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

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ClinicalTrials.gov Identifier: NCT04586335
Recruitment Status : Recruiting
First Posted : October 14, 2020
Last Update Posted : February 8, 2021
Sponsor:
Information provided by (Responsible Party):
Haihe Biopharma Co., Ltd.

Tracking Information
First Submitted Date  ICMJE August 25, 2020
First Posted Date  ICMJE October 14, 2020
Last Update Posted Date February 8, 2021
Actual Study Start Date  ICMJE September 28, 2020
Estimated Primary Completion Date January 28, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 7, 2020)
  • Dose Limiting Toxicities (DLT) [ Time Frame: 12 months ]
    Incidence rate of dose limiting toxicities (DLT) in the first cycle (of 28 days) of each investigated dose levels.
  • Tumor objective response rate (ORR) [ Time Frame: 38 months ]
    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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 7, 2020)
  • Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 [ Time Frame: 38 months ]
    Number, type, incidence, duration, severity and seriousness of adverse events (AEs) as assessed by CTCAE v5.0
  • Disease control rate (DCR) [ Time Frame: 38 months ]
    Disease control rate (DCR) defined as the sum of CR, PR and stable disease (SD) by RECIST version 1.1. - Progression Free Survival (PFS).
  • Pharmacokinetic measures - Plasma concentration time Area Under the Curve [ Time Frame: 12 months ]
    Measure the variation of CHY33/olaparib concentration in blood plasma as a function of time
  • Pharmacokinetic measures - Cmax [ Time Frame: 12 months ]
    Measure the maximum (peak) plasma concentration(s) of CHY33/olaparib
  • Pharmacokinetic measures - Tmax [ Time Frame: 12 months ]
    Measure of time to reach maximum (peak) plasma concentration(s) following administration of CHY33/olaparib
  • Pharmacokinetic measures - CL/F [ Time Frame: 12 months ]
    Measure apparent total clearance(s) of CHY33/olaparib from plasma after oral administration
  • Pharmacokinetic measures - Vz/F [ Time Frame: 12 months ]
    Measure apparent volume of distribution during terminal phase after administration of CHY33/olaparib
  • Pharmacokinetic measures - terminal half- life (t1/2) [ Time Frame: 12 months ]
    Measure elimination half-life of CHY33/olaparib, when administered in combination
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of CYH33 in Combination With Olaparib an Oral PARP Inhibitor in Patients With Advanced Solid Tumors.
Official Title  ICMJE 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.
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Sequential Assignment
Intervention Model Description:
Open-label, multicenter study which is composed of 2 parts: 1.) dose escalation and 2.) dose expansion. Bayesian optimal interval (BOIN) design will be used to determine the MTD and/or RP2D. Safety, tolerability, PK, PD, and clinical activity will also be evaluated. The CYH33 starting dose of this trial is 20 mg QD in combination with olaparib 300 mg BID. Two additional dose levels of CYH33 at 30 mg QD and 40 mg QD in combination with olaparib 300 mg BID will be evaluated. In the initial dose cohort of 20 mg CYH33 as well as in subsequent dose cohorts 30 mg QD and 40 mg QD in combination with olaparib 300 mg BID, 3 patients will be initially enrolled at each dose level of CYH33. These evaluable patients will be included into this dose level for decision making on dose selection for the next cohort. 10 mg QD of CYH33 will be evaluated in the combination with olaparib 300 mg BID, according to the BOIN design.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Ovarian Cancer
  • Breast Cancer
  • Solid Tumor
  • Prostate Cancer
  • Endometrial Cancer
Intervention  ICMJE Drug: CYH33
Clinical Activity of CYH33, an Oral α-specific PI3K Inhibitor in Combination with Olaparib, an Oral PARP Inhibitor
Other Name: Olaparib
Study Arms  ICMJE Experimental: CYH33 in Combination with Olaparib
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.
Intervention: Drug: CYH33
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 7, 2020)
350
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 28, 2024
Estimated Primary Completion Date January 28, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jason Sudia, PhD, MPH 9083801329 jason.sudia@haihepharma.com
Contact: Frank Tan, MD Base GZ 1392229168 fei.tan@haihepharma.com
Listed Location Countries  ICMJE Australia,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04586335
Other Study ID Numbers  ICMJE CYH33-G102
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Haihe Biopharma Co., Ltd.
Study Sponsor  ICMJE Haihe Biopharma Co., Ltd.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Joan Yu, MD Haihe Biopharma
PRS Account Haihe Biopharma Co., Ltd.
Verification Date February 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP