Brief Title: PC14586 in Patients with Advanced Solid Tumors Harboring a TP53 Y220C Mutation (PYNNACLE)

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: Phase 1 Monotherapy (Dose Escalation): Determine the number and type of adverse events to characterize the safety of rezatapopt

Primary Outcome 1 - Timeframe: 40 months

Primary Outcome 2 - Measure: Phase 1 Monotherapy (Dose Escalation): Establish the Recommended Phase 2 Dose (RP2D)

Primary Outcome 2 - Timeframe: 30 months

Primary Outcome 3 - Measure: Phase 1 Monotherapy (Dose Escalation): Establish the maximum tolerated dose (MTD) (Phase 1)

Primary Outcome 3 - Timeframe: The first 28 days of treatment (Cycle 1) per patient

Primary Outcome 4 - Measure: Phase 1b Combination Therapy (Part 1: Dose Escalation): Determine the number and type of adverse events to characterize the safety of rezatapopt when administered in combination with pembrolizumab

Primary Outcome 4 - Timeframe: 18 months for treatment arm

Primary Outcome 5 - Measure: Phase 1b Combination Therapy (Part 1: Dose Escalation): Establish the maximum tolerated dose (MTD) of rezatapopt when administered in combination with pembrolizumab

Primary Outcome 5 - Timeframe: The first 28 days of combination treatment arm (starting on Day -7) per patient

Primary Outcome 6 - Measure: Phase 1b Combination Therapy (Part 1: Dose Escalation): Establish the Recommended Phase 2 Dose (RP2D) of rezatapopt when administered in combination with pembrolizumab

Primary Outcome 6 - Timeframe: 18 months

Primary Outcome 7 - Measure: Phase 1b Combination Therapy (Part 2: Dose Expansion): Determine the number and type of adverse events to characterize the safety of rezatapopt when administered in combination with pembrolizumab

Primary Outcome 7 - Timeframe: 12 months for treatment arm

Primary Outcome 8 - Measure: Phase 2 Monotherapy (Dose Expansion): Response rate assessment to evaluate the clinical activity / efficacy of rezatapopt

Primary Outcome 8 - Timeframe: 34 months

CONDITION

• 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
• Gall Bladder Cancer
• Small Cell Lung Cancer
• Small Cell Lung Cancer ( SCLC )
• Small Cell Lung Carcinoma
• NSCLC
• NSCLC (non-small Cell Lung Cancer)
• SCLC
• Non-Small Cell Lung Carcinoma
• Triple Negative Breast Cancer
• TNBC
• HER2+ Breast Cancer
• Non-Small Cell Lung Cancer
• ER/PR Positive Breast Cancer
• HER2- Breast Cancer
• HER2-positive Breast Cancer
• HER2-negative Breast Cancer
• ER/PR(+)
• Her2(-) Breast Cancer

ELIGIBILITY

Inclusion Criteria:
* At least 18 years of age or 12 to 17 years of age after Safety Review Committee approval.

- * Locally advanced or metastatic 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 (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 inducers

- * 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 (rezatapopt monotherapy)
* Known KRAS mutation, defined as a single nucleotide variant (SNV) (Phase 2)
Additional Criteria for Exclusion from Phase 1b (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 rezatapopt

Gender: All

Minimum Age: 12 Years

Maximum Age: N/A

Healthy Volunteers: No

OFFICIAL INFORMATION

Name: Marc Fellous, MD

Role: Study Director

Affiliation: Sr. Vice President of Medical Affairs

Overall Contact

Name: PMV Pharma Clinical Study Information Center

Phone: (609) 235-4038

Email: [email protected]

LOCATION