A Study of BPI-1178 in Patients With Advanced Solid Tumor and HR+/HER2- Breast Cancer
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1/Phase 2 |
Detailed Description
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: phase 1 (dose escalation) Participants will first receive single dose BPI-1178 orally at dose levels of 25mg, 75mg, 150mg, 250mg and 400mg followed by a 7-day washout period , and then start receiving the 28 days/cycle continuous treatment until disease progression or unacceptable toxicity. |
Drug: BPI-1178
BPI-1178 once daily on Days 1 to 21 of a 28-day cycle
|
| Experimental: phase 2a cohort A Participants will receive BPI-1178 at dose levels of MTD, MTD-1 or MTD-2 in combination with fulvestrant for 3 weeks followed by 1 week off as a treatment cycle, until disease progression or unacceptable toxicity. |
Drug: BPI-1178
BPI-1178 once daily on Days 1 to 21 of a 28-day cycle
Drug: Fulvestrant
Fulvestrant 500mg intramuscularly on Days 1 and 15 of Cycle 1, and on Day 1 of Cycle 2 and beyond
|
| Experimental: phase 2a cohort B Participants will receive BPI-1178 at dose levels of MTD, MTD-1 or MTD-2 in combination with letrozole for 3 weeks followed by 1 week off as a treatment cycle, until disease progression or unacceptable toxicity. |
Drug: BPI-1178
BPI-1178 once daily on Days 1 to 21 of a 28-day cycle
Drug: Letrozole
Letrozole 2.5 mg once daily of a 28-day cycle
|
Outcome Measures
Primary Outcome Measures
- phase 1 and 2a: Number of subjects with dose limiting toxicity (DLT) [Up to Day 28 of Cycle 1 (28 days/cycle)]
- phase 1: Maximum tolerated dose (MTD) [Up to Day 28 in Cycle 1 (28 days/cycle)]
- phase 2a: Objective response rate (ORR) [Up to approximately 18 months]
Secondary Outcome Measures
- phase 1 and 2a: Number of subjects with adverse events [Up to 30 days after the last dose of BPI-1178]
- phase 1: Objective response rate (ORR) [Up to approximately 18 months]
- Phase 1 and 2a: Maximum plasma concentration (Cmax) of BPI-1178 and its main metabolites [From single dosing in phase 1 or from baseline in phase 2a to the end of Cycle 1 (28 days/cycle)]
- Phase 1 and 2a: Peak Plasma Time (Tmax) of BPI-1178 and its main metabolites [From single dosing in phase 1 or from baseline in phase 2a to the end of Cycle 1 (28 days/cycle)]
- Phase 1 and 2a: Area under the plasma concentration versus time curve (AUC) of BPI-1178 and its main metabolites [From single dosing in phase 1 or from baseline in phase 2a to the end of Cycle 1 (28 days/cycle)]
Other Outcome Measures
- Clearance of BPI-1178 and its main metabolites [From single dosing in phase 1 or from baseline in phase 2a to the end of Cycle 1 (28 days/cycle)]
- Half life of BPI-1178 and its main metabolites [From single dosing in phase 1 or from baseline in phase 2a to the end of Cycle 1 (28 days/cycle)]
- Disease control rate ( DCR) [Up to approximately 18 months]
- Duration of response ( DoR) [Up to approximately 18 months]
- Progression free survival (PFS) [Up to approximately 18 months]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Have given written informed consent prior to any study specific procedures.
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Male or female, aged ≥18 years.
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Subjects with advanced solid tumors:
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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.
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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.
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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.
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At least 1 measurable lesion based on the RECIST v1.1 criteria.
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Life expectancy≥ 12 weeks.
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Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)≤1.
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Adequate bone marrow and organ function, defined as following:
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absolute neutrophil count≥1.5×109/L, platelets≥100×109/L, hemoglobin≥100 g/L;
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total bilirubin≤1.5×ULN(≤3×ULN for Gilbert syndrome), alanine aminotransferase and aspartate aminotransferase≤3×ULN;
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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;
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activated partial thromboplastin time and international normalized ratio≤1.5×ULN;
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LVEF≥50%;
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Corrected QT interval (QTcF)<450ms for men and <470ms for women at resting.
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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.
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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:
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Currently receiving or have received any CDK4/6 inhibitors.
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Have had allergies or history of severe allergies.
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Have participated in any clinical trials within 4 weeks prior to the dosing of BPI-1178.
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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).
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Any toxicity related to previous treatment before enrollment defined by CTCAE (v5.0) Grade≥2 (except hair loss).
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Presence of third interstitial fluid that cannot be controlled by drainage or other methods (such as large amounts of pleural fluid and ascites).
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Requiring long-term treatment of steroid.
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Having uncorrectable hypokalemia and hypomagnesemia at enrollment.
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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..
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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.
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Have a history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation.
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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).
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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.
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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.
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Have had major surgery (craniotomy, thoracotomy, or laparotomy) or unhealed wounds, ulcers, or fractures within 4 weeks prior to the dosing of BPI-1178.
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Pregnant or lactating women, or fertile women with pregnancy test positive at baseline.
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Any factors that may endanger subject's safety and may affect subject's compliance with the study.
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Fudan University Shanghai Cancer Center | Shanghai | Shanghai | China | 200032 |
Sponsors and Collaborators
- Beta Pharma (Suzhou) Co., Ltd.
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- BPI-1178-2019-001