The Evaluation of PC14586 in Patients With Advanced Solid Tumors Harboring a p53 Y220C Mutation (PYNNACLE)

Study Overview
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Brief Summary
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This study will assess the safety, tolerability, and efficacy of multiple dose levels of PC14586 alone and in combination with pembrolizumab in participants with advanced solid tumors containing a TP53 Y220C mutation.

Detailed Description
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PC14586 is a first-in-class, oral, small molecule p53 reactivator that is selective for the TP53 Y220C mutation. The primary objective of Phase 1 monotherapy is to establish the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of PC14586. Secondary objectives are to characterize the pharmacokinetic (PK) properties, safety and tolerability, and to assess preliminary efficacy including overall response rate (ORR). The primary objective of Phase 1b Combination Therapy Treatment Arm is to establish the MTD/RP2D of PC14586 when administered in combination with pembrolizumab. Secondary objectives of Phase 1b Combination Therapy Treatment Arm are to characterize PK, safety and tolerability, and to assess preliminary efficacy of PC14586 when administered in combination with pembrolizumab, including ORR. The primary objective of Phase 2 monotherapy is to assess the ORR as determined by blinded independent central review. Secondary objectives of include the safety, PK properties, quality of life, and other efficacy measures of PC14586 at the RP2D.

Official Title
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A Phase 1/2 Open-label, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of PC14586 in Patients With Advanced Solid Tumors Harboring a p53 Y220C Mutation (PYNNACLE)

Conditions
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Advanced Solid Tumor, Advanced Malignant Neoplasm, Metastatic Cancer, Metastatic Solid Tumor, Lung Cancer, Ovarian Cancer, Endometrial Cancer, Prostate Cancer, Colorectal Cancer, Breast Cancer, Other Cancer

