Study of CYH33 in Combination With Olaparib an Oral PARP Inhibitor in Patients With Advanced Solid Tumors.

NCT ID: NCT04586335

Last Updated: 2024-03-21

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-09-28
• Study Completion Date: 2023-02-15

Brief Summary

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.

Detailed Description

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.

Conditions

Ovarian Cancer; Breast Cancer; Solid Tumor; Prostate Cancer; Endometrial Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

CYH33 in Combination with Olaparib

CYH33 in Combination with Olaparib; 20 mg CYH33 QD in combination with olaparib 300 mg BID. Additional dose levels of CYH33 at20 and 30 mg QD and CYH33 at 40 mg QD in combination with olaparib 200 mg BID will be evaluated.

Group Type: EXPERIMENTAL

CYH33

Intervention Type: DRUG

Clinical Activity of CYH33, an Oral α-specific PI3K Inhibitor in Combination with Olaparib, an Oral PARP Inhibitor

Interventions

CYH33

Clinical Activity of CYH33, an Oral α-specific PI3K Inhibitor in Combination with Olaparib, an Oral PARP Inhibitor

Intervention Type: DRUG

Other Intervention Names

Olaparib

Eligibility Criteria

Inclusion Criteria

Patients eligible for inclusion in this study have to meet all of the following criteria:

1. Provide informed consent voluntarily.

2. Male and female patients ≥ 18 years of age (or having reached the age of majority according to local laws and regulations, if the age is > 18 years).

3. Patients with advanced solid tumor who have failed at least one line of prior systemic therapy or for whom standard therapy do not exist and meet the following eligibility for the corresponding part of the study:

1. Patient must have a histologically or cytologically confirmed diagnosis of advanced recurrent or metastatic solid tumor.

2. At least one measurable lesion as per RECIST 1.1. (Ovarian cancer participants must have measurable disease by RECIST 1.1 criteria or evaluable cancer via CA125 GCIG criteria; Prostate cancer participants must have measurable disease by RECIST 1.1 criteria or evaluable cancer via PSA response).

3. Population eligibility:

• Patients eligible for Part 1 dose escalation: Advanced solid tumors with any DDR gene 1) or PIK3CA 2) mutation who have failed or cannot tolerate standard treatment or currently have no standard treatment.
• Patients eligible for Part 2 dose expansion:

• Cohort 1: Advanced solid tumors with any selected DDR3) gene mutation
• Cohort 2: Advanced solid tumors with PIK3CA hotspot mutation
• Cohort 3: Advanced high grade serous ovarian, fallopian tube or primary peritoneal cancer patients with acquired PARP inhibitor resistance4)
• Cohort 4: Advanced solid tumors with any selected DDR3) gene mutation with acquired PARP inhibitor resistance4).
• Cohort 5: Platinum resistant/refractory5) recurrent high grade serous ovarian, fallopian tube, or primary peritoneal cancer.

4. Availability of tumor tissue sample (either fresh tumor biopsy or archival tumor tissue sample) or blood samples.

5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.

Exclusion Criteria

Patients eligible for this study must not meet any of the following criteria:

1. Patient has received any anticancer therapy (including chemotherapy, targeted therapy, hormonal therapy, biotherapy, immunotherapy, or other investigational agents.) within 28 days or 5 times of half-lives (whichever is shorter) prior to the first dose of the study treatment or who have not recovered from the side effect of such therapy.

2. Patients with contraindication to olaparib treatment or who did not tolerate olaparib previously.

3. Patients who had prior treatment with PARP inhibitor, PI3Kα inhibitor, AKT inhibitor or mTOR inhibitor (Part 2 dose expansion cohort 1& 2 only).

4. Radical radiation therapy (including radiation therapy for over 25% bone marrow) within 4 weeks prior to the first dose of the investigational product or received local palliative radiation therapy for bone metastases within 2 weeks.

5. Any toxicities from prior treatment that have not recovered to baseline or ≤ CTCAE Grade 1 before the start of study treatment, with exception of hair loss.

6. Patients with an established diagnosis of diabetes mellitus including steroid-induced diabetes mellitus.

7. Major surgery or had significant traumatic injury within 28 days prior to the first dose of the investigational product or has not recovered from major side effects.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Haihe Biopharma Co., Ltd.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Fugen Li, PhD

Role: STUDY_DIRECTOR

Haihe Biopharma

Locations

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

Countries

United States; Australia; China

Other Identifiers

CYH33-G102

Identifier Type: -

Identifier Source: org_study_id