PC14586 for Solid Tumors

Recruiting at 84 trial locations

Overseen By PMV Pharma Clinical Study Information Center

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: PMV Pharmaceuticals, Inc

Must not be taking: Strong CYP3A4 inducers

Disqualifiers: Primary CNS tumor, Heart conditions, Active infection, others

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

Compensation: Varies

Number of Visits: Unknown

230 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial is testing a new oral drug, PC14586 (rezatapopt), alone and with pembrolizumab, in patients with advanced cancers that have a specific genetic mutation. The drug aims to fix a mutated protein to help control cancer growth. The study will determine the best dose and evaluate the drug's safety and effectiveness.

Will I have to stop taking my current medications?

The trial requires that you stop any anti-cancer therapy at least 21 days before starting the study drug. If you are taking strong CYP3A4 inducers, you may also need to stop those medications.

What safety information is available for pembrolizumab (Keytruda) in humans?

Pembrolizumab (Keytruda) has been associated with some common side effects like fatigue, cough, nausea, and rash, as well as more serious immune-related side effects such as pneumonitis (lung inflammation), colitis (inflammation of the colon), and thyroid disorders. Rarely, it can cause type 1 diabetes. These side effects have been observed in various cancer treatments. ^{1 2 3 4 5}

What makes the drug PC14586 with Pembrolizumab unique for treating solid tumors?

PC14586 combined with Pembrolizumab is unique because Pembrolizumab is an immune checkpoint inhibitor that helps the immune system recognize and attack cancer cells by blocking the PD-1 pathway, which is a mechanism tumors use to hide from the immune system. This combination may offer a novel approach for treating solid tumors by enhancing the body's immune response against cancer. ^{1 4 5 6 7}

What data supports the effectiveness of the drug pembrolizumab (Keytruda) for treating solid tumors?

Pembrolizumab (Keytruda) has shown effectiveness in treating various solid tumors, including non-small cell lung cancer and melanoma, by improving survival rates compared to chemotherapy. It works by helping the immune system attack cancer cells more effectively. ^{1 5 8 9 10}

Who Is on the Research Team?

Marc Fellous, MD

Principal Investigator

Sr. Vice President of Medical Affairs

Are You a Good Fit for This Trial?

Adults with advanced solid tumors that have a specific mutation (TP53 Y220C) can join this trial. They should have tried other cancer treatments without success and be in good physical condition (ECOG 0 or 1). People with certain heart conditions, recent strokes, brain metastases needing steroids, or those on drugs affecting the immune system cannot participate.

Inclusion Criteria

My organs are working well.

My cancer has worsened despite previous treatments.

My cancer has a specific TP53 mutation.

Exclusion Criteria

My brain metastases are stable without needing steroids for symptoms.

I do not have recent severe heart problems or uncontrolled blood pressure.

My cancer started in the brain or spinal cord.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Monotherapy

Establish the maximum tolerated dose (MTD) and RP2D of rezatapopt, assess safety, tolerability, and preliminary efficacy

41 months

Phase 1b Combination Therapy

Evaluate safety, tolerability, and preliminary efficacy of rezatapopt in combination with pembrolizumab

30 months

Phase 2 Monotherapy

Evaluate the efficacy and safety of rezatapopt at the RP2D in various cancer cohorts

34 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• PC14586
• Pembrolizumab

Trial Overview The trial is testing PC14586 alone and combined with pembrolizumab to see how safe and effective they are for treating cancers with the TP53 Y220C mutation. Participants will receive different doses of PC14586 to find out which one works best.

How Is the Trial Designed?

Group I: Phase 2 Monotherapy Dose Expansion, Ovarian Cancer Cohort Experimental Treatment 1 Intervention

Additional (expansion of) participants will dose with 2000 mg daily oral PC14586 (INN: rezatapopt) with food for continued evaluation. Ovarian Cancer Cohort participants will have locally advanced or metastatic ovarian cancer harboring a TP53 Y220C mutation who meet all eligibility criteria and have measurable disease per RECIST 1.1.

Group II: Phase 2 Monotherapy Dose Expansion, Other Solid Tumors Cohort Experimental Treatment 1 Intervention

Additional (expansion of) participants will dose with 2000 mg daily oral PC14586 (INN: rezatapopt) with food for continued evaluation. Other Solid Tumors Cohort participants will have locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation who meet all eligibility criteria and have measurable disease per RECIST 1.1.

Group III: Phase 2 Monotherapy Dose Expansion, Lung Cancer Cohort Experimental Treatment 1 Intervention

Additional (expansion of) participants will dose with 2000 mg daily oral PC14586 (INN: rezatapopt) with food for continued evaluation. Lung Cancer Cohort participants will have locally advanced or metastatic lung cancer harboring a TP53 Y220C mutation who meet all eligibility criteria and have measurable disease per RECIST 1.1.

