Overview
BPI-1178 is a novel, orally administered inhibitor of both cyclin-dependent kinase 4（CDK4）and CDK6 kinase activity. This Phase I study is a first-in-human (FIH) clinical trial designed to evaluate the safety, tolerability, and pharmacokinetic (PK) profile of oral BPI-1178 in patients with advanced solid tumors. The Phase IIa trial is designed to investigate the anti-tumor activity and safety of BPI-1178 in combination with endocrine therapy in patients with HR+/HER2-advanced breast cancer and to determine the dosing regimen for combination with endocrine therapy in a later confirmatory study.
Description
This is a study which consists of phase １study（dose-escalation study、dose-expansion study and PK trial） and phase 2a study.
Phase 1 study will adopt the classical 3+3 dose escalation design, exploring the safety and tolerance of 6 dose cohorts (25mg, 75mg, 150mg, 250mg, 400mg and 500mg) in subjects with advanced solid tumor and determining the maximum tolerated dose of BPI-1178 for phase 2a study.
Phase 2a is an open-label clinical study in subjects of HR+/HER2- breast cancer using 3+3 design, to evaluate the efficacy and safety of BPI-1178 in combination with endocrine therapy. Cohort A is BPI-1178 in combination with fulvestrant for advanced or recurrent HR+/HER2- breast cancer after failure or intolerance of non-fulvestrant first-line endocrine therapy. Cohort B is BPI-1178 in combination with letrozole for advanced or relapse more than 1 year after the end of adjuvant endocrine therapy as first-line treatment.
Phase 1 and 2a consist of screening period (28 days before enrollment), treatment period and follow up period (every 3 months until death or the end of study). Phase 1 study: Subjects in each dose group will first receive a single dose. After a single dose for washout period, if the subject has no dose-limiting toxicity (DLT) related to the investigational product, the subject will enter the continuous dose cycle and receive continuous dose in a 28-day treatment cycle (single daily dose for 3 consecutive weeks/drug withdrawal for 1 week) .Once the maximum tolerated dose (MTD) is reached in phase 1, phase 2a study will explore the dose of BPI-1178 from MTD in combination with fulvestrant or letrozole. Phase 2a study: Subjects in Cohort A and Cohort B with intermittent dosing (3-week continuous dosing followed by 1-week rest) and continuous dosing (28-day continuous dosing) will be received in combination with fulvestrant or letrozole. Each 28-day is a complete treatment cycle during the concomitant-drug period.
Dose limiting toxicity (DLT) will be recorded for the single dose period of 7 days and the multiple dose period up to 28 days in phase 1 study, as well as 28 days after the first dose of BPI-1178 in phase 2a. Efficacy will be evaluated by RECIST v1.1 and the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) every 2 months. Adverse events will be monitored throughout the trial. Other exploration of pharmacokinetic information will be assessed throughout the trial.
Eligibility
Inclusion Criteria:
1. Have given written informed consent prior to any study specific procedures.
2. Male or female, aged ≥18 years.
3. Subjects with advanced solid tumors:
* Phase 1: Histologically or cytologically confirmed, locally advanced (not amenable to curative treatment of surgical resection or radiation therapy), recurrent, or metastatic solid tumors that were refractory to standard therapy or for which no standard-of-care therapy.
* Phase 2a Cohort A: HR+/HER2- locally advanced, recurrent, or metastatic breast cancer with disease progression after first-line endocrine therapy (not fulvestrant) or intolerant of it, histologically confirmed by the primary and/or metastatic lesions, not amenable to chemotherapy or curative treatment of surgical resection or radiation therapy; if the pathology of the primary and metastatic lesions are inconsistent, diagnosis should be based on metastatic lesions' pathology.
* Phase 2a Cohort B: HR+/HER2- locally advanced, recurrent, or metastatic breast cancer with no prior systemic therapy in this disease setting or relapse more than 1 years from completion of adjuvant endocrine therapy, histologically confirmed by the primary and/or metastatic lesions, not amenable to chemotherapy or curative treatment of surgical resection or radiation therapy; if the pathology of the primary and metastatic lesions are inconsistent, diagnosis should be based on metastatic lesions' pathology.
* Female patients with breast cancer at Phase IIa must also meet the following criteria:
(1) Postmenopausal patients must meet at least one of the following criteria:
1. Age ≥ 60 years old;
2. Patients \< 60 years of age who have menstruation ceased for at least 12 consecutive months and have not received chemotherapy, tamoxifen, toremifene or ovarian function inhibitors, and have blood estrogen and FSH levels within the reference range for postmenopausal women;
3. Previous bilateral ovariectomy;
4. Patients \< 60 years of age who are being treated with tamoxifen or toremifene with blood estrogen and FSH levels within the reference range for postmenopausal women.
(2) Premenopausal/perimenopausal patients must meet the following criteria: Premenopausal/perimenopausal patients requiring ovarian function suppression must start treatment at least 4 weeks prior to enrollment and the treatment should be maintained during the trial.
4. At least 1 measurable lesion based on the RECIST v1.1 criteria.
5. Life expectancy≥ 12 weeks.
6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)≤1.
7. Adequate bone marrow and organ function, defined as following:
1. absolute neutrophil count≥1.5×10\^9/L, platelets≥100×10\^9/L, hemoglobin≥100 g/L;
2. total bilirubin≤1.5×ULN(≤3×ULN for Gilbert syndrome), alanine aminotransferase and aspartate aminotransferase≤3×ULN;
3. serum creatinine≤1.5×ULN or a creatinine clearance calculated by Cockcroft-Gault formula≥50 mL/min; urinary protein measured by semi-quantitative method\<2+; if urinary protein measured by semi-quantitative method at baseline ≥2+, 24-h urinary protein\<1g;
4. activated partial thromboplastin time and international normalized ratio≤1.5×ULN;
5. LVEF≥50%;
6. Corrected QT interval (QTcF)\<450ms for men and \<470ms for women at resting.
8. Female subjects should take effective contraceptive methods during the study and for 60 days after the last dose of BPI-1178, and must have a negative pregnancy test prior to dosing if of child-bearing potential, or must have evidence of non-child-bearing potential; male subjects should take effective contraceptive methods during the study and for 120 days after the last dose of BPI-1178.
9. All subjects must have enough mental behavior ability, understand the nature and significance of the study, as well as the risks associated with the study.
Exclusion Criteria:
1. Currently receiving or have received any CDK4/6 inhibitors.
2. Have had allergies or history of severe allergies.
3. Have participated in any clinical trials within 4 weeks prior to the dosing of BPI-1178.
4. Have received anti-tumor therapy (including chemotherapy, endocrine therapy, targeted therapy, immunotherapy, tumor embolization, etc.; have received radiotherapy within 2 weeks before taking the investigational product) within 4 weeks before starting to take the investigational product \