A Study of BPI-1178 in Patients With Advanced Solid Tumor and HR+/HER2- Breast Cancer
A Study of BPI-1178 in Patients With Advanced Solid Tumor and HR+/HER2- Breast Cancer
BPI-1178 is a novel, orally administered inhibitor of both cyclin-dependent kinase 4（CDK4）and
 CDK6 kinase activity. The purpose of this study is to evaluate the safety, efficacy and
 pharmacokinetics of BPI-1178 in subjects with advanced solid tumor, as well as the subjects
 with advanced hormone receptor-positive(HR+)/human epidermal growth factor receptor 2
 negative (HER2-) breast cancer.
This is a study which consists of phase １study（dose escalation stage) and phase 2a study
 (expansion stage)．

 Phase 1 study will adopt the classical 3+3 dose escalation design, exploring the safety and
 tolerance of 5 dose cohorts (25mg, 75mg, 150mg, 250mg and 400mg) in subjects with advanced
 solid tumor and determining the maximum tolerated dose of BPI-1178 for phase 2a study.

 Phase 2a is an expansion 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 first-line standard therapy. Cohort B is BPI-1178 in
 combination with letrozole for advanced or recurrent HR+/HER2- breast cancer 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). Subjects will receive
 BPI-1178 daily for 3 weeks, followed by 1 week-off treatment. Once the maximum tolerated dose
 (MTD) is reached in phase 1, phase 2a study will explore the dose of BPI-1178 from MTD to
 MTD-1 and MTD-2 level in combination with fulvestrant or letrozole.

 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.
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.

 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 last dose of anti-cancer treatment (chemotherapy, endocrine therapy,
 targeted therapy, immunotherapy or embolization therapy, etc.) within 4 weeks prior to
 the dosing of BPI-1178; have received last dose of biological products (if endocrine
 therapy, within 4 weeks prior to the dosing of BPI-1178), nitrosourea or mitomycin C
 within 6 weeks prior to the dosing of BPI-1178; (except GnRHa treatment for
 pre/peri-menopausal subjects in phase 2a study).

 5. Any toxicity related to previous treatment before enrollment defined by CTCAE (v5.0)
 Grade≥2 (except hair loss).

 6. Presence of third interstitial fluid that cannot be controlled by drainage or other
 methods (such as large amounts of pleural fluid and ascites).

 7. Requiring long-term treatment of steroid.

 8. Having uncorrectable hypokalemia and hypomagnesemia at enrollment.

 9. Any of the following criteria: any cardiac rhythm and conduction abnormalities with
 clinical significance, such as atrial fibrillation, complete left bundle branch block,
 3rd-degree atrioventricular block, 2nd-degree atrioventricular block, PR
 interval>250ms; any risk of QT interval prolongation and arrhythmia, such as
 symptomatic heart failure-New York Heart Association (NYHA) grades II～ IV, congenital
 long QT syndrome, Brugada syndrome, history of QT interval prolongation (male>470ms,
 female>480ms) or history of torsade de pointes, family history of long QT syndrome or
 sudden death with unknown cause before 40 years old in the first-degree relatives, any
 concomitant medications that may prolong QT interval; any following diseases within 6
 months prior to the dosing of BPI-1178: unstable angina pectoris, myocardial
 infarction, coronary heart disease, cerebrovascular events, pulmonary embolism, or
 cardiac revascularization,etc..

 10. Have active infection, such as hepatitis B (HBsAg positive and hepatitis B virus
 DNA≥1×10^3 copy/ml), hepatitis C and human immunodeficiency virus (HIV) infection.

 11. Have a history of allogeneic organ transplantation and allogeneic hematopoietic stem
 cell transplantation.

 12. Any factors, in the judgment of the investigator, that may affect the administration
 and absorption of BPI-1178 (for example, uncontrolled inflammatory gastrointestinal
 diseases, abdominal fistula or gastrointestinal perforation within 6 months, extensive
 resection of small intestinal, with tube feeding or parenteral nutrition, inability to
 swallow, chronic diarrhea, and intestinal obstruction).

 13. Have spinal cord compression, metastases of the meninges, or brain metastases with
 obvious symptoms. The following cases of brain metastases without symptoms can be
 enrolled: brain metastases without obvious symptoms diagnosed at screening visit,
 steroids and/or local treatment not required judged by investigator; brain metastases
 without obvious symptoms after local treatment (such as radiotherapy), and steroids
 and/or antiepileptic therapy has stopped for at least 7 days before the first dosing
 of BPI-1178.

 14. In the judgment of the investigator, have a concomitant disease (such as severe
 hypertension, diabetes, thyroid disease, severe infection, portal hypertension,
 cirrhosis, etc.) that would endanger the subjects' safety or affect the completion of
 the study.

 15. Have had major surgery (craniotomy, thoracotomy, or laparotomy) or unhealed wounds,
 ulcers, or fractures within 4 weeks prior to the dosing of BPI-1178.

 16. Pregnant or lactating women, or fertile women with pregnancy test positive at
 baseline.

 17. Any factors that may endanger subject's safety and may affect subject's compliance
 with the study.

 18. Drug abuse, alcoholic addiction, medical and mental illness and social barriers judged
 by investigator, which may interfere the subjects' participation in the study or
 affect the evaluation of study endpoints . Any factor that investigator believes may
 make the subjects not suitable to receive BPI-1178. Subjects are unwilling or unable
 to comply with the requirements of the study protocol.