Pembrolizumab + Entinostat for Lymphoma

Recruiting at 8 trial locations

Overseen By Alison Moskowitz, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must be taking: Checkpoint inhibitors, HDAC inhibitors

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: HIV, Active hepatitis, Active TB, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 2 years

47 Participants Needed

Trial Summary

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

The trial does not specify if you need to stop taking your current medications. However, you can be on a checkpoint inhibitor or HDAC inhibitor, including one of the study drugs, at the time of screening.

What data supports the effectiveness of the drug Pembrolizumab + Entinostat for Lymphoma?

Pembrolizumab has shown effectiveness in treating advanced melanoma by improving survival rates, and Entinostat has demonstrated activity in B-cell lymphoma, enhancing the effects of other treatments like rituximab. Additionally, Entinostat combined with Pembrolizumab has induced durable responses in patients with melanoma who were resistant to PD-1 blockade alone, suggesting potential effectiveness in lymphoma. ^{1 2 3 4 5}

Is the combination of Pembrolizumab and Entinostat safe for humans?

Pembrolizumab is generally well tolerated, with common side effects like fatigue, rash, itching, and diarrhea, and less common ones like thyroid issues and lung inflammation. Entinostat has been tested in various cancers and is generally well tolerated, though it is not yet approved for clinical use. In a study combining Pembrolizumab with another similar drug, Vorinostat, common side effects included high blood pressure and diarrhea, with some serious reactions like Stevens-Johnson syndrome (a severe skin reaction). ^{1 4 6 7 8}

What makes the drug Pembrolizumab + Entinostat unique for treating lymphoma?

Pembrolizumab + Entinostat is unique because it combines a PD-1 inhibitor (Pembrolizumab) that helps the immune system attack cancer cells with an HDAC inhibitor (Entinostat) that can enhance the immune response and potentially improve the effectiveness of other treatments. This combination aims to provide a synergistic effect, potentially offering better outcomes for lymphoma patients compared to using these drugs individually. ^{2 4 9 10 11}

What is the purpose of this trial?

The purpose of this study is to test any good and bad effects of the study drugs called Pembrolizumab and Entinostat when used in combination to treat lymphoma. This combination could shrink the lymphoma but it could also cause side effects. Researchers also hope to learn whether adding entinostat to pembrolizumab can be more effective for patients with lymphoma than either drug alone.

Research Team

Alison Moskowitz, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

Adults over 18 with classical Hodgkin lymphoma, who have tried at least two treatments and aren't eligible for a transplant. They must have measurable disease, be in good physical condition (ECOG ≤ 1), and have proper organ function. Women of childbearing age need a negative pregnancy test and agree to use contraception; men also must commit to using birth control.

Inclusion Criteria

Patient has adequate bone marrow and organ function by: ANC ≥ 1.0 x 10^9/L, Platelets ≥75 x 10^9/L, Hemoglobin (Hgb) ≥ 9.0 g/dL, ALT and AST ≤ 1.5 x ULN (or ≤3 x ULN if liver involved with disease), Total serum bilirubin or plasma bilirubin ≤ 1.5 x ULN (≤ 3 x ULN with direct bilirubin within normal range in patients with documented hepatic involvement), INR or PT ≤1.5×ULN unless patient is receiving anticoagulant therapy, aPTT ≤1.5×ULN unless patient is receiving anticoagulant therapy, GFR>45 ml/min, Female subject of childbearing potential should have a negative pregnancy test within 72 hours prior to receiving the first dose of study medication and must be willing to use adequate contraception, Male subjects of childbearing potential must agree to use adequate contraception

I have Hodgkin lymphoma and have tried at least 2 treatments but can't or won't get a stem cell transplant.

I have benefited from specific cancer treatments and may still be on them.

Exclusion Criteria

Diagnosed or treated for malignancy other than the indication under study except for certain cases, History of HIV, Active Hepatitis B or C infection, History of active TB, Concurrent enrollment in another therapeutic investigational clinical study within 4 weeks of the first dose of study drug, Known CNS lymphoma involvement, Any uncontrolled active systemic infection or any life-threatening illness, History of certain cardiac events within specified timeframes, Uncontrolled heart failure or hypertension or uncontrolled diabetes mellitus, Any active autoimmune disease or a documented history of autoimmune disease, Syndrome requiring ongoing systemic treatment with corticosteroids or other immunosuppressive medications, Women who are pregnant or breastfeeding, Recent live vaccine or live-attenuated vaccine administration, Prior anti-cancer monoclonal antibody within 4 weeks prior to study Day 1, Prior allogenic tissue/solid organ transplant <1 year ago, Recent chemotherapy or small molecule therapy within specified timeframes, Recent radiotherapy within 2 weeks prior to study day 1, Allergy to benzamide or inactive components of entinostat

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive entinostat by mouth once weekly and pembrolizumab intravenously every 3 weeks

2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

Treatment Details

Interventions

• Entinostat
• Pembrolizumab

Trial Overview The trial is testing the combination of Pembrolizumab and Entinostat against lymphoma to see if they're more effective together than alone. The goal is to shrink the cancer but researchers are also watching for any side effects that might occur from this drug combo.

