Pembrolizumab + Epigenetic Drugs for Lung Cancer

Recruiting at 2 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Memorial Sloan Kettering Cancer Center

Must be taking: Anti-PD1/PD-L1

Must not be taking: Immunosuppressants, Live vaccines

Disqualifiers: EGFR/ALK mutations, Autoimmune, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

28 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to test the safety of a combination of three drugs, pembrolizumab, guadecitabine and mocetinostat. Pembrolizumab is a drug given by vein and all patients will receive the same dose. Guadecitabine and mocetinostat will be given at different doses to find out what effects, if any, they have on treating your cancer and side effects.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have any systemic anti-cancer therapy within 3 weeks before starting the trial, and certain other treatments may also need to be paused. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination of Pembrolizumab, Guadecitabine, and Mocetinostat for lung cancer?

Research shows that combining pembrolizumab, an immune therapy drug, with other drugs like mocetinostat (an epigenetic drug) can improve outcomes in lung cancer patients, especially those who have not responded to previous treatments. Studies suggest that these combinations can help the immune system better fight cancer. ^{1 2 3 4 5}

Is the combination of Pembrolizumab and epigenetic drugs safe for humans?

Pembrolizumab, also known as Keytruda, has been shown to be generally safe in humans when used alone for treating certain types of lung cancer, with ongoing studies exploring its use in combination with other drugs. However, specific safety data for the combination of Pembrolizumab with epigenetic drugs like Guadecitabine and Mocetinostat is not detailed in the available research. ^{6 7 8 9 10}

What makes the drug combination of Pembrolizumab, Guadecitabine, and Mocetinostat unique for lung cancer?

This treatment is unique because it combines Pembrolizumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells, with epigenetic drugs Guadecitabine and Mocetinostat, which may modify gene expression to enhance the immune response and overcome resistance in lung cancer. ^{2 6 9 10 11}

Research Team

Kathryn Arbour, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

Adults over 18 with advanced stage IIIb or IV NSCLC who have previously been treated with anti-PD1/PD-L1 therapy and experienced disease progression. Participants must be able to undergo biopsies, have an ECOG performance status of 0-1, and adequate organ function. Women must test negative for pregnancy and use effective contraception.

Inclusion Criteria

My cancer tissue sample was taken through a core biopsy.

My lung cancer is at stage IIIb or IV.

I am able and willing to sign the consent form.

Exclusion Criteria

I am currently on medication for an infection.

Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment

You have a history of autoimmune disease.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab, guadecitabine, and mocetinostat to assess safety and efficacy

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• Guadecitabine
• Mocetinostat
• Pembrolizumab

Trial Overview The trial is testing the safety of combining pembrolizumab (an immunotherapy drug) with guadecitabine and mocetinostat (epigenetic drugs). The goal is to determine the effects on lung cancer treatment and identify any side effects at various doses.

Participant Groups

Group I: pembrolizumab plus guadecitabine and mocetinostat Experimental Treatment 3 Interventions

Pembrolizumab given IV; guadecitabine given SQ, mocetinostat given PO.

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Mirati Therapeutics Inc.

Industry Sponsor

Trials

73

Recruited

8,900+

Dr. Charles M. Baum

Mirati Therapeutics Inc.

Chief Executive Officer since 2023

MD, PhD

Dr. Joseph Leveque

Mirati Therapeutics Inc.

Chief Medical Officer since 2021

MD

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

Stand Up To Cancer

Collaborator

Trials

53

Recruited

40,100+

Astex Pharmaceuticals, Inc.

Industry Sponsor

Trials

97

Recruited

7,400+

Dr. Harren Jhoti

Astex Pharmaceuticals, Inc.

Chief Executive Officer since 2007

PhD in Biochemistry from Birkbeck College, London

Dr. Harold N. Keer

Astex Pharmaceuticals, Inc.

Chief Medical Officer since 2020

MD

Van Andel Research Institute

Collaborator

Trials

28

Recruited

5,200+

Findings from Research

The combination of mocetinostat (70 mg TIW) and durvalumab was generally well tolerated in patients with advanced non-small cell lung cancer (NSCLC), with an objective response rate (ORR) of 11.5% across all phase II cohorts, indicating some effectiveness in this challenging population.

Notably, the treatment showed a higher ORR of 23.1% in patients whose disease was refractory to prior checkpoint inhibitor therapies, suggesting that mocetinostat may help overcome resistance to existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mocetinostat in Combination With Durvalumab for Patients With Advanced NSCLC: Results From a Phase I/II Study. Johnson, ML., Strauss, J., Patel, MR., et al.[2023]

In a long-term study of 123 patients with advanced nonsquamous NSCLC, the combination of pembrolizumab with pemetrexed-carboplatin significantly improved the objective response rate (58% vs. 33%) and progression-free survival (24.5 months vs. 9.9 months) compared to chemotherapy alone.

