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

Sponsor

PMV Pharmaceuticals, Inc (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04585750

Collaborator

(none)

145

Enrollment

Locations

Arms

61.5

Anticipated Duration (Months)

13.2

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study will assess the safety, tolerability, and efficacy of multiple dose levels of PC14586 in participants with advanced solid tumors containing a TP53 Y220C mutation.

Condition or Disease	Intervention/Treatment	Phase
Advanced Solid Tumor Advanced Malignant Neoplasm Metastatic Cancer Metastatic Solid Tumor	Drug: PC14586	Phase 1/Phase 2

Detailed Description

PC14586 is a first-in-class, oral, small molecule p53 reactivator that is selective for the TP53 Y220C mutation. The trial will be conducted in 2 parts: dose escalation (Phase 1) and dose expansion (Phase 2).

The primary objective of Phase 1 is to establish the maximum tolerated dose / recommended dose of PC14586 to treat participants with advanced solid tumors harboring a TP53 Y220C mutation. Secondary objectives of Phase 1 are to characterize the pharmacokinetic properties of the investigational drug, its safety and tolerability, and to assess preliminary efficacy of PC14586 including overall response rate (ORR).

The primary objective of Phase 2 is to assess the ORR in participants with advanced solid tumors harboring a TP53 Y220C mutation as determined by blinded independent central review. Secondary objectives of Phase 2 include the safety, pharmacokinetic properties, quality of life, and other efficacy measures of PC14586 at the recommended dose.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

145 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

During Phase 1 (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. A Recommended Phase 2 Dose (RP2D) will be selected at the end of Phase 1 and in Phase 2 (Dose Expansion) the RP2D will be assigned to all participants.During Phase 1 (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. A Recommended Phase 2 Dose (RP2D) will be selected at the end of Phase 1 and in Phase 2 (Dose Expansion) the RP2D will be assigned to all participants.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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)

Actual Study Start Date :

Oct 29, 2020

Anticipated Primary Completion Date :

Nov 1, 2024

Anticipated Study Completion Date :

Dec 15, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1 Dose Escalation Multiple dose levels of 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 PC14586 is a first-in-class, oral, small molecule p53 reactivator that is selective for the p53 Y220C mutation, being developed for the treatment of patients with advanced solid tumors harboring a p53 Y220C mutation. PC14586 will be administered orally on a continuous regimen.
Experimental: Phase 2 Dose Expansion, Cohort A Additional (expansion of) participants will enroll at the RP2D of PC14586 for continued evaluation. Cohort A participants will have advanced solid tumors harboring a p53 Y220C mutation who meet all eligibility criteria and have measureable disease per RECIST 1.1.	Drug: PC14586 PC14586 is a first-in-class, oral, small molecule p53 reactivator that is selective for the p53 Y220C mutation, being developed for the treatment of patients with advanced solid tumors harboring a p53 Y220C mutation. PC14586 will be administered orally on a continuous regimen.
Experimental: Phase 2 Dose Expansion, Cohort B Additional (expansion of) participants will enroll at the RP2D of 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 PC14586 is a first-in-class, oral, small molecule p53 reactivator that is selective for the p53 Y220C mutation, being developed for the treatment of patients with advanced solid tumors harboring a p53 Y220C mutation. PC14586 will be administered orally on a continuous regimen.

Arm

Intervention/Treatment

Experimental: Phase 1 Dose Escalation

Multiple dose levels of 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

PC14586 is a first-in-class, oral, small molecule p53 reactivator that is selective for the p53 Y220C mutation, being developed for the treatment of patients with advanced solid tumors harboring a p53 Y220C mutation. PC14586 will be administered orally on a continuous regimen.

Experimental: Phase 2 Dose Expansion, Cohort A

Additional (expansion of) participants will enroll at the RP2D of PC14586 for continued evaluation. Cohort A participants will have advanced solid tumors harboring a p53 Y220C mutation who meet all eligibility criteria and have measureable disease per RECIST 1.1.

Drug: PC14586

Experimental: Phase 2 Dose Expansion, Cohort B

Additional (expansion of) participants will enroll at the RP2D of 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

Outcome Measures

Primary Outcome Measures

Determine the number and type of adverse events to characterize the safety of PC14586 [48 months for study (Phase 1 and 2)]
Number of participants with treatment related adverse events
Establish the maximum tolerated dose (MTD) (Phase 1) [The first 21 days of treatment (Cycle 1) per patient]
Incidence of dose limiting toxicities (DLTs) during the first 21-day cycle of PC14586
Establish the Recommended Phase 2 Dose (RP2D) (Phase 1) [20 months for study (end of Phase 1)]
RP2D will be determined using available safety and pharmacokinetics and pharmacodynamics data
Response rate assessment to evaluate the clinical activity / efficacy of PC14586 (Phase 2) [48 months for study (Phase 1 and 2)]
Overall response rate in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 as assessed by independent review

Secondary Outcome Measures

Blood plasma assessment to characterize the pharmacokinetics (PK) of PC14586 and metabolites (Phase 1 and 2) [Approximately 12 months per patient (48 months for study)]
Blood plasma concentration
Preliminary efficacy of PC14586 using tumor response criteria to assess clinical activity / efficacy of PC14586 (Phase 1) [20 months for study (end of 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
Efficacy evaluation of PC14586 using tumor response criteria to assess clinical activity / efficacy of PC14586 (Phase 2) [48 months for study (end of Phase 2)]
ORR and other response rate assessments, PFS, and OS in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1
Quality of life assessment [Evaluated at every visit. Approximately 6 months per patient (48 months for study)]
Changes from baseline in quality of life as measured by a validated instrument, for participants 18 and older

Eligibility Criteria

Criteria

Ages Eligible for Study:

12 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	USC Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
2	Hoag Memorial Hospital Presbyterian	Newport Beach	California	United States	92663
3	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
4	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
5	Memorial Sloan Kettering	New York	New York	United States	10065
6	Oregon Heath & Science University (OHSU)	Portland	Oregon	United States	97210
7	Sarah Cannon and HCA Research Institute	Nashville	Tennessee	United States	37203
8	New Experimental Therapeutics - NEXT Oncology	Austin	Texas	United States	78705
9	The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
10	New Experimental Therapeutics of San Antonio - NEXT Oncology	San Antonio	Texas	United States	78229
11	University of Washington, Seattle Cancer Care Alliance (SCCA)	Seattle	Washington	United States	98109