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

[...] half-lives) of receiving the study drug Radiotherapy within 2814 days of receiving the study drug Primary CNS tumor History [...] prior to screening Heart conditions such as unstable angina within 6 months prior to screening, uncontrolled hypertension, a heart attack within 6 months [...] terval, or other rhythm abnormalities Strong CYP3A4 inducers and strong CYP2C9 inhibitors/inducers within 14 days of first dose of rezatapopt History of gastrointestinal (GI) disease that may interfere [...]

Phase 1 Monotherapy: Blood plasma assessment to describe the concentration of PC14586 and metabolite (M1)metabolites when rezatapopt is administered orally. Phase 1b Combinatio [...] assessment to describe the concentration of rezatapopt and metabolite (M1)metabolites when rezatapopt is administered orally in combination with [...] assessment to describe the concentration of rezatapopt and metabolite (M1)metabolites when rezatapopt is administered orally.

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

Inclusion Criteria: At least 18 years of age or 12 to 17 years of age after Safety Review Committee approval. AdvancedLocally advanced or metastatic solid malignancy with a TP53 Y220C mutation Eastern Coopera [...] .1 (Phase 2) Additional Criteria for Inclusion in Phase 1b (PC14586 (INN: rezatapopt) + pembrolizumab combination) Anti-PD-1/PD-L1 nai [...] 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 [...] s infection Additional Criteria for [...]

Phase 1 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Peak concentration (Cmax) Phase 1 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Time of peak concentration (Tmax) Phase 1 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Area under the plasma concentration-time curve from time [...] pling timepoint (AUC0-t) Phase 1 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Area under the plasma concentration-time curve in one dosing interval (AUCtau) Phase 1 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Trough observed concentrations (Ctrough/Ctau) Phase 1 Mon [...] cribe t [...]

Phase 1 Monotherapy (Dose Escalation): Determine the number and type of adverse events to characterize the safety of PC14586 (INN: rezatapopt) Phase 1b Combination Therapy (Part 1: Dose Escalation): Det [...] er and type of adverse events to characterize the safety of PC14586 (INN: rezatapopt) when administered in combination with pembrolizumab Phase 1 [...] calation): Establish the Recommended Phase 2 Dose (RP2D) of PC14586 (INN: rezatapopt) when administered in combination with pembrolizumab Phase 1 [...] Escalation): Establish the maximum tolerated dose (MTD) of PC14586 (INN: rezatapopt) when administered in c [...] [...]

PC14586 (INN: rezatapopt)Rezatapopt is a first-in-class, oral, small molecule p53 reactivator t [...] ctive of Phase 2 Monotherapy is to evaluate the efficacy of PC14586 (INN: rezatapopt) at the Recommended Phase 2 Dose (RP2D) including the Overal [...] es, quality of life, and other efficacy measures of PC14586 (INN: rezatapopt) at the RP2D. Enrollment is open for the Phase 2 Monotherapy [...] s to establish the maximum tolerated dose (MTD) and RP2D of PC14586 (INN: rezatapopt). Secondary objectives are to characterize the PK properties [...] hase 1b Combination Therapy is to establish the MTD/RP2D of PC14586 (INN: reza [...] [...]

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

[...] reactivator that is selective for the TP53 Y220C mutation. The primary objective of Phase 2 Monotherapy is to evaluate the efficacy of PC14586 (INN: 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. Seco [...] 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, sa [...] [...]

RoyalFreeman Victoria InfirmaryHospital

Inclusion Criteria: At least 18 years of age or 12 to 17 years of age after adequateSafety adultReview safetyCommittee data become availableapproval. Advanced solid malignancy with a TP53 Y220C mutation Easter [...] cer 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 h [...] within 28 days of receiving the study drug Primary CNS tumor (Phase 1, Phase 2 Cohort A) History of leptomeningeal disease or spinal cord compressio [...] nd do [...]

Phase 1 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Peak concentration (Cmax) Phase 1 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Time of peak concentration (Tmax) Phase 1 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Area under the plasma concentration-time curve from [...] Blood plasma assessment to characterizedescribe the pharmacokinetics (PK)concentration of PC14586 and metabolitesmetabolite (M1) when PC14586 (INN: rezatapopt) is administered orally. Phase 1 andMonotherapy 2(Dose Escalation): Overall Response Rate per RECIST v1.1 or PCWG3 modified RECIST v1.1 Blood [...]

