GB491 Combined With Fulvestrant for HR+ HER2- Locally Advanced or Metastatic Breast Cancer

Study Overview
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Brief Summary
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GB491-004 is a multicenter, randomized, double-blind, placebo-controlled Phase III study to evaluate the efficacy and safety of GB491 in combination with fulvestrant in patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer who have progressed on prior endocrine therapy.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Phase III Clinical Trial of GB491 Combined With Fulvestrant in Subjects With HR+, HER2- Locally Advanced or Metastatic Breast Cancer Who Have Progressed on Prior Endocrine Therapy

Conditions
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Locally Advanced or Metastatic Breast Cancer

Intervention / Treatment
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* Drug: GB491+ Fulvestrant
* Drug: Placebo+Fulvestrant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Females or males 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 Subject has HER2-negative breast cancer in the local laboratory Menopausal status is not limited (including Premenopausal/perimenopausal/postmenopausal state) 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. Exclusion Criteria: Previous treatment with fulvestrant, everolimus and any other CDK4/6 inhibitors Subjects with known hypersensitivity to any component of GB491 or Fulvestrant 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 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 Subjects have significant hepatic disease Coagulation abnormalities 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

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: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GB491+ Fulvestrant<br>GB491: 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. The drug is administered according to the patient's dose group until the progression of disease or an intolerable toxicity occur or meet the criteria for termination of treatment or the patient withdraw informed consent or the sponsor discontinues the trial. Fulvestrant: Intramuscular injection of flurvexine 500mg on day 1 and day 15 of the first cycle, and flurvexine 500mg on day 1 of the second and subsequent cycles Flurvexine 500mg should be given slowly (1-2 minutes per injection) on both sides of the buttocks, once 250 mg on each side.The drug is administered according to the patient's dose group until the progression of disease or an intolerable toxicity occur or meet the criteria for termination of treatment or the patient withdraw informed consent or the sponsor discontinues the trial. | Drug: GB491+ Fulvestrant<br>* GB491: 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. Fulvestrant: Intramuscular injection of flurvexine 500mg on day 1 and day 15 of the first cycle, and flurvexine 500mg on day 1 of the second and subsequent cycles Flurvexine 500mg should be given slowly (1-2 minutes per injection) on both sides of the buttocks, once 250 mg on each side.<br>* Other names: test drug + Fulvestrant;|
| Placebo Comparator: Placebo+Fulvestrant<br>Placebo: The dose of placebo 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. The placebo is administered according to the patient's dose group until the progression of disease occur or meet the criteria for termination of treatment or the patient withdraw informed consent or the sponsor discontinues the trial. Fulvestrant: Intramuscular injection of flurvexine 500mg on day 1 and day 15 of the first cycle, and flurvexine 500mg on day 1 of the second and subsequent cycles Flurvexine 500mg should be given slowly (1-2 minutes per injection) on both sides of the buttocks, once 250 mg on each side. The drug is administered according to the patient's dose group until the progression of disease or an intolerable toxicity occur or meet the criteria for termination of treatment or the patient withdraw informed consent or the sponsor discontinues the trial. | Drug: Placebo+Fulvestrant<br>* Placebo: The dose of Placebo 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. Fulvestrant: Intramuscular injection of flurvexine 500mg on day 1 and day 15 of the first cycle, and flurvexine 500mg on day 1 of the second and subsequent cycles Flurvexine 500mg should be given slowly (1-2 minutes per injection) on both sides of the buttocks, once 250 mg on each side.<br>* Other names: placebo control + Fulvestrant;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS by BICR. | To assess the progression free survial (PFS), which is assessed by BICR. | Approximately 1.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS by PI | To assess the progression free survial (PFS), which is assessed by PI. | Approximately 1.5 years | 
| OS | To assess the overall survival (OS) | Approximately 3 years | 
| ORR | To assess the objective response rate (ORR) | Approximately 1.5 years | 
| DOR | To assess the duration of response | Approximately 1.5 years | 
| DCR | To assess the disease control rate | Approximately 1.5 years | 
| CBR | To assess the clinical benefit rate by BICR | Approximately 1.5 years | 
| SAE | To assess the incidence of SAE by Graded according to the National Cancer Institute (NCI CTCAE) | Approximately 3 years | 
| AE | To assess the incidence of AE by Graded according to the National Cancer Institute (NCI CTCAE) | Approximately 3 years | 
| TEAE | To assess the incidence of TEAE by Graded according to the National Cancer Institute (NCI CTCAE) | Approximately 3 years | 
| Cmax | To evaluate the Cmax of GB491 and its metabolites G1T30 | On Day15 of Cycle 1 and Day 1 of Cycle 2-4 (each cycle is 28 days) | 
| Tmax | To evaluate the Tmax of GB491 and its metabolites G1T30 | On Day15 of Cycle 1 and Day 1 of Cycle 2-4 (each cycle is 28 days) | 
| AUC | To evaluate the AUC of GB491 and its metabolites G1T30 | On Day15 of Cycle 1 and Day 1 of Cycle 2-4 (each cycle is 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CDK46, Phase III, GB491