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

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Advanced Breast Cancer
• Intervention / Treatment: Drug: CYH33; Drug: Fulvestrant; Drug: Palbociclib; Drug: Letrozole

• Study Type: Interventional
• Enrollment (Anticipated): 228
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Yong Yuan, MD; Phone Number: 86 13820384005; Email: yong.yuan@haihepharma.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Main 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 Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CYH33 + fulvestrant; Participants will receive CYH33 in combination with a standard fixed dose of fulvestrant 500 mg.	Drug: CYH33; Participants will receive oral CYH33 once daily on Days 1-28 of each 28-day cycle.; Drug: Fulvestrant; 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.
Experimental: CYH33 + fulvestrant + palbociclib; Participants will receive CYH33 in combination with standard fixed dose of fulvestrant (500 mg) and palbociclib (125 mg).	Drug: CYH33; Participants will receive oral CYH33 once daily on Days 1-28 of each 28-day cycle.; Drug: Fulvestrant; 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.; Drug: Palbociclib; Participants will receive palbociclib once daily continuous on Day 1-21 of each 28-day cycle.
Experimental: CYH33 + letrozole + palbociclib; Participants will receive CYH33 in combination with standard fixed dose of letrozole (2.5 mg) and palbociclib (125 mg)	Drug: CYH33; Participants will receive oral CYH33 once daily on Days 1-28 of each 28-day cycle.; Drug: Palbociclib; Participants will receive palbociclib once daily continuous on Day 1-21 of each 28-day cycle.; Drug: Letrozole; Participants will receive oral letrozole once daily continuous on Day 1-28 of each cycle.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Haihe Biopharma Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Anticipated): April 1, 2021
• Primary Completion (Anticipated): March 1, 2022
• Study Completion (Anticipated): December 1, 2022

Study Registration Dates

• First Submitted: April 11, 2021
• First Submitted That Met QC Criteria: April 19, 2021
• First Posted (Actual): April 23, 2021

Study Record Updates

• Last Update Posted (Actual): April 23, 2021
• Last Update Submitted That Met QC Criteria: April 19, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: PIK3CA Mutant; Advanced Breast Cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protein Kinase Inhibitors; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Estrogen Receptor Antagonists; Letrozole; Fulvestrant; Palbociclib
• Other Study ID Numbers: CYH33-G103

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No