Study of CYH33 in Combination With Endocrine Therapy With or Without Palbociclib in Patients With HR+, HER2- Advanced Breast Cancer

Study Overview
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Brief Summary
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This is a multicenter, open-label, phase Ib study designed to evaluate the safety, tolerability, pharmacokinetics and preliminary efficacy of CYH33 administered orally in combination with standard-of-care ET ± CDK4/6 inhibitor therapies for the treatment of locally advanced, recurrent or metastatic hormone-receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Patients will be enrolled in two stages, including dose exploration phase (Stage 1) and dose expansion phase (Stage 2) of each cohort.

Official Title
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A Multicenter, Open-label, Phase Ib Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of CYH33 in Combination With Endocrine Therapy With or Without Palbociclib in Patients With PIK3CA Mutant, HR+, HER2- Advanced Breast Cancer

Conditions
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Advanced Breast Cancer

Intervention / Treatment
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* Drug: CYH33
* Drug: Fulvestrant
* Drug: Letrozole
* Drug: Palbociclib


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Provide informed consent voluntarily. Male and female patients ≥ 18 years of age. Patient must have a histologically or cytologically documented locally advanced, recurrent or metastatic breast cancer. In case of women, both premenopausal and postmenopausal patients can be enrolled in the study. Confirmed diagnosis of HR+, HER2- breast cancer. For Stage 1 dose exploration phase, patients with or without PIK3CA mutation may be enrolled; For Stage 2 dose expansion phase, patients with PIK3CA mutations are required. Patient must have evidence of disease radiological progression after previous endocrine therapy, or other systemic therapy. Patient has measurable disease per RECIST v1.1. ECOG ≤ 1. Patient must have adequate organ and bone marrow function. Main Exclusion Criteria: Previously received any anticancer therapy within 28 days or 5 times of half-lives prior to the first dose of the study treatment. Previously received treatment with any PI3Kα inhibitor, AKT inhibitor, or mTOR inhibitor. Radical radiation therapy within 4 weeks prior to the first dose of the study treatment. Patient with an established diagnosis of diabetes mellitus. Any other concurrent disease with potential risk of insulin resistance or current use of medication with potential risk of insulin resistance. Patient with clinically significant cardiovascular disease.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CYH33 + fulvestrant<br>Participants will receive CYH33 in combination with a standard fixed dose of fulvestrant 500 mg. | Drug: CYH33<br>* Participants will receive oral CYH33 once daily on Days 1-28 of each 28-day cycle.<br>Drug: Fulvestrant<br>* Participants will receive fulvestrant 500 mg, administered intramuscularly on Days 1, 15 on Cycle 1 (28-day cycle) and Day 1 at each 28-day cycle thereafter.<br>|
| Experimental: CYH33 + fulvestrant + palbociclib<br>Participants will receive CYH33 in combination with standard fixed dose of fulvestrant (500 mg) and palbociclib (125 mg). | Drug: CYH33<br>* Participants will receive oral CYH33 once daily on Days 1-28 of each 28-day cycle.<br>Drug: Fulvestrant<br>* Participants will receive fulvestrant 500 mg, administered intramuscularly on Days 1, 15 on Cycle 1 (28-day cycle) and Day 1 at each 28-day cycle thereafter.<br>Drug: Palbociclib<br>* Participants will receive palbociclib once daily continuous on Day 1-21 of each 28-day cycle.<br>|
| Experimental: CYH33 + letrozole + palbociclib<br>Participants will receive CYH33 in combination with standard fixed dose of letrozole (2.5 mg) and palbociclib (125 mg) | Drug: CYH33<br>* Participants will receive oral CYH33 once daily on Days 1-28 of each 28-day cycle.<br>Drug: Letrozole<br>* Participants will receive oral letrozole once daily continuous on Day 1-28 of each cycle.<br>Drug: Palbociclib<br>* Participants will receive palbociclib once daily continuous on Day 1-21 of each 28-day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicities (DLT) | Incidence rate of DLT in the first cycle (of 28 days). | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability | Type, incidence, duration, severity and seriousness of adverse events (AEs). | 30 months | 
| Preliminary efficacy-ORR | Tumor objective response rate (ORR) assessed by RECIST v1.1 | 30 months | 
| Preliminary efficacy-CBR | Clinical benefit rate (CBR) assessed by RECIST v1.1 | 30 months | 
| Preliminary efficacy-PFS | Progression Free Survival (PFS) assessed by RECIST v1.1 | 30 months | 
| Pharmacokinetic measures - AUC | Measure the variation of concentration in blood plasma as a function of time | 20 months | 
| Pharmacokinetic measures - C trough | Measure the minimum (trough) plasma concentration | 20 months | 
| Pharmacokinetic measures - Cmax | Measure the maximum (peak) plasma concentration | 20 months | 
| Pharmacokinetic measures - Tmax | Measure of time to reach maximum (peak) plasma concentration | 20 months | 
| Pharmacokinetic measures - CL/F | Measure apparent total clearance(s) from plasma after administration | 20 months | 
| Pharmacokinetic measures - Vz/F | Measure apparent volume of distribution during terminal phase | 20 months | 
| Assess downstream effects of PI3K pathway inhibition on blood glucose | Pre- and post-treatment of blood glucose | 20 months | 
| Assess downstream effects of PI3K pathway inhibition on C peptide | Pre- and post-treatment of C peptide | 20 months | 
| Assess the changes of biomarker-PIK3CA | Pre- and post-treatment PIK3CA changes in ctDNA samples. | 20 months | 
| Assess the changes of biomarker-PTEN | Pre- and post-treatment PTEN changes in ctDNA samples. | 20 months | 
| Assess the changes of biomarker-KRAS | Pre- and post-treatment KRAS changes in ctDNA samples. | 20 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced Breast Cancer, PIK3CA Mutant