Criteria

Participants must have negative HIV serology

My blood, kidney, liver, and clotting tests are all within normal ranges.

I am a woman who can have children and have a recent negative pregnancy test.

Exclusion Criteria

Participants who cannot undergo MRI

I have fluid buildup in my chest, abdomen, or swelling throughout my body.

Known psychiatric or substance abuse disorders

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Induction Treatment

Participants receive Methotrexate, Temozolomide, Rituximab, and Pembrolizumab in cycles to treat PCNSL

16 weeks

Multiple visits per cycle

Consolidation Treatment

Participants may receive additional treatment cycles based on the study doctor's assessment

4-8 weeks

Imaging every other cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 106 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Methotrexate
• Pembrolizumab
• Rituximab
• Temozolomide

Trial Overview The study tests Pembrolizumab combined with chemotherapy (Methotrexate, Temozolomide, Rituximab) to see if it's effective and tolerable for treating central nervous system lymphoma.

How Is the Trial Designed?

Group I: Induction Treatment: Experimental Treatment 4 Interventions

Participants will be enrolled and will complete procedures as follows, starting at Dose Level 0 for Methotrexate and Temozolomide: * Baseline visit with assessments and imaging. * Imaging on cycles 3 and 6 only. * Cycles 1 through 3: ---Days 3 and 10 of 14 day cycle: Predetermined dose of Rituximab 1x daily. * Cycles 1, 3, 5, and 7: ---Days 7 through 11 of 14 day cycle: Predetermined dose of Temozolomide 1x daily. * Cycles 1 through 8: ---Day 1 of 14 day cycle: Predetermined dose of Methotrexate 1x daily. * Cycles 1, 4, 7 * Day 10 of 14 day cycle: Predetermined dose of Pembrolizumab 1x daily. Treatment will de-escalate per protocol if greater than or equal to 2 out of 6 participants experience a dose-limiting toxicity.

Group II: Consolidation Treatment: Experimental Treatment 1 Intervention

4-8 weeks after the completion of Induction Cycle 8, the study doctor will determine if it is appropriate to move on to consolidation therapy and participants will complete: * Imaging every other cycle. * Cycles 1 through 15: * Day 1 of 42 day cycle: Lumbar puncture * Day 1 of 42 day cycle: Predetermined dose of Pembrolizumab 1x daily. * End of treatment visit with lumbar puncture and imaging. * Follow up

Methotrexate is already approved in United States, Canada, European Union for the following indications:

Approved in United States as Trexall for:

• Acute lymphoblastic leukemia
• Non-Hodgkin's lymphoma
• Osteosarcoma
• Breast cancer
• Lung cancer
• Head and neck cancer
• Psoriasis
• Rheumatoid arthritis

Approved in Canada as Mexate for:

• Acute lymphoblastic leukemia
• Non-Hodgkin's lymphoma
• Osteosarcoma
• Breast cancer
• Lung cancer
• Head and neck cancer
• Psoriasis
• Rheumatoid arthritis

Approved in European Union as Methotrexate for:

• Acute lymphoblastic leukemia
• Non-Hodgkin's lymphoma
• Osteosarcoma
• Breast cancer
• Lung cancer
• Head and neck cancer
• Psoriasis
• Rheumatoid arthritis
• Crohn's disease
• Ulcerative colitis

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

Published Research Related to This Trial

In a study of seven patients with CNS lymphoma, the combination of rituximab and temozolomide was well tolerated, with no toxicity reported from rituximab and manageable side effects from temozolomide, indicating a safer alternative to traditional chemotherapy regimens.

The treatment showed promising efficacy, with five patients achieving a complete response and two achieving a partial response, although the median survival was 8 months, suggesting that this regimen could be beneficial for elderly patients with limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunochemotherapy with rituximab and temozolomide for central nervous system lymphomas. Wong, ET., Tishler, R., Barron, L., et al.[2018]

A phase 2 study demonstrated that a combination of induction immunochemotherapy and high-dose consolidation chemotherapy followed by autologous stem cell transplantation is being tested for newly diagnosed primary central nervous system lymphoma (PCNSL).