Participant Groups

Group I: Entinostat and Pembrolizumab Experimental Treatment 2 Interventions

patients will be assigned to receive therapy with entinostat given by mouth once weekly and pembrolizumab given intravenously every 3 weeks

Entinostat is already approved in China, European Union for the following indications:

Approved in China as Entinostat for:

• Cancer

Approved in European Union as Entinostat for:

• Orphan Drug designation for cancer treatment

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

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

Syndax Pharmaceuticals

Industry Sponsor

Trials

49

Recruited

2,700+

Findings from Research

Pembrolizumab, an anti-PD-1 antibody, has shown significant efficacy in treating advanced melanoma, demonstrating superior progression-free survival compared to chemotherapy in Phase II trials and improved overall survival in Phase III trials.

The treatment is generally well tolerated with a favorable safety profile, though common side effects include fatigue and rash, while less frequent but serious immune-related adverse events can occur.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in the management of metastatic melanoma. Spain, L., Younger, E., Hatipoglu, E., et al.[2020]

The combination of pembrolizumab and vorinostat was found to be tolerable in patients with relapsed/refractory B-cell lymphomas, although there were serious adverse events, including one case of Stevens-Johnson syndrome that led to a fatal infection.

The treatment showed promising efficacy, especially in primary mediastinal B-cell lymphoma (PMBL), with a complete response rate of 80% and overall response rate of 80%, while overall response rates for other non-PMBL diffuse large B-cell lymphoma (DLBCL) were lower at 33%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results from a phase I trial of pembrolizumab plus vorinostat in relapsed/refractory B-cell non-Hodgkin lymphoma. Godfrey, J., Mei, M., Chen, L., et al.[2023]

Entinostat, an oral HDAC inhibitor, was well tolerated in a phase I trial with 21 pediatric patients, showing no dose-limiting toxicities at doses of 3 mg/m2 and 4 mg/m2, indicating a favorable safety profile for this age group.

The recommended phase 2 dose (RP2D) for entinostat in children with relapsed or refractory solid tumors is established at 4 mg/m2, with pharmacokinetic studies revealing a significantly higher drug exposure in children compared to adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1 study of entinostat in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1513, Pediatric Early Phase-Clinical Trial Network (PEP-CTN). Bukowinski, A., Chang, B., Reid, JM., et al.[2022]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating unresectable or metastatic melanoma based on two clinical trials involving 1,374 patients, showing significant improvements in overall survival compared to ipilimumab, with hazard ratios indicating a reduced risk of death.

Patients receiving pembrolizumab also experienced significant improvements in progression-free survival, although some immune-mediated adverse reactions like hypothyroidism and pneumonitis were noted, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. Barone, A., Hazarika, M., Theoret, MR., et al.[2022]

In a study of 655 patients with advanced melanoma, pembrolizumab showed a 5-year overall survival rate of 34%, with even better outcomes (41%) for treatment-naive patients, indicating its long-term efficacy.

The treatment was generally well-tolerated, with 86% of patients experiencing treatment-related adverse events, but only 7.8% discontinued due to these effects, suggesting a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Hamid, O., Robert, C., Daud, A., et al.[2023]

Entinostat is a selective HDAC inhibitor that promotes histone hyperacetylation, leading to the activation of specific genes that inhibit cancer cell growth and induce apoptosis, making it a promising treatment for advanced malignancies.

Currently being evaluated in a Phase III trial for advanced breast cancer, entinostat has shown a potential overall survival advantage when combined with exemestane, based on earlier Phase II results, although it is not yet approved for clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Entinostat: a promising treatment option for patients with advanced breast cancer. Connolly, RM., Rudek, MA., Piekarz, R.[2022]

Pembrolizumab is a monoclonal antibody that effectively blocks the PD-1 receptor on T cells, enhancing their ability to attack cancer cells, particularly in melanoma patients.

In a Phase I study involving 411 patients, pembrolizumab demonstrated high durable response rates with minimal toxicity, indicating its potential as a safe and effective treatment option for melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. Hersey, P., Gowrishankar, K.[2017]

Pembrolizumab, a monoclonal antibody targeting PD-1, has shown significant clinical efficacy in treating Hodgkin Lymphoma and promising early results in certain subtypes of Non-Hodgkin Lymphoma, particularly those with genetic similarities to HL.

Current data suggest that pembrolizumab has a favorable safety profile and efficacy as a single agent in treating diffuse large B cell lymphomas, with future strategies likely to focus on biomarker-driven approaches and combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of diffuse large B-cell lymphoma. Sheikh, S., Kuruvilla, J.[2020]

Pembrolizumab, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab in the management of metastatic melanoma. [2020]

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

Entinostat, a novel histone deacetylase inhibitor is active in B-cell lymphoma and enhances the anti-tumour activity of rituximab and chemotherapy agents. [2018]

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

Entinostat Helps Thwart Immunotherapy Resistance. [2020]

4. Italy pubmed.ncbi.nlm.nih.gov

Results from a phase I trial of pembrolizumab plus vorinostat in relapsed/refractory B-cell non-Hodgkin lymphoma. [2023]

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

A phase 1 study of entinostat in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1513, Pediatric Early Phase-Clinical Trial Network (PEP-CTN). [2022]

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

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Entinostat: a promising treatment option for patients with advanced breast cancer. [2022]

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

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. [2017]

10. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of diffuse large B-cell lymphoma. [2020]

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

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. [2022]