Patients who completed 2 years of pembrolizumab treatment had a remarkable 92% survival rate at the data cutoff, indicating a durable clinical benefit, while the safety profile remained manageable with no new safety concerns identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Overall Survival From KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin With or Without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous NSCLC. Awad, MM., Gadgeel, SM., Borghaei, H., et al.[2021]

The KEYNOTE-001 trial demonstrated that pembrolizumab significantly improves clinical outcomes for patients with advanced non-small cell lung cancer, indicating its efficacy as a treatment option.

Patients whose tumors express PD-L1 in at least 50% of cells showed better responses to pembrolizumab, suggesting that PD-L1 expression is a key factor in predicting treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Shows Promise for NSCLC. [2015]

In a phase 2 trial involving 100 patients with advanced non-small cell lung cancer, combining pembrolizumab with CC-486 (oral azacitidine) did not show a significant improvement in progression-free survival compared to pembrolizumab with placebo, with median PFS of 2.9 months versus 4.0 months, respectively.

While the combination treatment did not enhance efficacy, it resulted in more treatment-emergent adverse events, particularly gastrointestinal issues, which may have limited the duration and feasibility of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomised phase 2 study of pembrolizumab plus CC-486 versus pembrolizumab plus placebo in patients with previously treated advanced non-small cell lung cancer. Levy, BP., Giaccone, G., Besse, B., et al.[2020]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

Pembrolizumab (Keytruda) was approved by the FDA for treating metastatic non-small cell lung cancer (mNSCLC) in patients with tumors expressing PD-L1, showing significant improvements in overall survival (OS) and progression-free survival (PFS) in two major clinical trials with thousands of participants.

In the KEYNOTE-024 trial, pembrolizumab demonstrated a 40% reduction in the risk of death compared to chemotherapy, while in the KEYNOTE-010 trial, it also showed a significant survival advantage over chemotherapy in patients who had previously progressed on treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond. Pai-Scherf, L., Blumenthal, GM., Li, H., et al.[2022]

In the phase Ib KEYNOTE-001 study, pembrolizumab monotherapy showed durable antitumor activity in advanced non-small-cell lung cancer (NSCLC), with a median overall survival (OS) of 22.3 months for treatment-naive patients and 10.5 months for previously treated patients, and 5-year OS rates of 23.2% and 15.5%, respectively.

Patients with a PD-L1 tumor proportion score of 50% or greater had even better outcomes, with 5-year OS rates of 29.6% for treatment-naive and 25.0% for previously treated patients, while the treatment maintained a favorable safety profile with minimal late-onset adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Five-Year Overall Survival for Patients With Advanced Non‒Small-Cell Lung Cancer Treated With Pembrolizumab: Results From the Phase I KEYNOTE-001 Study. Garon, EB., Hellmann, MD., Rizvi, NA., et al.[2022]

Pembrolizumab is a safe and effective immune checkpoint inhibitor that targets the PD-1 receptor, currently approved for treating advanced melanoma and metastatic non-small cell lung cancer (NSCLC).

Ongoing studies are exploring the potential of pembrolizumab in combination with other treatments for lung cancer and other cancer types, while also investigating biomarkers that may predict patient response to this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of PD-L1 positive advanced or metastatic non-small cell lung cancer. Dang, TO., Ogunniyi, A., Barbee, MS., et al.[2020]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

In a Phase 2 study involving 35 patients with non-small cell lung cancer, neoadjuvant pembrolizumab was found to be safe and well tolerated, with only one surgery delay due to thyroiditis and no mortality within 90 days post-surgery.

The study showed a high rate of R0 resection (88%) and a major pathologic response in 28% of patients, indicating that pembrolizumab may be more effective than standard neoadjuvant chemotherapy in this setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perioperative outcomes of pulmonary resection after neoadjuvant pembrolizumab in patients with non-small cell lung cancer. Tong, BC., Gu, L., Wang, X., et al.[2022]

References

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

Mocetinostat in Combination With Durvalumab for Patients With Advanced NSCLC: Results From a Phase I/II Study. [2023]

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

Entinostat plus Pembrolizumab in Patients with Metastatic NSCLC Previously Treated with Anti-PD-(L)1 Therapy. [2023]

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

Long-Term Overall Survival From KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin With or Without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous NSCLC. [2021]

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

Pembrolizumab Shows Promise for NSCLC. [2015]

5. England pubmed.ncbi.nlm.nih.gov

Randomised phase 2 study of pembrolizumab plus CC-486 versus pembrolizumab plus placebo in patients with previously treated advanced non-small cell lung cancer. [2020]

6. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]

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

FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond. [2022]

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

Five-Year Overall Survival for Patients With Advanced Non‒Small-Cell Lung Cancer Treated With Pembrolizumab: Results From the Phase I KEYNOTE-001 Study. [2022]

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

Pembrolizumab for the treatment of PD-L1 positive advanced or metastatic non-small cell lung cancer. [2020]

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

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017]

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

Perioperative outcomes of pulmonary resection after neoadjuvant pembrolizumab in patients with non-small cell lung cancer. [2022]