A Phase I, Open, Multicenter Study of BEBT-209 in Women With Advanced Breast Cancer
Overview
- Phase
- Phase 1
- Status
- Active, not recruiting
- Sponsor
- BeBetter Med Inc
- Enrollment
- 106
- Locations
- 2
- Primary Endpoint
- MTD
Overview
Brief Summary
This clinical study includes a dose escalation trial of BEBT-209 monotherapy in HR +/HER2- advanced breast cancer patients and a Phase 1b trial of BEBT-209 as a single therapy, in combination with letrozole, and in combination with fulvestrant in ER +/HER2- advanced breast cancer in women. To evaluate the safety, tolerability, pharmacokinetic profile, and preliminary efficacy of BEBT-209 as a single therapy, in combination with letrozole, and in combination with fulvestrant. To determine the recommended dose for late clinical studies of monotherapy or combination therapy in patients with HR +/HER2- advanced breast cancer.
Detailed Description
- Dose escalation phase: To conduct approximately 6 dose levels, with a starting dose of 25 mg/day of BEBT-209, and subsequent dose groups were first dose escalated at 100%, with dose escalation at 50% for subsequent dose groups if one drug-related Grade 2 nonhematologic or Grade 3 hematologic toxicity was identified and dose-limiting toxicity was not reached. If one dose limiting toxicity was identified and the maximum tolerated dose was not reached, dose escalation was performed at 33% for the subsequent dose groups.
- Phase Ib of BEBT-209 as single therapy, in Combination with Letrozole, in Combination with Fulvestrant: According to the pharmacokinetics, safety and preliminary efficacy of BEBT-209 in the dose escalation phase, one dose was selected for the BEBT-209 monotherapy group, two doses were selected for the combination with letrozole group, and two doses were selected for the combination with fulvestrant group, and all five groups were continuously administered until disease progression or unacceptable toxicity or patient withdrawal or death. Late phase clinical trials were conducted as appropriate based on preliminary safety tolerability, pharmacokinetics, and preliminary efficacy results from Phase 1b.
Participants will need to understand the requirements and risks of the trial, sign an informed consent form, accept the dosing regimen required by the trial protocol, and follow the investigator's guidance.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- Female
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Age: ≥18 years old;
- •Confirmed HR +/HER2- breast cancer in women with evidence of focal recurrence or metastasis not amenable to curative surgical resection or radiation therapy.
- •Menstrual status:
- •3.1 Subjects enrolled in the dose escalation phase, Phase Ib combined with letrozole, combined with fulvestrant first-line therapy were required to be female patients who achieved menopausal status or were treated with LHRH agonists; 3.2 Subjects enrolled in Phase Ib monotherapy and combined fulvestrant second-line/third-line therapy are required to be postmenopausal, premenopausal/ perimenopausal, and amenorrheic women;
- •Menopausal status(note 2) is defined as having met any of the following:
- •Prior bilateral oophorectomy;
- •Age≥ 60 years old
- •Age \< 60 years, Spontaneous amenorrhea ≥ 12 months and blood follicle-stimulating hormone (FSH) and estradiol (E2) levels within the postmenopausal range (in conjunction with reference ranges at each site) in the absence of chemotherapy, tamoxifen, toremifene, or ovarian castration within the past year;
- •Patients \< 60 years of age who were taking tamoxifen or toremifene had blood follicle-stimulating hormone (FSH) and estradiol (E2) levels within the postmenopausal range on two consecutive occasions (in conjunction with reference ranges at each site);
- •Not meeting the above criteria for menopause is considered premenopausal or perimenopausal; Note 2:Premenopausal/perimenopausal female patients agree to use concomitant luteinizing hormone-releasing hormone (LHRH agonist) and start treatment with LHRH agonist at least 28 ± 2 days before the start of the first dose of study drug can be considered to meet inclusion criteria 3.1 (if LHRH agonist has been used for ≥ 21 days but \< 26 days before the first dose, hormone levels are eligible can be considered to meet inclusion criteria 3.1) ;
Exclusion Criteria
- •combined with any other malignancy (except adequately treated basal cell or squamous cell skin cancer or cervical carcinoma in situ).
