1. Phase 1 Monotherapy (Dose Escalation): Determine the number and type of adverse events to characterize the safety of PC14586 (INN: rezatapopt) (Time Frame - 40 months): Number of participants with treatment related adverse events
2. Phase 1 Monotherapy (Dose Escalation): Establish the Recommended Phase 2 Dose (RP2D) (Time Frame - 30 months): RP2D will be determined using available safety and pharmacokinetics and pharmacodynamics
data
3. Phase 1 Monotherapy (Dose Escalation): Establish the maximum tolerated dose (MTD) (Phase 1) (Time Frame - The first 28 days of treatment (Cycle 1) per patient): Incidence of dose limiting toxicities (DLTs) during the first 28 days of treatment with
PC14586 (INN: rezatapopt)
4. Phase 1b Combination Therapy (Part 1: Dose Escalation): Determine the number and type of adverse events to characterize the safety of PC14586 (INN: rezatapopt) when administered in combination with pembrolizumab (Time Frame - 18 months for treatment arm): Number of participants with treatment related adverse events
5. Phase 1b Combination Therapy (Part 1: Dose Escalation): Establish the maximum tolerated dose (MTD) of PC14586 (INN: rezatapopt) when administered in combination with pembrolizumab (Time Frame - The first 28 days of combination treatment arm (starting on Day -7) per patient): Incidence of dose limiting toxicities (DLTs) during the first 28 days of treatment with
PC14586 (INN: rezatapopt)
6. Phase 1b Combination Therapy (Part 1: Dose Escalation): Establish the Recommended Phase 2 Dose (RP2D) of PC14586 (INN: rezatapopt) when administered in combination with pembrolizumab (Time Frame - 18 months): RP2D will be determined using available safety and pharmacokinetics and pharmacodynamics
data
7. Phase 1b Combination Therapy (Part 2: Dose Expansion): Determine the number and type of adverse events to characterize the safety of PC14586 (INN: rezatapopt) when administered in combination with pembrolizumab (Time Frame - 12 months for treatment arm): Number of participants with treatment related adverse events
8. Phase 2 Monotherapy (Dose Expansion): Response rate assessment to evaluate the clinical activity / efficacy of PC14586 (INN: rezatapopt) (Time Frame - 34 months): Overall response rate in accordance with Response Evaluation Criteria across all cohorts
(RECIST) v.1.1 as assessed by independent review
Secondary outcome:
1. Phase 1 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Peak concentration (Cmax) (Time Frame - Approximately 12 months per patient (75 months for Phase 1 and Phase 2)): Pharmacokinetic parameters will be determined by non-compartmental methods using
pharmacokinetic profile of PC14586 (INN: rezatapopt)
2. Phase 1 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Time of peak concentration (Tmax) (Time Frame - Approximately 12 months per patient (75 months for Phase 1 and Phase 2)): Pharmacokinetic parameters will be determined by non-compartmental methods using
pharmacokinetic profile of PC14586 (INN: rezatapopt)
3. Phase 1 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Area under the plasma concentration-time curve from time zero to time of last sampling timepoint (AUC0-t) (Time Frame - Approximately 12 months per patient (75 months for Phase 1 and Phase 2)): Pharmacokinetic parameters will be determined by non-compartmental methods using
pharmacokinetic profile of PC14586 (INN: rezatapopt)
4. Phase 1 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Area under the plasma concentration-time curve in one dosing interval (AUCtau) (Time Frame - Approximately 12 months per patient (75 months for Phase 1 and Phase 2)): Pharmacokinetic parameters will be determined by non-compartmental methods using
pharmacokinetic profile of PC14586 (INN: rezatapopt)
5. Phase 1 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Trough observed concentrations (Ctrough/Ctau) (Time Frame - Approximately 12 months per patient (75 months for Phase 1 and Phase 2)): Pharmacokinetic parameters will be determined by non-compartmental methods using
pharmacokinetic profile of PC14586 (INN: rezatapopt)
6. Phase 1 Monotherapy: Blood plasma assessment to describe the concentration of PC14586 and metabolite (M1) when PC14586 (INN: rezatapopt) is administered orally. (Time Frame - Approximately 12 months per patient (75 months for Phase 1 and Phase 2)): Blood plasma concentration
7. Phase 1 Monotherapy (Dose Escalation): Overall Response Rate per RECIST v1.1 or PCWG3 modified RECIST v1.1 (Time Frame - 41 months for study (end of Phase 1)): Evaluation of preliminary anti-tumor activity of PC14586 (INN: rezatapopt) as a single
agent
8. Phase 1 Monotherapy (Dose Escalation): Time to Response per RECIST v1.1 or PCWG3 modified RECIST v1.1 (Time Frame - 41 months for study (end of Phase 1)): Evaluation of preliminary anti-tumor activity of PC14586 (INN: rezatapopt) as a single
agent
9. Phase 1 Monotherapy (Dose Escalation): Duration of Response per RECIST v1.1 or PCWG3 modified RECIST v1.1 (Time Frame - 41 months for study (end of Phase 1)): Evaluation of preliminary anti-tumor activity of PC14586 (INN: rezatapopt) as a single
agent
10. Phase 1 Monotherapy (Dose Escalation): Disease Control Rate per RECIST v1.1 or PCWG3 modified RECIST v1.1 (Time Frame - 41 months for study (end of Phase 1)): Evaluation of preliminary anti-tumor activity of PC14586 (INN: rezatapopt) as a single