Intervention / Treatment
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* Drug: PC14586
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At least 18 years of age or 12 to 17 years of age after adequate adult safety data become available Advanced solid malignancy with a TP53 Y220C mutation Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 Previously treated with one or more lines of anticancer therapy and progressive disease Adequate organ function Additional Criteria for Inclusion in Phase 1b (PC14586 + pembrolizumab combination) Anti-PD-1/PD-L1 naive or must have progressed on treatment Measurable disease Exclusion Criteria: Anti-cancer therapy within 21 days (or 5 half-lives) of receiving the study drug Radiotherapy within 28 days of receiving the study drug Primary CNS tumor (Phase 1, Phase 2 Cohort A) History of leptomeningeal disease or spinal cord compression Brain metastases, unless neurologically stable and do not require steroids to treat associated neurological symptom Stroke or transient ischemic attack within 6 months prior to screening Heart conditions such as unstable angina, uncontrolled hypertension, a heart attack within 6 months prior to screening, congestive heart failure, prolongation of QT interval, or other rhythm abnormalities Strong CYP3A4 inhibitors or inducers, medications with a known risk of QT/QTc prolongation, or proton pump inhibitors History of gastrointestinal (GI) disease that may interfere with absorption of study drug or patients unable to take oral medication History of prior organ transplant Known, active malignancy, except for treated cervical intraepithelial neoplasia, or non-melanoma skin cancer Known, active uncontrolled Hepatitis B, Hepatitis C, or human immunodeficiency virus infection Additional Criteria for Exclusion from Phase 1b (PC14586 + pembrolizumab combination) Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor and discontinued from that treatment due to a Grade 3 or higher immune-related AE (irAE). Received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention. Diagnosis of immunodeficiency or receiving chronic systemic steroid therapy within 7 days prior to the first dose of study drug. Hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients. Active autoimmune disease that has required systemic treatment in past 2 years. History of radiation pneumonitis. History of (non-infectious) or active pneumonitis / interstitial lung disease that required steroids Active infection requiring systemic therapy. Known history of HIV infection.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: During Phase 1 monotherapy (Dose Escalation), participants will be assigned a dose level using an accelerated titration design in the initial dose cohorts, followed by a modified toxicity probability interval (mTPI) design in subsequent dose cohorts. During Part 1 of the Ph 1b Combination Therapy Treatment arm, patients will be assigned a dose level using mTPI design. A recommended PC14586 Phase 2 Dose (RP2D) when administered in combination with pembrolizumab will be selected at the end of Phase 1b Part 1, and the RP2D will be assigned to all participants in Part 2. A Recommended Phase 2 Dose (RP2D) will be selected at the end of Phase 1 monotherapy and in Phase 2 (Dose Expansion) the RP2D will be assigned to all participants.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Dose Escalation<br>Multiple dose levels of daily oral PC14586 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). | Drug: PC14586<br>* First-in-class, oral, small molecule p53 reactivator selective for the p53 Y220C mutation.<br>|
| Experimental: Phase 2 Dose Expansion, Cohort A<br>Additional (expansion of) participants will enroll at the RP2D of daily oral PC14586 for continued evaluation. Cohort A participants will have advanced solid tumors harboring a p53 Y220C mutation who meet all eligibility criteria and have measurable disease per RECIST 1.1. | Drug: PC14586<br>* First-in-class, oral, small molecule p53 reactivator selective for the p53 Y220C mutation.<br>|
| Experimental: Phase 2 Dose Expansion, Cohort B<br>Additional (expansion of) participants will enroll at the RP2D of daily oral PC14586 for continued evaluation. Cohort B participants will have advanced solid tumors harboring a p53 Y220C mutation who do not meet all eligibility criteria (e.g. have a primary central nervous system (CNS) tumor) and do not have measurable disease per RECIST 1.1. | Drug: PC14586<br>* First-in-class, oral, small molecule p53 reactivator selective for the p53 Y220C mutation.<br>|
| Experimental: Phase 1b Dose Escalation, Part 1<br>Multiple dose levels of daily oral PC14586 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 PC14586 when administered in combination with pembrolizumab. | Drug: PC14586<br>* First-in-class, oral, small molecule p53 reactivator selective for the p53 Y220C mutation.<br>Drug: Pembrolizumab<br>* Participants receive pembrolizumab 200 mg by intravenous (IV) infusion over 30 minutes.<br>* Other names: MK-3475;|
| Experimental: Phase 1b Dose Expansion, PD(L)-1 naive patients<br>Additional (expansion of) participants will enroll at the RP2D of daily oral PC14586 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. | Drug: PC14586<br>* First-in-class, oral, small molecule p53 reactivator selective for the p53 Y220C mutation.<br>Drug: Pembrolizumab<br>* Participants receive pembrolizumab 200 mg by intravenous (IV) infusion over 30 minutes.<br>* Other names: MK-3475;|
| Experimental: Phase 1b Dose Expansion, PD(L)-1 relapsed/refractory patients<br>Additional (expansion of) participants will enroll at the RP2D of daily oral PC14586 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. | Drug: PC14586<br>* First-in-class, oral, small molecule p53 reactivator selective for the p53 Y220C mutation.<br>Drug: Pembrolizumab<br>* Participants receive pembrolizumab 200 mg by intravenous (IV) infusion over 30 minutes.<br>* Other names: MK-3475;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the number and type of adverse events to characterize the safety of PC14586 | Number of participants with treatment related adverse events | 48 months for study (Phase 1 and 2) | 
| Determine the number and type of adverse events to characterize the safety of PC14586 when administered in combination with pembrolizumab | Number of participants with treatment related adverse events | 18 months for treatment arm (Phase 1b, parts 1 & 2) | 
| Establish the maximum tolerated dose (MTD) (Phase 1) | Incidence of dose limiting toxicities (DLTs) during the first 21-day cycle of PC14586 | The first 21 days of treatment (Cycle 1) per patient | 
| Establish the maximum tolerated dose (MTD) of PC14586 when administered in combination with pembrolizumab (Phase 1b, Part 1) | Incidence of dose limiting toxicities (DLTs) during the first 21-day cycle of PC14586 | The first 21 days of combination treatment arm (starting on C1D1) per patient | 
| Establish the Recommended Phase 2 Dose (RP2D) (Phase 1) | RP2D will be determined using available safety and pharmacokinetics and pharmacodynamics data | 20 months for study (end of Phase 1) | 
| Establish the Recommended Phase 2 Dose (RP2D) of PC14586 when administered in combination with pembrolizumab (Phase 1b, Part 1) | RP2D will be determined using available safety and pharmacokinetics and pharmacodynamics data | 9 months for treatment arm (end of Phase 1b, Part 1) | 
| Response rate assessment to evaluate the clinical activity / efficacy of PC14586 (Phase 2) | Overall response rate in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 as assessed by independent review | 48 months for study (Phase 1 and 2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood plasma assessment to characterize the pharmacokinetics (PK) of PC14586 and metabolites (Phase 1 and 2) | Blood plasma concentration | Approximately 12 months per patient (48 months for study) | 
| Blood plasma assessment to characterize the pharmacokinetics (PK) of PC14586 and metabolites when administered in combination with pembrolizumab (Phase 1b, Part 1 and 2) | Blood plasma concentration | Approximately 12 months per patient (18 months for treatment arm) | 
| Preliminary efficacy of PC14586 using tumor response criteria to assess clinical activity / efficacy of PC14586 (Phase 1) | ORR and other response rate assessments, Progression Free Survival (PFS), and Overall Survival (OS) in accordance with Response Evaluation Criteria in Solid Tumors Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 | 20 months for study (end of Phase 1) | 
| Preliminary efficacy of PC14586 using tumor response criteria to assess clinical activity / efficacy of PC14586 when administered in combination with pembrolizumab (Phase 1b, Part 1 and 2) | ORR and other response rate assessments, Progression Free Survival (PFS), and Overall Survival (OS) in accordance with Response Evaluation Criteria in Solid Tumors Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 | 18 months for treatment arm (end of Phase 1b) | 
| Efficacy evaluation of PC14586 using tumor response criteria to assess clinical activity / efficacy of PC14586 (Phase 2) | ORR and other response rate assessments, PFS, and OS in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 | 48 months for study (end of Phase 2) | 
| Efficacy evaluation of PC14586 using tumor response criteria to assess clinical activity / efficacy of PC14586 when administered in combination with pembrolizumab (Phase 1b, Part 1 and 2) | ORR and other response rate assessments, PFS, and OS in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 | 18 months for treatment arm (end of Phase 1b) | 
| Quality of life assessment | Changes from baseline in quality of life as measured by a validated instrument, for participants 18 and older | Evaluated at every visit. Approximately 6 months per patient (48 months for study) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PC14586, p53, Y220C, Phase 1, Phase 1/2, PMV, PMV Pharma, p53 mutation, TP53, TP53 mutation, p53 mutant, p53 reactivator, pembrolizumab, Keytruda, combination, PD-1, PD-L1, anti-PD-1, Merck, MSD, IgG4, mAb, Phase 1b, NGS, Next Generation Sequencing, precision