- •symptomatic, advanced patients who have disseminated to the viscera and are at risk of life-threatening complications in the short term (patients with visceral crisis); inflammatory breast cancer.
- •Known or symptomatic active CNS metastases characterized by clinical symptoms, cerebral edema, spinal cord compression, carcinomatous meningitis, leptomeningeal disease, and/or progressive growth.
- •Major surgery, chemotherapy, radiation therapy, any investigational agent, or other anticancer therapy within 4 weeks prior to the first dose.
- •Patients who have received the following treatments within 7 days prior to study entry: drugs known to be potent inhibitors/inducers of CYP3A4; drugs known to significantly prolong the QT interval.
- •previous treatment with CDK4/6 inhibitors.
- •Patients previously treated with fulvestrant and everolimus cannot be enrolled in cohorts 4 and
- •QTc interval \> 480 msec (based on the average of three screening electrocardiograms \[ECGs\]); a history or confirmed family history of long QT syndrome; a history of clinically significant ventricular arrhythmias, or current use of antiarrhythmic drugs or a defibrillator device implanted to treat ventricular arrhythmias.
- •Uncontrolled electrolyte disturbances that may affect the effects of QTc prolonging drugs.
- •previous myocardial infarction, severe/unstable angina pectoris, NCICTCAE version 5.0 grade ≥ 2 sustained arrhythmia, atrial fibrillation of any grade, coronary/peripheral artery bypass grafting, symptomatic congestive heart failure, cerebrovascular accident (including transient ischemic attack or symptomatic pulmonary embolism);
Arms & Interventions
Monotherapy group 1
BEBT-209 capsules, 25mg once daily, were administered continuously for 3 weeks and discontinued for 1 week, and 4 weeks were used as a treatment cycle.
Intervention: BEBT-209 capsules (Drug)
Monotherapy group 2
BEBT-209 capsules, 25mg each time, twice daily, were administered continuously for 3 weeks and discontinued for 1 week, and 4 weeks were used as a treatment cycle.
Intervention: BEBT-209 capsules (Drug)
Monotherapy group 3
BEBT-209 capsules, 50mg each time, twice daily, were administered continuously for 3 weeks and discontinued for 1 week, and 4 weeks were used as a treatment cycle.
Intervention: BEBT-209 capsules (Drug)
Monotherapy group 4
BEBT-209 capsules, 75mg each time, twice daily, were administered continuously for 3 weeks and discontinued for 1 week, and 4 weeks were used as a treatment cycle.
Intervention: BEBT-209 capsules (Drug)
Monotherapy group 5
BEBT-209 capsules, 100mg each time, twice daily, were administered continuously for 3 weeks and discontinued for 1 week, and 4 weeks were used as a treatment cycle.
Intervention: BEBT-209 capsules (Drug)
Monotherapy group 6
BEBT-209 capsules, 150mg each time, twice daily, were administered continuously for 3 weeks and discontinued for 1 week, and 4 weeks were used as a treatment cycle.
Intervention: BEBT-209 capsules (Drug)
BEBT-209 combined with the letrozole group 1
BEBT-209 capsules, 100mg each time, twice daily, were administered continuously for 3 weeks and discontinued for 1 week, and 4 weeks were used as a treatment cycle.
Letrozole tablets, 2.5mg each time, once a day for 4 weeks, 4 weeks as a treatment cycle.
Intervention: BEBT-209 capsules (Drug)
BEBT-209 combined with the letrozole group 1
BEBT-209 capsules, 100mg each time, twice daily, were administered continuously for 3 weeks and discontinued for 1 week, and 4 weeks were used as a treatment cycle.