Group IV: Phase 2 Monotherapy Dose Expansion, Endometrial Cancer Cohort Experimental Treatment 1 Intervention

Additional (expansion of) participants will dose with 2000 mg daily oral rezatapopt with food for continued evaluation. Endometrial Cancer Cohort participants will have locally advanced or metastatic endometrial cancer harboring a TP53 Y220C mutation who meet all eligibility criteria and have measurable disease per RECIST 1.1.

Group V: Phase 2 Monotherapy Dose Expansion, Breast Cancer Cohort Experimental Treatment 1 Intervention

Additional (expansion of) participants will dose with 2000 mg daily oral PC14586 (INN: rezatapopt) with food for continued evaluation. Breast Cancer Cohort participants will have locally advanced or metastatic breast cancer harboring a TP53 Y220C mutation who meet all eligibility criteria and have measurable disease per RECIST 1.1.

Group VI: Phase 1b Combination Therapy Dose Expansion, PD(L)-1 relapsed/refractory patients Experimental Treatment 2 Interventions

Additional (expansion of) participants will enroll at the RP2D of daily oral rezatapopt when administered in combination with pembrolizumab (200 mg IV q3 weeks) for continued evaluation. Participants will have advanced solid tumors harboring a p53 Y220C mutation and are PD(L)-1 relapsed/refractory patients.

Group VII: Phase 1b Combination Therapy Dose Expansion, PD(L)-1 naive patients Experimental Treatment 2 Interventions

Additional (expansion of) participants will enroll at the RP2D of daily oral PC14586 (INN: rezatapopt) when administered in combination with pembrolizumab (200 mg IV q3 weeks) for continued evaluation. Participants will have advanced solid tumors harboring a p53 Y220C mutation and are PD(L)-1 naive patients.

Group VIII: Phase 1b Combination Therapy Dose Escalation, Part 1 Experimental Treatment 2 Interventions

Multiple dose levels of daily oral rezatapopt in combination with a stable dose of pembrolizumab (200 mg IV q3 weeks) will be evaluated in an escalating manner, to determine the maximum tolerated dose and to ensure sufficient safety experience, pharmacokinetic information, and early evidence of clinical activity of PC14586 to recommend a Phase 2 dose (RP2D) of rezatapopt when administered in combination with pembrolizumab.

Group IX: Phase 1 Monotherapy Dose Escalation Experimental Treatment 1 Intervention

Multiple dose levels of daily oral rezatapopt will be evaluated in an escalating manner, to determine the maximum tolerated dose and to ensure sufficient safety experience, pharmacokinetic information, and early evidence of clinical activity of rezatapopt to recommend a Phase 2 dose (RP2D).

Who Is Running the Clinical Trial?

PMV Pharmaceuticals, Inc

Lead Sponsor

Trials

6

Recruited

340+

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 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, 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]

A systematic review of four trials involving 3425 patients found that lower doses of pembrolizumab (2 mg/kg every 3 weeks) are equally effective as higher doses (10 mg/kg) in treating advanced melanoma and non-small-cell lung cancer (NSCLC).

The safety profile of pembrolizumab was similar across different doses, suggesting that the lower dose may be sufficient for routine treatment without compromising efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of efficacy and safety of different pembrolizumab dose/schedules in treatment of non-small-cell lung cancer and melanoma: a systematic review. Abdel-Rahman, O.[2018]

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]

Pembrolizumab (Keytruda) is the first anti-PD-1 therapy approved in the US for treating advanced malignant melanoma, specifically for patients who have progressed after prior treatments.

It is designed to target the PD-1 protein, enhancing the immune system's ability to fight cancer, and is currently under review for approval in the EU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab: first global approval. Poole, RM.[2021]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

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]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

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 (Keytruda) is an approved treatment for metastatic or locally advanced esophageal and gastroesophageal junction cancer, indicating its efficacy in targeting these specific cancer types.

It is used in combination with platinum- and fluoropyrimidine-based chemotherapy, suggesting a synergistic approach to enhance treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Approved for Esophageal or Gastroesophageal Cancer. Aschenbrenner, DS.[2023]

Citations

1. 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]

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

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

3. England pubmed.ncbi.nlm.nih.gov

Evaluation of efficacy and safety of different pembrolizumab dose/schedules in treatment of non-small-cell lung cancer and melanoma: a systematic review. [2018]

4. 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]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Pembrolizumab: first global approval. [2021]

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

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021]

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

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

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

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]

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

Pembrolizumab Approved for Esophageal or Gastroesophageal Cancer. [2023]