PC14586 for Solid Tumors
Recruiting in Palo Alto (17 mi)
+73 other locations
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: PMV Pharmaceuticals, Inc
Must not be taking: Strong CYP3A4 inducers
Disqualifiers: Primary CNS tumor, Heart conditions, Active infection, others
No Placebo Group
Breakthrough Therapy
Trial Summary
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 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.
12345What 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.
12678What 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.
128910Eligibility Criteria
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
I am 18 years or older, or between 12 to 17 years with adult safety data available.
My organs are working well.
My cancer has worsened despite previous treatments.
+2 more
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.
+9 more
Trial Timeline
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
Participant Groups
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.
9Treatment groups
Experimental Treatment
Group I: Phase 2 Monotherapy Dose Expansion, Ovarian Cancer CohortExperimental Treatment1 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 CohortExperimental Treatment1 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 CohortExperimental Treatment1 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 CohortExperimental Treatment1 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 CohortExperimental Treatment1 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 patientsExperimental Treatment2 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 patientsExperimental Treatment2 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 1Experimental Treatment2 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 EscalationExperimental Treatment1 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).
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Rocky Mountain Cancer CenterDenver, CO
Duke UniversityDurham, NC
Robert H. Lurie Comprehensive Cancer Center of Northwestern UniversityChicago, IL
UT Southwest Simmons Cancer CenterDallas, TX
More Trial Locations
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Who Is Running the Clinical Trial?
PMV Pharmaceuticals, IncLead Sponsor
Merck Sharp & Dohme LLCIndustry Sponsor
References
Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]A phase II trial investigating the therapeutic effect of neoadjuvant programmed cell death 1 (PD-1) inhibitor pembrolizumab (MK-3475, KEYTRUDA®) administered prior to surgery for the treatment of non-small cell lung cancer (NSCLC) has been conducted (NCT03197467). We report the first clinical results of a planned interim safety analysis after 15 patients were enrolled.
Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017]New insights into the interaction between the immune system and the tumor microenvironment have led to the development of checkpoint inhibitors that target the PD-1/PD-L1 pathway. Pembrolizumab (MK-3475, lambrolizumab, Keytruda(®)) is a PD-1 inhibitor that has shown clinical activity in a variety of solid tumors and is currently approved for the second-line treatment of PD-L1-positive non-small-cell lung cancer and for unresectable/metastatic melanoma. This article will discuss the results of early-phase trials of pembrolizumab in thoracic malignancies as well as ongoing studies aimed to confirm clinical benefit.
Evaluation of efficacy and safety of different pembrolizumab dose/schedules in treatment of non-small-cell lung cancer and melanoma: a systematic review. [2018]Pembrolizumab is a fully humanized anti-PD-1 agent currently approved for the treatment of advanced melanoma and pretreated non-small-cell lung cancer (NSCLC).
FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond. [2022]On October 24, 2016, the U.S. Food and Drug Administration (FDA) approved pembrolizumab (Keytruda; Merck & Co., Inc., https://www.merck.com) for treatment of patients with metastatic non-small cell lung cancer (mNSCLC) whose tumors express programmed death-ligand 1 (PD-L1) as determined by an FDA-approved test, as follows: (a) first-line treatment of patients with mNSCLC whose tumors have high PD-L1 expression (tumor proportion score [TPS] ≥50%), with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations, and (b) treatment of patients with mNSCLC whose tumors express PD-L1 (TPS ≥1%), with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab.Approval was based on two randomized, open-label, active-controlled trials demonstrating statistically significant improvements in progression-free survival (PFS) and overall survival (OS) for patients randomized to pembrolizumab compared with chemotherapy. In KEYNOTE-024, patients with previously untreated mNSCLC who received pembrolizumab (200 mg intravenously [IV] every 3 weeks) had a statistically significant improvement in OS (hazard ratio [HR] 0.60; 95% confidence interval [CI]: 0.41-0.89; p = .005), and significant improvement in PFS (HR 0.50; 95% CI: 0.37-0.68; p < .001). In KEYNOTE-010, patients with disease progression on or after platinum-containing chemotherapy received pembrolizumab IV 2 mg/kg, 10 mg/kg, or docetaxel 75 mg/m2 every 3 weeks. The HR and p value for OS was 0.71 (95% CI: 0.58-0.88), p < .001 comparing pembrolizumab 2 mg/kg with chemotherapy and the HR and p value for OS was 0.61 (95% CI: 0.49-0.75), p < .001 comparing pembrolizumab 10 mg/kg with chemotherapy.