Letrozole tablets, 2.5mg each time, once a day for 4 weeks, 4 weeks as a treatment cycle.
Intervention: Letrozole tablets (Drug)
BEBT-209 combined with the letrozole group 2
BEBT-209 capsules, 75mg each time, twice daily, were administered continuously for 3 weeks and discontinued for 1 week, and 4 weeks were used as a treatment cycle.
Letrozole tablets, 2.5mg each time, once a day for 4 weeks, 4 weeks as a treatment cycle.
Intervention: BEBT-209 capsules (Drug)
BEBT-209 combined with the letrozole group 2
BEBT-209 capsules, 75mg each time, twice daily, were administered continuously for 3 weeks and discontinued for 1 week, and 4 weeks were used as a treatment cycle.
Letrozole tablets, 2.5mg each time, once a day for 4 weeks, 4 weeks as a treatment cycle.
Intervention: Letrozole tablets (Drug)
BEBT-209 combined with the Fulvestrant Group 1
BEBT-209 capsules, 75mg each time, twice daily, were administered continuously for 3 weeks and discontinued for 1 week, and 4 weeks were used as a treatment cycle.
Fulvestrant, injection, 500mg each time, 1 time on day 1 and day 15 of the first cycle, and once on the first day of each cycle from the second cycle, 4 weeks as a treatment cycle
Intervention: BEBT-209 capsules (Drug)
BEBT-209 combined with the Fulvestrant Group 1
BEBT-209 capsules, 75mg each time, twice daily, were administered continuously for 3 weeks and discontinued for 1 week, and 4 weeks were used as a treatment cycle.
Fulvestrant, injection, 500mg each time, 1 time on day 1 and day 15 of the first cycle, and once on the first day of each cycle from the second cycle, 4 weeks as a treatment cycle
Intervention: Fulvestrant (Drug)
BEBT-209 combined with the Fulvestrant Group 2
BEBT-209 capsules, 100mg each time, twice daily, were administered continuously for 3 weeks and discontinued for 1 week, and 4 weeks were used as a treatment cycle.
Fulvestrant, injection, 500mg each time, 1 time on day 1 and day 15 of the first cycle, and once on the first day of each cycle from the second cycle, 4 weeks as a treatment cycle
Intervention: BEBT-209 capsules (Drug)
BEBT-209 combined with the Fulvestrant Group 2
BEBT-209 capsules, 100mg each time, twice daily, were administered continuously for 3 weeks and discontinued for 1 week, and 4 weeks were used as a treatment cycle.
Fulvestrant, injection, 500mg each time, 1 time on day 1 and day 15 of the first cycle, and once on the first day of each cycle from the second cycle, 4 weeks as a treatment cycle
Intervention: Fulvestrant (Drug)
Outcomes
Primary Outcomes
MTD
Time Frame: 4 weeks
Maximum tolerated dose
DLT
Time Frame: 4 weeks
Dose-limiting toxicity
Secondary Outcomes
- ORR(From date of administration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months)
- CBR(From date of administration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months)
- PFS(From date of administration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months)
- DOR(From date of administration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months)
- Cmax(Day 1 and Day 21 of cycle 1 before and within 48 hours after administration (each cycle is 28 days))
- Tmax(Day 1 and Day 21 of cycle 1 before and within 48 hours after administration (each cycle is 28 days))
- t1/2(Day 1 and Day 21 of cycle 1 before and within 48 hours after administration (each cycle is 28 days))
- AUC0-48h(Day 1 and Day 21 of cycle 1 before and within 48 hours after administration (each cycle is 28 days))
- Vd(Day 1 and Day 21 of cycle 1 before and within 48 hours after administration (each cycle is 28 days))
- AUC0-last(Day 1 and Day 21 of cycle 1 before and within 48 hours after administration (each cycle is 28 days))
- CL/F(Day 1 and Day 21 of cycle 1 before and within 48 hours after administration (each cycle is 28 days))