A Phase 1, Open-label, 2-part, Drug-Drug Interaction Study to Evaluate the Effects of Multiple Oral Doses of Rezatapopt on the Pharmacokinetics of Metformin, Rosuvastatin, Repaglinide, and Midazolam in Patients With Advanced Solid Tumors Harboring a TP53 Y220C Mutation.
Summary
This study aims to evaluate the effects of rezatapopt on the pharmacokinetics of metformin, rosuvastatin, repaglinide, and midazolam in patients with advanced solid tumors harboring a TP53 Y220C mutation.
Detailed description
Rezatapopt (PC14586) is a first-in-class oral, small molecule p53 reactivator that is selective for the TP53 Y220C mutation. This Phase 1, open-label, drug-drug interaction study will investigate the effect of multiple oral doses of rezatapopt on the pharmacokinetics (PK) of metformin, rosuvastatin, repaglinide, and midazolam in patients with advanced solid tumors harboring a TP53 Y220C mutation. This study will consist of 2 parts, Part A and Part B. Part A is a 24-day drug-drug interaction (DDI) portion that follows a fixed- sequence design, including a screening period and 2 treatment periods. In Treatment Period 1 patients will receive metformin and rosuvastatin, followed by repaglinide and midazolam. Patients will not receive rezatapopt during Treatment Period 1. Following washout, in Treatment Period 2 which will begin on Day 6, patients will receive 2000 mg rezatapopt administered orally once daily along with metformin and rosuvastatin, and then repaglinide and midazolam in accordance with the fixed-sequence dosing schedule. Serial PK samples will be collected on designated days throughout Part A. Patients who complete Part A without suspected disease progression and unacceptable toxicity or another discontinuation criterion and who are deemed likely to continue benefiting from the study treatment, will be allowed to continue treatment with rezatapopt in Part B. In Part B, patients will receive 2000 mg rezatapopt orally daily in 21-day cycles, up to Cycle 33 (approximately 2 years of rezatapopt treatment, inclusive of Part A) or until another discontinuation criterion is met. A maximum of approximately 14 patients are planned to enroll in this study.
Arms & interventions
- Drugmetformin hydrochloride 500 mg tablet
500-mg immediate release tablet PO
- Drugrosuvastatin 10 mg tablet
10-mg tablet PO
- Drugrepaglinide 0.5 mg tablet
0.5-mg tablet PO
- Drugmidazolam hydrochloride syrup
2 mg dose (5-mg/2.5 mL syrup) PO
- Drugrezatapopt
2000 mg dose (4 x 500-mg tablets) PO
Outcome measures
Primary
Metformin Cmax geometric mean ratio
Geometric mean metformin peak concentration (Cmax) when administered with rezatapopt versus metformin alone.
Time frame: Day 1 to Day 24 of Part A
Rosuvastatin Cmax geometric mean ratio
Geometric mean rosuvastatin peak concentration (Cmax) when administered with rezatapopt versus rosuvastatin alone.
Time frame: Day 1 to Day 24 of Part A
Repaglinide Cmax geometric mean ratio
Geometric mean repaglinide peak concentration (Cmax) when administered with rezatapopt versus repaglinide alone
Time frame: Day 1 to Day 24 of Part A
Midazolam Cmax geometric mean ratio
Geometric mean midazolam peak concentration (Cmax) when administered with rezatapopt versus midazolam alone
Time frame: Day 1 to Day 24 of Part A
Metformin AUC0-t geometric mean ratio
Geometric mean metformin area under the concentration-time curve from pre-dose (time 0) to t post-dose (AUC0-t) when administered with rezatapopt versus metformin alone
Time frame: Day 1 to Day 24 of Part A
Rosuvastatin AUC0-t geometric mean ratio
Geometric mean rosuvastatin area under the concentration-time curve from pre-dose (time 0) to t post-dose (AUC0-t) when administered with rezatapopt versus rosuvastatin alone
Time frame: Day 1 to Day 24 of Part A
Repaglinide AUC0-t geometric mean ratio
Geometric mean repaglinide area under the concentration-time curve from pre-dose (time 0) to t post-dose (AUC0-t) when administered with rezatapopt versus repaglinide alone
Time frame: Day 1 to Day 24 of Part A
Midazolam AUC0-t geometric mean ratio
Geometric mean midazolam area under the concentration-time curve from pre-dose (time 0) to t post-dose (AUC0-t) when administered with rezatapopt versus midazolam alone
