Clinical Trials /

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

NCT04586335

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.

Related Conditions:
  • High Grade Fallopian Tube Serous Adenocarcinoma
  • High Grade Ovarian Serous Adenocarcinoma
  • Malignant Solid Tumor
  • Primary Peritoneal High Grade Serous Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

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

DrugSynonymsArms
CYH33OlaparibCYH33 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

NameTypeDescriptionInterventions
CYH33 in Combination with OlaparibExperimentalCYH33 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.
  • CYH33

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

  • PIK3CA
  • Olaparib

Last Updated

February 8, 2021