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

Phase 1

• Conditions: Advanced Breast Cancer
• Interventions: Drug: CYH33; Drug: Fulvestrant; Drug: Letrozole; Drug: Palbociclib

• Registration Number: NCT04856371
• Lead Sponsor: Haihe Biopharma Co., Ltd.

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Status Verified: 2021-03
• Study Start: 2021-04
• Study First Submitted: 2021-04-11
• Study First Submitted QC: 2021-04-19
• Last Update Submitted: 2021-04-19
• Study First Posted: 2021-04-23
• Last Update Posted: 2021-04-23
• Primary Completion: 2022-03
• Study Completion: 2022-12

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 228

Inclusion Criteria

1. Provide informed consent voluntarily.
2. Male and female patients ≥ 18 years of age.
3. Patient must have a histologically or cytologically documented locally advanced, recurrent or metastatic breast cancer.
4. In case of women, both premenopausal and postmenopausal patients can be enrolled in the study.
5. Confirmed diagnosis of HR+, HER2- breast cancer.
6. 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.
7. Patient must have evidence of disease radiological progression after previous endocrine therapy, or other systemic therapy.
8. Patient has measurable disease per RECIST v1.1.
9. ECOG ≤ 1.
10. Patient must have adequate organ and bone marrow function.

Main

Exclusion Criteria

1. Previously received any anticancer therapy within 28 days or 5 times of half-lives prior to the first dose of the study treatment.
2. Previously received treatment with any PI3Kα inhibitor, AKT inhibitor, or mTOR inhibitor.
3. Radical radiation therapy within 4 weeks prior to the first dose of the study treatment.
4. Patient with an established diagnosis of diabetes mellitus.
5. Any other concurrent disease with potential risk of insulin resistance or current use of medication with potential risk of insulin resistance.
6. Patient with clinically significant cardiovascular disease.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
CYH33 + fulvestrant	CYH33	Participants will receive CYH33 in combination with a standard fixed dose of fulvestrant 500 mg.
CYH33 + letrozole + palbociclib	CYH33	Participants will receive CYH33 in combination with standard fixed dose of letrozole (2.5 mg) and palbociclib (125 mg)
CYH33 + fulvestrant + palbociclib	CYH33	Participants will receive CYH33 in combination with standard fixed dose of fulvestrant (500 mg) and palbociclib (125 mg).
CYH33 + fulvestrant	Fulvestrant	Participants will receive CYH33 in combination with a standard fixed dose of fulvestrant 500 mg.
CYH33 + fulvestrant + palbociclib	Fulvestrant	Participants will receive CYH33 in combination with standard fixed dose of fulvestrant (500 mg) and palbociclib (125 mg).
CYH33 + fulvestrant + palbociclib	Palbociclib	Participants will receive CYH33 in combination with standard fixed dose of fulvestrant (500 mg) and palbociclib (125 mg).
CYH33 + letrozole + palbociclib	Letrozole	Participants will receive CYH33 in combination with standard fixed dose of letrozole (2.5 mg) and palbociclib (125 mg)
CYH33 + letrozole + palbociclib	Palbociclib	Participants will receive CYH33 in combination with standard fixed dose of letrozole (2.5 mg) and palbociclib (125 mg)

Primary Outcome Measures

Name	Time	Method
Dose Limiting Toxicities (DLT)	28 days	Incidence rate of DLT in the first cycle (of 28 days).

Secondary Outcome Measures

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