Time frame: Day 1 to Day 24 of Part A
PK profile of metformin - area under the concentration-time curve from pre-dose (time 0) to 24 h post-dose (AUC0-24)
Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of metformin
Time frame: Day 1 to Day 24 of Part A
PK profile of rosuvastatin - area under the concentration-time curve from pre-dose (time 0) to 24 h post-dose (AUC0-24)
Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rosuvastatin
Time frame: Day 1 to Day 24 of Part A
PK profile of repaglinide - area under the concentration-time curve from pre-dose (time 0) to 24 h post-dose (AUC0-24)
Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of repaglinide
Time frame: Day 1 to Day 24 of Part A
PK profile of midazolam - area under the concentration-time curve from pre-dose (time 0) to the time 24 h post-dose (AUC0-24)
Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of midazolam
Time frame: Day 1 to Day 24 of Part A
PK profile of metformin - area under the concentration-time curve from pre-dose (time 0) to 48 h post-dose (AUC0-48)
Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of metformin
Time frame: Day 1 to Day 24 of Part A
PK profile of rosuvastatin - area under the concentration-time curve from pre-dose (time 0) to 48 h post-dose (AUC0-48)
Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rosuvastatin
Time frame: Day 1 to Day 24 of Part A
PK Profile of Metformin - Time of Peak Concentration (Tmax)
Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of metformin
Time frame: Day 1 to Day 24 of Part A
PK Profile of Rosuvastatin - Time of Peak Concentration (Tmax)
Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of rosuvastatin
Time frame: Day 1 to Day 24 of Part A
PK Profile of Repaglinide - Time of Peak Concentration (Tmax)
Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of repaglinide
Time frame: Day 1 to Day 24 of Part A
PK Profile of Midazolam - Time of Peak Concentration (Tmax)
Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of midazolam
Time frame: Day 1 to Day 24 of Part A
Secondary
Determine the incidence and severity of adverse events to characterize the safety of rezatapopt alone or co-administered with metformin and rosuvastatin, or repaglinide and midazolam
Time frame: From Day 6 to 24 of Part A
Assess the safety and tolerability of multiple doses of rezatapopt alone or co-administered with metformin and rosuvastatin, or repaglinide and midazolam
Time frame: Day 6 to 24 of Part A.
Assess the safety and tolerability of multiple doses of rezatapopt alone or co-administered with metformin and rosuvastatin, or repaglinide and midazolam
Time frame: Day 6 to Day 24 of Part A
Assess the safety and tolerability of multiple doses of rezatapopt alone or co-administered with metformin and rosuvastatin, or repaglinide and midazolam
Time frame: Day 6 to Day 24 of Part A
Assess the safety and tolerability of multiple doses of rezatapopt alone or co-administered with metformin and rosuvastatin, or repaglinide and midazolam
Time frame: Day 6 to Day 24 of Part A
Assess the safety and tolerability of multiple doses of rezatapopt alone or co-administered with metformin and rosuvastatin, or repaglinide and midazolam
Time frame: Day 6 to Day 24 of Part A
PK profile of rezatapopt and its metabolites, M13 and M14 - peak concentration (Cmax)
Time frame: Day 6 to Day 24 of Part A
PK profile of rezatapopt and its metabolites, M13 and M14 - area under the concentration-time curve from pre-dose (time 0) to the time t post-dose (AUC0-t)
Time frame: Day 6 to Day 24 of Part A
PK profile of rezatapopt and its metabolites, M13 and M14 - time of peak concentration (Tmax)
Time frame: Day 6 to Day 24 of Part A
PK profile of rezatapopt and its metabolites, M13 and M14 - area under the concentration-time curve from pre-dose (time 0) to the time 24 h post-dose (AUC0-24)
Time frame: Day 6 to Day 24 of Part A
Eligibility criteria
Study locations (5)
HealthOne Denver
Denver, Colorado, 80237
Florida Cancer Specialists
Orlando, Florida, 32827
SCRI Oncology Partners
Nashville, Tennessee, 37203
SCRI at Mary Crowley
Dallas, Texas, 75230
NEXT Oncology
San Antonio, Texas, 78229