PC14586 for Solid Tumors

Recruiting at 97 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

300 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness and safety of the medication PC14586 (Rezatapopt) for treating solid tumors with the TP53 Y220C mutation. The study consists of two parts: one tests PC14586 alone, and the other combines it with pembrolizumab (KEYTRUDA). Individuals with advanced or metastatic solid tumors, such as breast or lung cancer, who have this mutation and have previously received treatment but still experience disease progression, may be suitable candidates. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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.

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

Research has shown that rezatapopt (PC14586) was safe in early studies. In these trials, patients with solid tumors featuring a specific genetic change (TP53 Y220C) took rezatapopt. The treatment was generally well-tolerated, with most participants not experiencing serious side effects.

Current studies are examining the safety and tolerability of combining rezatapopt with pembrolizumab. Pembrolizumab is already approved for other uses, indicating its known safety, but its use with rezatapopt remains under investigation.

Overall, both rezatapopt alone and in combination appear safe based on current evidence. However, ongoing research is crucial to confirm these findings and further explore potential side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Rezatapopt (PC14586) is unique because it targets a specific mutation known as TP53 Y220C, which is found in several types of advanced solid tumors, including breast, lung, ovarian, and endometrial cancers. Most treatments for these conditions, like chemotherapy and immunotherapy, don't specifically target this mutation. Rezatapopt's ability to zero in on TP53 Y220C offers a more precise approach, potentially leading to better outcomes for patients with this mutation. Additionally, when combined with pembrolizumab, an existing immunotherapy, it aims to enhance the immune response against these tumors. Researchers are excited about this treatment because it represents a tailored therapy option that could provide significant benefits to patients who have few alternatives.

What evidence suggests that this trial's treatments could be effective for solid tumors?

Research has shown that the drug rezatapopt (PC14586) may help treat solid tumors with a specific change in the TP53 gene, known as the Y220C mutation. In earlier studies, about one-third of patients experienced a decrease in tumor size, with these effects lasting an average of 6.2 months. This mutation appears in about 1% of solid tumors, making this treatment quite targeted. In this trial, some participants will receive rezatapopt as a monotherapy, while others will receive it combined with pembrolizumab, which boosts the immune system to fight cancer. Overall, early results are promising for both the single drug and the combination treatment. ^{2 6 7 8 9}

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 PC14586 (INN: 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

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]

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]

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) 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]

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, 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]

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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04585750

Study Details | NCT04585750 | The Evaluation of PC14586 ... The Phase 2 monotherapy portion of this study is currently enrolling and will evaluate the efficacy and safety of PC14586 (INN rezatapopt) in participants ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12520105/

PYNNACLE phase II clinical trial protocol: rezatapopt ... The TP53 Y220C mutation is a key hot-spot TP53 missense mutation present in ~ 1% of all solid tumors [1,6,10]. This mutation destabilizes the ...

3. onclive.com onclive.com/view/rezatapopt-elicits-responses-in-several-solid-tumors-harboring-a-tp53-y220c-mutation

Rezatapopt Elicits Responses in Several Solid Tumors ... Rezatapopt achieved a 33% ORR in solid tumors with TP53 Y220C mutation, with a median response duration of 6.2 months. · Ovarian cancer patients ...

4. cancernetwork.com cancernetwork.com/view/rezatapopt-yields-responses-across-tp53-y220c-mutated-solid-tumor-types

Rezatapopt Yields Responses Across TP53 Y220C ... Rezatapopt achieved an ORR of 33% in all patients, and an ORR of 43% in patients with ovarian cancer, with 1 confirmed complete response.

5. ir.pmvpharma.com ir.pmvpharma.com/news-releases/news-release-details/pmv-pharmaceuticals-provides-progress-update-pynnacle-clinical

PMV Pharmaceuticals Provides a Progress Update on ... We remain excited by the potential for rezatapopt as a monotherapy in patients with advanced solid tumors harboring a TP53 Y220C mutation and ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04585750

Study Details | NCT04585750 | The Evaluation of PC14586 ... The Phase 2 monotherapy portion of this study is currently enrolling and will evaluate the efficacy and safety of PC14586 (INN rezatapopt) in participants ...

7. annalsofoncology.org annalsofoncology.org/article/S0923-7534(24)03681-0/fulltext

691TiP PYNNACLE phase II trial of rezatapopt (PC14586) ... In Phase 1, rezatapopt showed single-agent efficacy and favorable safety in heavily pre-treated patients (pts) with solid tumors harboring a TP53 Y220C mutation ...

8. pubs.acs.org pubs.acs.org/doi/10.1021/acs.jmedchem.5c00670

A First-in-Class Small Molecule p53 Y220C Mutant Protein ... In a Phase I clinical trial (NCT04585750), rezatapopt displayed a favorable safety profile across all efficacious doses. (9) Moreover, ...

9. pynnaclestudy.com pynnaclestudy.com/

PYNNACLE Study | Rezatapopt | PYNNACLE clinical study An ongoing Phase 1/2 clinical study of rezatapopt in patients with locally advanced or metastatic solid tumors that have a TP53 Y220C mutation (NCT04585750).