DeterminePhase the1 numberMonotherapy and(Dose typeEscalation): of adverse events to characterize the safety of PC14586 Determine the number and type of adverse events to characterize the safety of PC14586 when(INN: administeredrezatapopt) Phase in1 combinationMonotherapy with(Dose pembrolizumab Escalation): Establish the Recommended Phase 2 Dose (RP2D) Phase 1 Monotherapy (Dose Escalation): Establish the maximum tolerated dose (MTD) (Phase 1) Phase 1b Combination Therapy (Part 1: Dose Escalation): Determine the number and type of adverse events to characterize the safety of PC14586 (INN: reza [...] [...]

PC14586 (INN: rezatapopt) is a first-in-class, oral, small molecule p53 reactivator t [...] r the TP53 Y220C mutation. The primary objective of Phase 1 monotherapyMonotherapy is to establish the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of PC14586 (INN: rezatapopt). Secondary objectives are to characterize the pharmacokinet [...] (ORR). The primary objective of Phase 1b Combination Therapy Treatment Arm is to establish the MTD/RP2D of PC14586 (INN: rezatapopt) when administered in combination with pembrolizumab. Secondary objectives of Phase 1b Combination Therapy Treatment Arm are to [...] [...]

The Evaluation of PC14586 in Patients With Advanced Solid Tumors Harboring a p53TP53 Y220C Mutation (PYNNACLE)

[...] cer 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 [...] is 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 discontinue [...]

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 monotherapy is to establish the maximum tolerated dose /(MTD) and recommended Phase 2 dose (RP2D) of PC14586 to treat participants with advanced solid tumors harboring a TP53 Y220C mutation. Secondary objectives of Phase 1 are to characterize the pharmacokinetic (PK) properties of the investigational drug, its safety and tolerability, and to assess prelimi [...] [...]

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

[...] fety data become available Advanced solid malignancy with a p53TP53 Y220C mutation Eastern Cooperative Oncology Group (ECOG) st [...]

ResponsePreliminary rateefficacy assessmentof PC14586 using tumor response criteria to assess clinical activity / efficacy of PC14586 (Phase 1) Efficacy evaluation of PC14586 using tumor response criteria to assess clinical activity / efficacy of PC14586 (Phase 2) Quality of life assessment

PC14586 is a first-in-class, oral, small molecule p53 reactivator that is selective for the p53TP53 Y220C mutation. The trial will be conducted in 2 parts: dos [...] o treat participants with advanced solid tumors harboring a p53TP53 Y220C mutation. Secondary objectives of Phase 1 are to char [...] tigational drug, its safety and tolerability, and to assess thepreliminary efficacy of PC14586 including overall response rate (ORR). The primary objective of Phase [...] ORR in participants with advanced solid tumors harboring a p53TP53 Y220C mutation as determined by blinded independent central [...] of Phase 2 include the [...]

[...] disease or spinal cord compression Brain metastases, unless asymptomaticneurologically stable and do not requiringrequire steroids for at least 2 weeks prior to receivingtreat theassociated studyneurological drugsymptom Stroke or transient ischemic attack within 6 months prior t [...]

[...] olid tumors harboring a p53 Y220C mutation as determined by anblinded independent radiologycentral committeereview. Secondary objectives of Phase 2 include the safety, pharma [...]

[...] within 28 days of receiving the study drug Primary CNS tumor (Phase 1, Phase 2 Cohort A) History of leptomeningeal disease or spinal cord compressio [...]

ThisThe StudyEvaluation Will Evaluateof PC14586 in Patients With Advanced Solid Tumors Harboring a p53 Y220C Mutation

CharacteriseBlood plasma assessment to characterize the pharmacokinetics (PK) of PC14586 and metabolites (Phase 1 and 2) AssessResponse rate assessment to assess clinical activity / efficacy of PC14586 (Phase 1)

CharacterizeDetermine the number and type of adverse events to characterize the safety of PC14586 EvaluateResponse rate assessment to evaluate the clinical activity / efficacy of PC14586 (Phase 2)