The treatment regimen includes rituximab, high-dose methotrexate, vincristine, procarbazine, thiotepa, busulfan, and cyclophosphamide, aiming to improve outcomes for patients with this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of primary CNS lymphoma. Schmitz, N.[2021]

The combination of rituximab and temozolomide (TMZ) showed promising efficacy in two patients with recurrent and refractory primary central nervous system lymphoma (PCNSL), achieving complete and partial responses after treatment cycles.

This therapy was effective regardless of the patients' different tumor profiles, suggesting it could be a viable option for diverse cases of PCNSL, although further research in larger populations is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination therapy with rituximab and temozolomide for recurrent and refractory primary central nervous system lymphoma. Murakami, M., Fujimaki, T., Asano, S., et al.[2021]

The combination treatment of high dose methotrexate (HD-MTX), temozolomide (TMZ), and rituximab (R) significantly improved progression-free survival (PFS) and overall survival (OS) in patients with primary central nervous system lymphoma (PCNSL), with median PFS of 56.7 months compared to 7.3 months for those receiving only HD-MTX and TMZ.

The treatment was generally well-tolerated, with only mild side effects such as grade 1-2 nausea and vomiting reported during the induction phase, and no severe grade 3/4 toxicities observed during consolidation treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Efficacy of High Dose Methotrexate, Temozolomide and Rituximab in the Treatment of Patients with Primary Central Nervous System Lymphoma]. Pang, DW., Chen, FL., Guo, HG., et al.[2021]

The addition of temozolomide (TMZ) to the standard treatment of high-dose methotrexate (HD-MTX) and whole-brain radiotherapy (WBRT) for primary central nervous system lymphoma (PCNSL) did not improve overall survival, with a 2-year survival rate of 71.4% in the TMZ group compared to 86.8% in the standard treatment group.

The study, which included 134 patients and was terminated early due to futility, found that the methylation status of the MGMT promoter did not predict response to TMZ, indicating that this treatment may not be effective for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase III study of high-dose methotrexate and whole-brain radiotherapy with/without temozolomide for newly diagnosed primary CNS lymphoma: JCOG1114C. Mishima, K., Nishikawa, R., Narita, Y., et al.[2023]

Adding rituximab to high-dose methotrexate-based chemotherapy significantly increased the complete remission rate in patients with primary central nervous system lymphoma (PCNSL) from 33.3% to 66.7%.

The combination therapy (RMAD regimen) improved progression-free survival (PFS) without increasing serious toxicities, although it did not show a statistically significant improvement in overall survival (OS).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methotrexate-cytarabine-dexamethasone combination chemotherapy with or without rituximab in patients with primary central nervous system lymphoma. Sun, X., Liu, J., Wang, Y., et al.[2018]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39964705

Comparison of outcomes in postinduction strategies for ... At 5-years postinduction treatment initiation, the PFS rates in the auto-SCT cohort and HD-MTX maintenance cohort were 74.6% and 72.6%, ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0959804924011997

Clinical characteristics and survival outcomes of patients ... This retrospective, multicenter study evaluates clinical characteristics and outcomes (progression-free, overall and disease-specific survival)

3. ashpublications.org ashpublications.org/bloodadvances/article/9/4/924/534832/Comparison-of-outcomes-in-postinduction-strategies

Comparison of outcomes in postinduction strategies for ... Survival outcomes in patients who received maintenance MTX were comparable with those who underwent auto-SCT.

4. academic.oup.com academic.oup.com/noa/article/6/1/vdae119/7708538

Predicting prognosis outcomes of primary central nervous ... We developed a Cox regression model based on lipidomic data, which could effectively predict PCNSL patient prognosis before the HD-MTX-based chemotherapy ...

5. annalsofoncology.org annalsofoncology.org/article/S0923-7534(23)05074-3/fulltext

Primary central nervous system lymphomas: EHA–ESMO ... with significantly improved 7-year PFS (52% versus 29% versus 20%) and 7-year OS (56% versus 37% versus 26%) rates compared with HD-MTX–HD-AraC– ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12098186/

Efficacy and safety of the R2-MTX regimen in primary central ... Our results underscore the therapeutic potential of the R2-MTX regimen in managing newly diagnosed PCNSL patients.

7. nature.com nature.com/articles/s41598-017-17359-1

Efficacy and safety of HD-MTX based systemic ... We performed a retrospective study of 49 patients with newly diagnosed primary central nervous system lymphoma (PCNSL), to compare the ...