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

Trial Summary

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.

What data supports the effectiveness of the drug combination of Pembrolizumab, Methotrexate, Rituximab, and Temozolomide for central nervous system lymphoma?

Research shows that high-dose methotrexate, temozolomide, and rituximab have been effective in treating primary central nervous system lymphoma, with studies reporting improved survival and responses in patients. Additionally, the combination of rituximab and temozolomide has shown effectiveness in recurrent cases, suggesting potential benefits of these drugs in combination. ^{1 2 3 4 5}

Is the combination of Pembrolizumab, Methotrexate, Rituximab, and Temozolomide safe for treating central nervous system lymphoma?

The combination of methotrexate, rituximab, and temozolomide has been associated with some toxicities, such as effects on the kidneys and bone marrow, but these were considered acceptable in some studies. The safety of these drugs in combination warrants further study, but they have been used with manageable side effects in certain cases. ^{1 2 3 4 5}

What makes the drug combination of Pembrolizumab, Methotrexate, Rituximab, and Temozolomide unique for treating central nervous system lymphoma?

This treatment is unique because it combines Pembrolizumab, an immunotherapy drug that helps the immune system attack cancer cells, with chemotherapy drugs Methotrexate, Rituximab, and Temozolomide, which have shown effectiveness in treating central nervous system lymphoma. This combination aims to enhance the immune response while directly targeting cancer cells, potentially offering a more comprehensive approach than traditional chemotherapy alone. ^{1 3 4 5 6}

What is the purpose of this trial?

This research study is studying if the investigational drug, Pembrolizumab, in combination with chemotherapy helps primary central nervous system lymphoma with acceptable side effects. This research study involves a combination of the below drugs: * Pembrolizumab (a type of monoclonal antibody) * Methotrexate (a type of anti-metabolite) * Temozolomide (a type of alkylating agent) * Rituximab (a type of antibody)

Research Team

Lakshmi Nayak

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

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 not received a live vaccine in the last 30 days.

Pregnancy, breastfeeding, or expectation to conceive or father children within the study period

Timeline

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

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]

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]

References

1. Korea (South) pubmed.ncbi.nlm.nih.gov

Combination therapy with rituximab and temozolomide for recurrent and refractory primary central nervous system lymphoma. [2021]

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

Methotrexate-cytarabine-dexamethasone combination chemotherapy with or without rituximab in patients with primary central nervous system lymphoma. [2018]

3. China 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]. [2021]

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

Immunochemotherapy with rituximab and temozolomide for central nervous system lymphomas. [2018]

5. England 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. [2023]

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

Treatment of primary CNS lymphoma. [2021]