agent
11. Phase 1 Monotherapy (Dose Escalation): Progression Free Survival per RECIST v1.1 or PCWG3 modified RECIST v1.1 (Time Frame - 41 months for study (end of Phase 1)): Evaluation of preliminary anti-tumor activity of PC14586 (INN: rezatapopt) as a single
agent
12. Phase 1 Monotherapy (Dose Escalation): Overall Survival (Time Frame - 41 months for study (end of Phase 1)): Evaluation of preliminary anti-tumor activity of PC14586 (INN: rezatapopt) as a single
agent
13. Phase 1b Combination Therapy: PK profile of PC14586 (INN: rezatapopt) in combination with pembrolizumab - Peak concentration (Cmax) (Time Frame - Approximately 12 months per patient (30 months for treatment arm)): Pharmacokinetic parameters will be determined by non-compartmental methods using
pharmacokinetic profile of PC14586 (INN: rezatapopt)
14. Phase 1b Combination Therapy: PK profile of PC14586 (INN: rezatapopt) in combination with pembrolizumab - Time of peak concentration (Tmax) (Time Frame - Approximately 12 months per patient (30 months for treatment arm)): Pharmacokinetic parameters will be determined by non-compartmental methods using
pharmacokinetic profile of PC14586 (INN: rezatapopt)
15. Phase 1b Combination Therapy: PK profile of PC14586 (INN: rezatapopt) in combination with pembrolizumab - Area under the plasma concentration-time curve from time zero to time of last sampling timepoint (AUC0-t) (Time Frame - Approximately 12 months per patient (30 months for treatment arm)): Pharmacokinetic parameters will be determined by non-compartmental methods using
pharmacokinetic profile of PC14586 (INN: rezatapopt)
16. Phase 1b Combination Therapy: PK profile of PC14586 (INN: rezatapopt) in combination with pembrolizumab - Area under the plasma concentration-time curve in one dosing interval (AUCtau) (Time Frame - Approximately 12 months per patient (30 months for treatment arm)): Pharmacokinetic parameters will be determined by non-compartmental methods using
pharmacokinetic profile of PC14586 (INN: rezatapopt)
17. Phase 1b Combination Therapy: PK profile of PC14586 (INN: rezatapopt) in combination with pembrolizumab - Trough observed concentrations (Ctrough/Ctau) (Time Frame - Approximately 12 months per patient (30 months for treatment arm)): Pharmacokinetic parameters will be determined by non-compartmental methods using
pharmacokinetic profile of PC14586 (INN: rezatapopt)
18. Phase 1b Combination Therapy: Blood plasma assessment to describe the concentration of PC14586 (INN: rezatapopt) and metabolite (M1) when PC14586 (INN: rezatapopt) is administered orally in combination with pembrolizumab. (Time Frame - Approximately 12 months per patient (30 months for treatment arm)): Blood plasma concentration
19. Phase 1b Combination Therapy: Overall Response Rate per RECIST v1.1, iRECIST, or PCWG3 as assessed by Investigator and as assessed by independent review (Time Frame - 30 months for study (end of Phase 1b)): Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) in combination with
pembrolizumab
20. Phase 1b Combination Therapy: Time to Response per RECIST v1.1, iRECIST, or PCWG3 as assessed by Investigator and as assessed by independent review (Time Frame - 30 months for study (end of Phase 1b)): Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) in combination with
pembrolizumab
21. Phase 1b Combination Therapy: Duration of Response per RECIST v1.1, iRECIST, or PCWG3 as assessed by Investigator and as assessed by independent review (Time Frame - 30 months for study (end of Phase 1b)): Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) in combination with
pembrolizumab
22. Phase 1b Combination Therapy: Disease Control Rate per RECIST v1.1, iRECIST, or PCWG3 as assessed by Investigator and as assessed by independent review (Time Frame - 30 months for study (end of Phase 1b)): Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) in combination with
pembrolizumab
23. Phase 1b Combination Therapy: Overall Survival (Time Frame - 30 months for study (end of Phase 1b)): Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) in combination with
pembrolizumab
24. Phase 1b Combination Therapy: Determine the number and type of adverse events to characterize the safety of PC14586 (INN: rezatapopt) (Time Frame - 30 months for study (end of Phase 1b)): Number of participants with treatment related adverse events
25. Phase 1b Combination Therapy: Progression Free Survival per RECIST v1.1, iRECIST, or PCWG3 as assessed by Investigator and as assessed by independent review (Time Frame - 30 months for study (end of Phase 1b)): Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) in combination with
pembrolizumab
26. Phase 2 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Time of peak concentration (Tmax) (Time Frame - Approximately 12 months per patient (75 months for Phase 1 and Phase 2)): Pharmacokinetic parameters will be determined by non-compartmental methods using
pharmacokinetic profile of PC14586 (INN: rezatapopt)
27. Phase 2 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Peak concentration (Cmax) (Time Frame - Approximately 12 months per patient (75 months for Phase 1 and Phase 2)): Pharmacokinetic parameters will be determined by non-compartmental methods using
pharmacokinetic profile of PC14586 (INN: rezatapopt)
