The Evaluation of PC14586 in Patients With Advanced Solid Tumors Harboring a TP53 Y220C Mutation (PYNNACLE)

Purpose

This Phase 1/2 study will assess the safety, tolerability, and efficacy of multiple dose levels of PC14586 (INN: rezatapopt) alone (monotherapy) and in combination with pembrolizumab in participants with advanced solid tumors containing a TP53 Y220C mutation.

Conditions

  • 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
  • Locally Advanced
  • Head and Neck Cancer

Eligibility

Eligible Ages
Over 12 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Inclusion Criteria

  • At least 18 years of age or 12 to 17 years of age after Safety Review Committee approval. - 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 - Measurable disease per RECIST v1.1 (Phase 2) Additional Criteria for Inclusion in Phase 1b (PC14586 (INN: rezatapopt) + 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 - History of leptomeningeal disease or spinal cord compression - Brain metastases, unless neurologically stable and do not require steroids to treat associated neurological symptoms - 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 2 (PC14586 monotherapy) - Known KRAS mutation, defined as a single nucleotide variant (SNV) (Phase 2) Additional Criteria for Exclusion from Phase 1b (PC14586 (INN: rezatapopt) + 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 - Has previously received PC14586 (INN: rezatapopt)

Study Design

Phase
Phase 1/Phase 2
Study Type
Interventional
Allocation
Non-Randomized
Intervention Model
Parallel Assignment
Intervention 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, patients will be assigned a dose level using mTPI design. A recommended PC14586 (INN: rezatapopt) 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. During Phase 2 Monotherapy the Recommended Phase 2 Dose (RP2D) selected at the end of Phase 1 Monotherapy and in Phase 2 (Dose Expansion) the RP2D will be assigned to all participants. Participants will be assigned to one of five cohorts: ovarian cancer, lung cancer, breast cancer, endometrial cancer, or other solid tumors.
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Phase 1 Monotherapy Dose Escalation 		Multiple dose levels of daily oral PC14586 (INN: 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 PC14586 (INN: rezatapopt) to recommend a Phase 2 dose (RP2D).
  • Drug: PC14586
    First-in-class, oral, small molecule p53 reactivator selective for the p53 Y220C mutation.
    Other names:
    • rezatapopt
Experimental
Phase 1b Combination Therapy Dose Escalation, Part 1 		Multiple dose levels of daily oral PC14586 (INN: 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 PC14586 (INN: rezatapopt) when administered in combination with pembrolizumab.
  • Drug: PC14586
    First-in-class, oral, small molecule p53 reactivator selective for the p53 Y220C mutation.
    Other names:
    • rezatapopt
  • Drug: pembrolizumab
    Participants receive pembrolizumab 200 mg by intravenous (IV) infusion over 30 minutes.
    Other names:
    • KEYTRUDA®
    • MK-3475
    • KEYNOTE-D79
    • MK-3475-D79
Experimental
Phase 1b Combination Therapy Dose Expansion, PD(L)-1 naive patients 		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.
  • Drug: PC14586
    First-in-class, oral, small molecule p53 reactivator selective for the p53 Y220C mutation.
    Other names:
    • rezatapopt
  • Drug: pembrolizumab
    Participants receive pembrolizumab 200 mg by intravenous (IV) infusion over 30 minutes.
    Other names:
    • KEYTRUDA®
    • MK-3475
    • KEYNOTE-D79
    • MK-3475-D79
Experimental
Phase 1b Combination Therapy Dose Expansion, PD(L)-1 relapsed/refractory patients 		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 relapsed/refractory patients.
  • Drug: PC14586
    First-in-class, oral, small molecule p53 reactivator selective for the p53 Y220C mutation.
    Other names:
    • rezatapopt
  • Drug: pembrolizumab
    Participants receive pembrolizumab 200 mg by intravenous (IV) infusion over 30 minutes.
    Other names:
    • KEYTRUDA®
    • MK-3475
    • KEYNOTE-D79
    • MK-3475-D79
Experimental
Phase 2 Monotherapy Dose Expansion, Ovarian Cancer Cohort 		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.
  • Drug: PC14586
    First-in-class, oral, small molecule p53 reactivator selective for the p53 Y220C mutation.
    Other names:
    • rezatapopt
Experimental
Phase 2 Monotherapy Dose Expansion, Lung Cancer Cohort 		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.
  • Drug: PC14586
    First-in-class, oral, small molecule p53 reactivator selective for the p53 Y220C mutation.
    Other names:
    • rezatapopt
Experimental
Phase 2 Monotherapy Dose Expansion, Breast Cancer Cohort 		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.
  • Drug: PC14586
    First-in-class, oral, small molecule p53 reactivator selective for the p53 Y220C mutation.
    Other names:
    • rezatapopt
Experimental
Phase 2 Monotherapy Dose Expansion, Endometrial Cancer Cohort 		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.
  • Drug: PC14586
    First-in-class, oral, small molecule p53 reactivator selective for the p53 Y220C mutation.
    Other names:
    • rezatapopt
Experimental
Phase 2 Monotherapy Dose Expansion, Other Solid Tumors Cohort 		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.
  • Drug: PC14586
    First-in-class, oral, small molecule p53 reactivator selective for the p53 Y220C mutation.
    Other names:
    • rezatapopt

Recruiting Locations

Massachusetts General Hospital
Boston, Massachusetts 02114
Contact:
Aparna Parikh, MD

More Details

Status
Recruiting
Sponsor
PMV Pharmaceuticals, Inc

Study Contact

PMV Pharma Clinical Study Information Center
(609) 235-4038
clinicaltrials@pmvpharma.com

Detailed Description

PC14586 (INN: rezatapopt) 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 (INN: rezatapopt). 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 is to establish the MTD/RP2D of PC14586 (INN: rezatapopt) when administered in combination with pembrolizumab. Secondary objectives of Phase 1b Combination Therapy are to characterize PK, safety and tolerability, and to assess preliminary efficacy of PC14586 (INN: rezatapopt) when administered in combination with pembrolizumab, including ORR. The primary objective of Phase 2 Monotherapy is to evaluate the efficacy of PC14586 (INN: rezatapopt) at the RP2D including the ORR in the Ovarian Cancer Cohort and the ORR across all cohorts as determined by blinded independent central review. Secondary objectives of Phase 2 are to characterize the safety, PK properties, quality of life, and other efficacy measures of PC14586 (INN: rezatapopt) at the RP2D.