Description:
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.
Title
- Brief Title: Study of CYH33 in Combination With Olaparib an Oral PARP Inhibitor in Patients With Advanced Solid Tumors.
- Official Title: Open Label, Phase Ib Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Clinical Activity of CYH33, an Oral PI3K Inhibitor in Combination With Olaparib, an Oral PARP Inhibitor in Patients With Advanced Solid Tumors.
Clinical Trial IDs
- ORG STUDY ID:
CYH33-G102
- NCT ID:
NCT04586335
Conditions
- Ovarian Cancer
- Breast Cancer
- Solid Tumor
- Prostate Cancer
- Endometrial Cancer
Interventions
Drug | Synonyms | Arms |
---|
CYH33 | Olaparib | CYH33 in Combination with Olaparib |
Purpose
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.
Trial Arms
Name | Type | Description | Interventions |
---|
CYH33 in Combination with Olaparib | Experimental | CYH33 in Combination with Olaparib; 20 mg CYH33 QD in combination with olaparib 300 mg BID. Two additional dose levels of CYH33 at 30 mg QD and CYH33 at 40 mg QD in combination with olaparib 300 mg BID will be evaluated. | |
Eligibility Criteria
Key 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.
Key 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.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Dose Limiting Toxicities (DLT) |
Time Frame: | 12 months |
Safety Issue: | |
Description: | Incidence rate of dose limiting toxicities (DLT) in the first cycle (of 28 days) of each investigated dose levels. |
Secondary Outcome Measures
Measure: | Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 |
Time Frame: | 38 months |
Safety Issue: | |
Description: | Number, type, incidence, duration, severity and seriousness of adverse events (AEs) as assessed by CTCAE v5.0 |
Measure: | Disease control rate (DCR) |
Time Frame: | 38 months |
Safety Issue: | |
Description: | 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: | Pharmacokinetic measures - Plasma concentration time Area Under the Curve |
Time Frame: | 12 months |
Safety Issue: | |
Description: | Measure the variation of CHY33/olaparib concentration in blood plasma as a function of time |
Measure: | Pharmacokinetic measures - Cmax |
Time Frame: | 12 months |
Safety Issue: | |
Description: | Measure the maximum (peak) plasma concentration(s) of CHY33/olaparib |
Measure: | Pharmacokinetic measures - Tmax |
Time Frame: | 12 months |
Safety Issue: | |
Description: | Measure of time to reach maximum (peak) plasma concentration(s) following administration of CHY33/olaparib |
Measure: | Pharmacokinetic measures - CL/F |
Time Frame: | 12 months |
Safety Issue: | |
Description: | Measure apparent total clearance(s) of CHY33/olaparib from plasma after oral administration |
Measure: | Pharmacokinetic measures - Vz/F |
Time Frame: | 12 months |
Safety Issue: | |
Description: | Measure apparent volume of distribution during terminal phase after administration of CHY33/olaparib |
Measure: | Pharmacokinetic measures - terminal half- life (t1/2) |
Time Frame: | 12 months |
Safety Issue: | |
Description: | Measure elimination half-life of CHY33/olaparib, when administered in combination |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | Haihe Biopharma Co., Ltd. |
Trial Keywords
Last Updated
February 8, 2021