The purpose of this study is to assess the safety, tolerability and preliminary efficacy of CYH33 in combination with olaprib in patients with DDR gene mutations and/or PIK3CA mutations, in patients who have progressed on prior PARP inhibitor, and in patients with recurrent high grade serous ovarian, fallopian tube, or primary peritoneal cancer who are platinum resistant or refractory. The study will assess if this combination will optimize anti-tumor activity, block tumor growth and overcome the resistance to PARP inhibitor treatment. The study consists 2 parts. In Part 1 dose escalation, the objective is to determine the maximum toleration dose (MTD) of the combination. The final recommended phase 2 dose (RP2D) of CYH33 in combination with olaparib will be based on the totality of an overall assessment of available safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy which could be the MTD or a dose level lower in specific cohorts of patients. In Part 2 dose expansion, the main objective is to evaluate the efficacy at RP2D.
Name: CYH33
Description: Incidence rate of dose limiting toxicities (DLT) in the first cycle (of 28 days) of each investigated dose levels.
Measure: Dose Limiting Toxicities (DLT) Time: 12 monthsDescription: Tumor objective response rate (ORR) defined as the sum of complete response (CR) and partial response (PR) as best reported by RECIST version 1.1.
Measure: Tumor objective response rate (ORR) Time: 38 monthsDescription: Number, type, incidence, duration, severity and seriousness of adverse events (AEs) as assessed by CTCAE v5.0
Measure: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 Time: 38 monthsDescription: Disease control rate (DCR) defined as the sum of CR, PR and stable disease (SD) by RECIST version 1.1. - Progression Free Survival (PFS).
Measure: Disease control rate (DCR) Time: 38 monthsDescription: Measure the variation of CHY33/olaparib concentration in blood plasma as a function of time
Measure: Pharmacokinetic measures - Plasma concentration time Area Under the Curve Time: 12 monthsDescription: Measure the maximum (peak) plasma concentration(s) of CHY33/olaparib
Measure: Pharmacokinetic measures - Cmax Time: 12 monthsDescription: Measure of time to reach maximum (peak) plasma concentration(s) following administration of CHY33/olaparib
Measure: Pharmacokinetic measures - Tmax Time: 12 monthsDescription: Measure apparent total clearance(s) of CHY33/olaparib from plasma after oral administration
Measure: Pharmacokinetic measures - CL/F Time: 12 monthsDescription: Measure apparent volume of distribution during terminal phase after administration of CHY33/olaparib
Measure: Pharmacokinetic measures - Vz/F Time: 12 monthsDescription: Measure elimination half-life of CHY33/olaparib, when administered in combination
Measure: Pharmacokinetic measures - terminal half- life (t1/2) Time: 12 monthsSequential Assignment
There are 2 SNPs
The mechanistic rationale for the combination of PI3K and PARP inhibitors is that PI3K inhibition leads to a downregulation of BRCA1/2 proteins, which increase the degree of HRR deficiency CYH33 is a novel, highly potent and selective inhibitor of phosphatidylinositol 3-kinase αsignificantly inhibited the activities of wild-type and mutant PI3Kα kinase as well as the specific mutant of E542K, 1047R or E545K, On July13, 2018, a Phase I first-in-human dose escalation and expansion single-agent study of CYH33 (CYH33-101) started in China (ClinicalTrials.gov --- E542K ---
The mechanistic rationale for the combination of PI3K and PARP inhibitors is that PI3K inhibition leads to a downregulation of BRCA1/2 proteins, which increase the degree of HRR deficiency CYH33 is a novel, highly potent and selective inhibitor of phosphatidylinositol 3-kinase αsignificantly inhibited the activities of wild-type and mutant PI3Kα kinase as well as the specific mutant of E542K, 1047R or E545K, On July13, 2018, a Phase I first-in-human dose escalation and expansion single-agent study of CYH33 (CYH33-101) started in China (ClinicalTrials.gov --- E542K --- --- E545K ---