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.
DNA damage repair (DDR) pathways can modulate cancer risk, progression and therapeutic responses. Germline mutations in genes encoding key players in the DNA-damage response (DDR), including BRCA1, BRCA2,BLM, FANCA, TP53, RAD51C, and MSH2, result in cancer susceptibility syndromes, in part because failure to adequately protect the genome against endogenous and exogenous sources of DNA damage results in the accumulation of oncogenic mutations. 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 identifier: NCT03544905) identify the MTD of CYH33 single agent was 40 mg. The most common treatment related adverse events (\>5%) of Grade 3 was hyperglycemia. No treatment-related Grade 4 adverse event or death was reported in the ongoing trial by the cut-off date. In this combination 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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
24
Clinical Activity of CYH33, an Oral α-specific PI3K Inhibitor in Combination with Olaparib, an Oral PARP Inhibitor
Yale Cancer Center
New Haven, Connecticut, United States
UT Southwestern: Simmons Cancer Center
Dallas, Texas, United States
MD Anderson Cancer Center
Houston, Texas, United States
Scientia Cancer Centre
Sydney, New South Wales, Australia
Integrated Oncology Network PTY LTD
Brisbane, Queensland, Australia
Monash Cancer Centre
Melbourne, Victoria, Australia
Fudan University - Pudong Medical Center
Shanghai, Shanghai Municipality, China
Dose Limiting Toxicities (DLT)
Incidence rate of dose limiting toxicities (DLT) in the first cycle (of 28 days) of each investigated dose levels.
Time frame: 12 months
Tumor objective response rate (ORR)
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.
Time frame: 38 months
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
Number, type, incidence, duration, severity and seriousness of adverse events (AEs) as assessed by CTCAE v5.0
Time frame: 38 months
Disease control rate (DCR)
Disease control rate (DCR) defined as the sum of CR, PR and stable disease (SD) by RECIST version 1.1. - Progression Free Survival (PFS).
Time frame: 38 months
Pharmacokinetic measures - Plasma concentration time Area Under the Curve
Measure the variation of CHY33/olaparib concentration in blood plasma as a function of time
Time frame: 12 months
Pharmacokinetic measures - Cmax
Measure the maximum (peak) plasma concentration(s) of CHY33/olaparib
Time frame: 12 months
Pharmacokinetic measures - Tmax
Measure of time to reach maximum (peak) plasma concentration(s) following administration of CHY33/olaparib
Time frame: 12 months
Pharmacokinetic measures - CL/F
Measure apparent total clearance(s) of CHY33/olaparib from plasma after oral administration
Time frame: 12 months
Pharmacokinetic measures - Vz/F
Measure apparent volume of distribution during terminal phase after administration of CHY33/olaparib
Time frame: 12 months
Pharmacokinetic measures - terminal half- life (t1/2)
Measure elimination half-life of CHY33/olaparib, when administered in combination
Time frame: 12 months
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