28. Phase 2 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Area under the plasma concentration-time curve from time zero to time of last sampling timepoint (AUC0-t) (Time Frame - Approximately 12 months per patient (75 months for Phase 1 and Phase 2)): Pharmacokinetic parameters will be determined by non-compartmental methods using
pharmacokinetic profile of PC14586 (INN: rezatapopt)
29. Phase 2 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Area under the plasma concentration-time curve in one dosing interval (AUCtau) (Time Frame - Approximately 12 months per patient (75 months for Phase 1 and Phase 2)): Pharmacokinetic parameters will be determined by non-compartmental methods using
pharmacokinetic profile of PC14586 (INN: rezatapopt)
30. Phase 2 Monotherapy: PK profile of PC14586 (INN: rezatapopt) - Trough observed concentrations (Ctrough/Ctau) (Time Frame - Approximately 12 months per patient (75 months for Phase 1 and Phase 2)): Pharmacokinetic parameters will be determined by non-compartmental methods using
pharmacokinetic profile of PC14586 (INN: rezatapopt)
31. Phase 2 Monotherapy: Blood plasma assessment to describe the concentration of PC14586 (INN: rezatapopt) and metabolite (M1) when PC14586 (INN: rezatapopt) is administered orally. (Time Frame - Approximately 12 months per patient (75 months for Phase 1 and Phase 2)): Blood plasma concentration
32. Phase 2 Monotherapy (Dose Expansion): Determine the number and type of adverse events to characterize the safety of PC14586 (INN: rezatapopt) (Time Frame - 34 months for study (end of Phase 2)): Number of participants with treatment related adverse events
33. Phase 2 Monotherapy (Dose Expansion): Overall Response Rate across all cohorts per RECIST v1.1 as assessed by Investigator (Time Frame - 34 months for study (end of Phase 2)): Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
34. Phase 2 Monotherapy (Dose Expansion): Overall Response Rate in ovarian cancer cohort per RECIST v1.1 as assessed by Investigator (Time Frame - 34 months for study (end of Phase 2)): Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
35. Phase 2 Monotherapy (Dose Expansion): Time to Response in ovarian cancer cohort per RECIST v1.1 as assessed by Investigator and as assessed by independent review (Time Frame - 34 months for study (end of Phase 2)): Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
36. Phase 2 Monotherapy (Dose Expansion): Time to Response across all cohorts per RECIST v1.1 as assessed by Investigator and as assessed by independent review (Time Frame - 34 months for study (end of Phase 2)): Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
37. Phase 2 Monotherapy (Dose Expansion): Duration of Response in ovarian cancer cohort per RECIST v1.1 as assessed by Investigator and as assessed by independent review (Time Frame - 34 months for study (end of Phase 2)): Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
38. Phase 2 Monotherapy (Dose Expansion): Duration of Response across all cohorts per RECIST v1.1 as assessed by Investigator and as assessed by independent review (Time Frame - 34 months for study (end of Phase 2)): Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
39. Phase 2 Monotherapy (Dose Expansion): Disease Control Rate in ovarian cancer cohort per RECIST v1.1 as assessed by Investigator and as assessed by independent review (Time Frame - 34 months for study (end of Phase 2)): Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
40. Phase 2 Monotherapy (Dose Expansion): Disease Control Rate across all cohorts per RECIST v1.1 as assessed by Investigator and as assessed by independent review (Time Frame - 34 months for study (end of Phase 2)): Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
41. Phase 2 Monotherapy (Dose Expansion): Progression Free Survival in ovarian cancer cohort per RECIST v1.1 as assessed by Investigator and as assessed by independent review (Time Frame - 34 months for study (end of Phase 2)): Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
42. Phase 2 Monotherapy (Dose Expansion): Progression Free Survival across all cohorts per RECIST v1.1 as assessed by Investigator and as assessed by independent review (Time Frame - 34 months for study (end of Phase 2)): Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
43. Phase 2 Monotherapy (Dose Expansion): Overall Survival in ovarian cancer cohort (Time Frame - 34 months for study (end of Phase 2)): Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
44. Phase 2 Monotherapy (Dose Expansion): Overall Survival across all cohorts (Time Frame - 34 months for study (end of Phase 2)): Evaluation of anti-tumor activity of PC14586 (INN: rezatapopt) as a single agent
45. Phase 2 Monotherapy (Dose Expansion): Quality of life assessment (Time Frame - Evaluated at every visit. 34 months for treatment arm (end of Phase 2)): Changes from baseline in quality of life as measured by a validated instrument, for
participants 18 and older
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).
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.
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.
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.
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.
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.
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.
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.
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.