A Study of BPI-1178 in Patients With Advanced Solid Tumor and HR+/HER2- Breast Cancer

  • STATUS
    Recruiting
  • End date
    Mar 15, 2024
  • participants needed
    122
  • sponsor
    Beta Pharma (Suzhou) Co., Ltd.
Updated on 8 August 2021
cancer
measurable disease
breast cancer
growth factor
endocrine therapy
international normalized ratio
neutrophil count
hormone therapy
epidermal growth factor receptor
HER2
EGFR
aptt
thromboplastin
solid tumour
fulvestrant
erbb2
epidermal growth factor
letrozole
immunostimulant
mammogram
her2/neu-negative breast cancer
advanced malignant solid tumor

Summary

BPI-1178 is a novel, orally administered inhibitor of both cyclin-dependent kinase 4CDK4and 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.

Description

This is a study which consists of phase studydose 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.

Details
Condition breast tumor, breast tumors, Advanced Malignant Solid Tumor, Breast Cancer, Advanced Solid Tumor, tumor of the breast
Treatment Letrozole, fulvestrant, BPI-1178
Clinical Study IdentifierNCT04282031
SponsorBeta Pharma (Suzhou) Co., Ltd.
Last Modified on8 August 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Have given written informed consent prior to any study specific procedures
Male or female, aged 18 years
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
At least 1 measurable lesion based on the RECIST v1.1 criteria
Life expectancy 12 weeks
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)1
Adequate bone marrow and organ function, defined as following
absolute neutrophil count1.510^9/L, platelets10010^9/L, hemoglobin100 g/L
total bilirubin1.5ULN(3ULN for Gilbert syndrome), alanine aminotransferase and aspartate aminotransferase3ULN
serum creatinine1.5ULN or a creatinine clearance calculated by Cockcroft-Gault formula50 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
activated partial thromboplastin time and international normalized ratio1.5ULN
LVEF50%
Corrected QT interval (QTcF)<450ms for men and <470ms for women at resting
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
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

Currently receiving or have received any CDK4/6 inhibitors
Have had allergies or history of severe allergies
Have participated in any clinical trials within 4 weeks prior to the dosing of BPI-1178
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)
Any toxicity related to previous treatment before enrollment defined by CTCAE (v5.0) Grade2 (except hair loss)
Presence of third interstitial fluid that cannot be controlled by drainage or other methods (such as large amounts of pleural fluid and ascites)
Requiring long-term treatment of steroid
Having uncorrectable hypokalemia and hypomagnesemia at enrollment
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
Have active infection, such as hepatitis B (HBsAg positive and hepatitis B virus DNA110^3 copy/ml), hepatitis C and human immunodeficiency virus (HIV) infection
Have a history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation
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)
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
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
Have had major surgery (craniotomy, thoracotomy, or laparotomy) or unhealed wounds, ulcers, or fractures within 4 weeks prior to the dosing of BPI-1178
Pregnant or lactating women, or fertile women with pregnancy test positive at baseline
Any factors that may endanger subject's safety and may affect subject's compliance with the study
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
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