A Phase Ib Study of GB491 Plus Letrozole in Patients With Advanced Breast Cancer

Study Overview
=================
Brief Summary
-----------------
GB491-005 is a multicenter, open-label, phase Ib Clinical Trial study to evaluate the safety, pharmacokinetic (PK), pharmacodynamic (PD) activity, and preliminary anti-tumor activity of GB491 in combination with Letrozole in Previously Untreated Patients with HR-positive, HER2-negative Advanced Breast Cancer

Official Title
-----------------
A Multicenter, Open-label, Phase Ib Clinical Trial of GB491 in Combination With Letrozole in Previously Untreated Patients With HR-positive, HER2-negative Advanced Breast Cancer

Conditions
-----------------
Advanced Breast Cancer

Intervention / Treatment
-----------------
* Drug: GB491+Letrozole


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Females of 18 years of age or older at study screening Histologically or cytologically confirmed locally advanced or advanced metastatic breast cancer that is not amenable to curative surgical resection or radiation therapy The subject has been diagnosed with ER-positive breast cancer in the local laboratory The subject has HER2-negative breast cancer in the local laboratory Menopausal status is not limited (including Premenopausal/perimenopausal/postmenopausal state) No previous systemic anti-tumor treatment for locally advanced or metastatic breast cancer; According to RECIST V1.1, the patient has at least one measurable lesion that has not been irradiated by radiotherapy and can be evaluated by CT/MRI; If only bone metastases are present, there must be at least one osteolytic bone lesion that can be evaluated by CT/MRI ECOG performance status of 0 or 1 Adequate organ and marrow function. The subject of childbearing potential must use one highly effective birth control method from the total duration of the study and 6 months after the last dose of study intervention. Provide informed consent Exclusion Criteria: Previous treatment with CDK4/6 inhibitors Subjects with known hypersensitivity to any component of GB491 or Letrozole Patients with disease progression or recurrence during or within 1 year after completion of previous endocrine neoadjuvant or adjuvant therapy Known active, uncontrolled, or symptomatic central nervous system metastasis, carcinomatous meningitis, or clinically manifested leptomeningeal disease, cerebral edema, spinal compression or/and tumor progressive growth Visceral crisis Patients with skin lesion only and radiographically non-measurable at baseline Persistent toxicities (CTCAE Grade ≥ 2) caused by previous anticancer therapy, excluding alopecia Major surgical procedure within 4 weeks of the first dose of study treatment or an anticipated need for major surgery, chemotherapy, radiotherapy, any other investigational drug or other anti-cancer therapy during the study Patients who have been on bisphosphonates and denosumab therapy at a stable dose for less than 14 days prior to randomization Patients who have received limited field radiotherapy in 2 weeks or extended field radiotherapy in 4 weeks before randomization or radiation with more than 30% of the bone marrow Subjects use drugs or fruits containing strong inducers or inhibitors of CYP3A4/5, or drugs with narrow therapeutic window that are mainly metabolized by CYP3A4/5 in 14 days before randomization Patients with long-term systematic use of corticosteroids Any severe and/or uncontrollable medical conditions Patients with severely impaired lung function Known history of HIV infection or history of HIV seropositivity Resting QTcF > 480 msec or there is a medical history of QTcF prolongation Subjects have significant hepatic disease Coagulation abnormalities Refractory nausea and vomiting, inability to swallow the formulated product, or other disease or clinical status would preclude adequate absorption, distribution, metabolism, or excretion of GB491 Previous allogeneic bone marrow transplant Inflammatory breast cancer; Subjects with a history of other primary malignancies, except for non-melanoma skin cancer and cervical cancer in situ disease-free status ≥ 3 years Lactating women Unlikely to comply with study procedures, restrictions, and requirements Judgment by the investigator that the patient should not participate into the study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GB491+Letrozole<br> | Drug: GB491+Letrozole<br>* Drug：The dose of GB491 is 150 mg, which should be taken with a meal and taken twice daily at approximately the same time each day, approximately 12 hours apart<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DLT | Number of Participants with Dose-Limiting Toxicities for GB491 in Combination with Letrozole | During Cycle 1 (up to 28 days) | 
| AE | Number of Participants with Adverse Events by Severity, According to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v5.0) | From Baseline until 30 days after the last treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS | To assess the progression free survival assessed by investigator | Approximately 2 years | 
| ORR | To assess the objective response rate for GB491 in Combination with Letrozole | Approximately 2 years | 
| DOR | To assess the duration of response for GB491 in Combination with Letrozole | Approximately 2 years | 
| DCR | To assess the disease control rate for GB491 in Combination with Letrozole | Approximately 2 years | 
| CBR | To assess the clinical benefit rate for GB491 in Combination with Letrozole by investigator | Approximately 2 years | 
| Plasma Concentration of GB491 | Plasma Concentration of GB491 Over Time | At predefined intervals from Cycle 1, Day 1 & Day 15; Cycle 2, Day 1 (each cycle is 28 days) | 
| Plasma Concentration of Letrozole | Plasma Concentration of Letrozole Over Time | At predefined intervals from Cycle 1, Day 1 & Day 15; Cycle 2, Day 1 (each cycle is 28 days) |