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

PMV Pharmaceuticals

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Small Cell Lung Cancer; Gall Bladder Cancer; Advanced Solid Tumor; HER2-positive Breast Cancer; HER2-negative Breast Cancer; HER2- Breast Cancer; Advanced Malignant Neoplasm; SCLC; Endometrial Cancer; Metastatic Cancer; Small Cell Lung Cancer ( SCLC ); ER/PR(+), Her2(-) Breast Cancer; TNBC; Other Cancer; HER2+ Breast Cancer; NSCLC (non-small Cell Lung Cancer); Metastatic Solid Tumor; NSCLC; Non-Small Cell Lung Carcinoma; Breast Cancer; Locally Advanced; Lung Cancer; Small Cell Lung Carcinoma; Ovarian Cancer; Non-Small Cell Lung Cancer; ER/PR Positive Breast Cancer; Triple Negative Breast Cancer; Head and Neck Cancer; Prostate Cancer; Colorectal Cancer

Treatments: Drug: rezatapopt; Drug: pembrolizumab

Study type: Interventional

Funder types: Industry

Identifiers

NCT04585750

PMV-586-101

MK-3475-D79 (Registry Identifier)

KEYNOTE-D79 (Registry Identifier)

Details and patient eligibility

About

The Phase 2 monotherapy portion of this study is currently enrolling and will evaluate the efficacy and safety of PC14586 (INN rezatapopt) in participants with locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation. The Phase 1 portion of the study will assess the safety, tolerability and preliminary efficacy of multiple dose levels of rezatapopt as monotherapy and in Phase 1b in combination with pembrolizumab.

Full description

Rezatapopt is a first-in-class, oral, small molecule p53 reactivator that is selective for the TP53 Y220C mutation.

The primary objective of Phase 2 Monotherapy is to evaluate the efficacy of rezatapopt at the Recommended Phase 2 Dose (RP2D) including the Overall Response Rate (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, pharmacokinetic (PK) properties, quality of life, and other efficacy measures of PC14586 rezatapopt at the RP2D. Enrollment is open for the Phase 2 Monotherapy portion of the study.

The primary objective of Phase 1 Monotherapy is to establish the maximum tolerated dose (MTD) and RP2D of rezatapopt. Secondary objectives are to characterize the PK properties, safety and tolerability, and to assess preliminary efficacy including ORR. Enrollment into Phase 1 Monotherapy is complete.

The primary objective of Phase 1b Combination Therapy is to establish the MTD/RP2D of 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 rezatapopt when administered in combination with pembrolizumab, including ORR. Enrollment into Phase 1b Combination Therapy is complete.

Enrollment: 230 estimated patients

Sex: All

Ages: 12+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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230 participants in 9 patient groups

Phase 1 Monotherapy Dose Escalation

Experimental group

Description:

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).

Treatment:

Drug: rezatapopt

Phase 1b Combination Therapy Dose Escalation, Part 1

Experimental group

Description:

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.

Treatment:

Drug: pembrolizumab

Drug: rezatapopt

Phase 1b Combination Therapy Dose Expansion, PD(L)-1 naive patients

Experimental group

Description:

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.

Treatment:

Drug: pembrolizumab

Drug: rezatapopt

Phase 1b Combination Therapy Dose Expansion, PD(L)-1 relapsed/refractory patients

Experimental group

Description:

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.

Treatment:

Drug: pembrolizumab

Drug: rezatapopt

Phase 2 Monotherapy Dose Expansion, Ovarian Cancer Cohort

Experimental group

Description:

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.

Treatment:

Drug: rezatapopt

Phase 2 Monotherapy Dose Expansion, Lung Cancer Cohort

Experimental group

Description:

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.

Treatment:

Drug: rezatapopt

Phase 2 Monotherapy Dose Expansion, Breast Cancer Cohort

Experimental group

Description:

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.

Treatment:

Drug: rezatapopt

Phase 2 Monotherapy Dose Expansion, Endometrial Cancer Cohort

Experimental group

Description:

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.

Treatment:

Drug: rezatapopt

Phase 2 Monotherapy Dose Expansion, Other Solid Tumors Cohort

Experimental group

Description:

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.

Treatment:

Drug: rezatapopt