Pembrolizumab: first global approval. [2021]Pembrolizumab [Keytruda(®) (US)], a humanized monoclonal antibody against the programmed death receptor-1 (PD-1) protein, has been developed by Merck & Co for the treatment of cancer. Pembrolizumab has received its first global approval for the treatment of advanced, unresectable or metastatic malignant melanoma in the US, for use in patients with disease progression after prior treatment with ipilimumab and, for BRAF V600 mutation-positive patients, a BRAF inhibitor. It is the first anti-PD-1 therapy to receive regulatory approval in the US, and is currently under regulatory review in the EU. This article summarizes the milestones in the development of pembrolizumab leading to this first approval for the treatment of malignant melanoma.
FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021]On September 4, 2014, the FDA approved pembrolizumab (KEYTRUDA; Merck Sharp & Dohme Corp.) with a recommended dose of 2 mg/kg every 3 weeks by intravenous infusion for the treatment of patients with unresectable or metastatic melanoma who have progressed following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on demonstration of objective tumor responses with prolonged response durations in 89 patients enrolled in a randomized, multicenter, open-label, dose-finding, and activity-estimating phase 1 trial. The overall response rate (ORR) by blinded independent central review per RECIST v1.1 was 24% (95% confidence interval, 15-34); with 6 months of follow-up, 86% of responses were ongoing. The most common (≥20%) adverse reactions were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. Immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, hypophysitis, and thyroid disorders. The benefits of the observed ORR with prolonged duration of responses outweighed the risks of immune-mediated adverse reactions in this life-threatening disease and represented an improvement over available therapy. Important regulatory issues in this application were role of durability of response in the evaluation of ORR for accelerated approval, reliance on data from a first-in-human trial, and strategies for dose selection. Clin Cancer Res; 23(19); 5666-70. ©2017 AACR.
Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. [2022]Pembrolizumab (Keytruda; Merck Sharp & Dohme) is a humanized IgG4 monoclonal antibody used in cancer immunotherapy. It targets the programmed cell death-1 (PD-1) receptor, which is important in maintaining self-tolerance. However, immune checkpoint blockade is associated with a risk for immune-related adverse events (irAEs) potentially affecting the endocrine organs. Type 1 diabetes mellitus is a rare irAE of PD-1 inhibitors, occurring in 0.2% of cases.
Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]Pembrolizumab (Keytruda) is a monoclonal antibody against the programmed cell death-1 (PD-1) receptor on lymphocytes, which is one of the immune checkpoint inhibitors (ICIs) approved for multiple solid and hematologic malignancies. Although ICIs have proven to be more effective and less toxic compared to chemotherapy, there are reports of adverse side effects with ICIs. For example, pneumonitis is a potentially lethal side effect occurring in 1%-5% of patients who received ICIs in clinical trials, and there are case reports with clinical and radiological features of checkpoint inhibitor-pneumonitis (CIP).
Pembrolizumab for the treatment of PD-L1 positive advanced or metastatic non-small cell lung cancer. [2020]The emergence of immune checkpoint inhibitors marked an important advancement in the development of cancer therapeutics. Pembrolizumab is a selective humanized IgG4 kappa monoclonal antibody that inhibits the programmed death-1 (PD-1) receptor, an integral component of immune checkpoint regulation in the tumor microenvironment. The drug is currently approved by the Food and Drug Administration for the treatment of advanced melanoma and metastatic squamous and nonsquamous non-small cell lung cancer (NSCLC). Several published studies demonstrate that single-agent pembrolizumab is safe and has efficacy in patients with NSCLC. Many ongoing protocols are investigating the role of pembrolizumab in combination with other agents in lung cancer and various other cancer types. We review the available data on pembrolizumab in NSCLC and examine the role of potential predictive biomarkers of response to therapy.
Pembrolizumab Approved for Esophageal or Gastroesophageal Cancer. [2023]Pembrolizumab (Keytruda) has been approved to treat metastatic or locally advanced esophageal or gastroesophageal junction cancer. It is used in combination with platinum- and fluoropyrimidine-based chemotherapy.