Clinical Trials /

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

NCT04282031

Description:

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.

Related Conditions:
  • Breast Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of BPI-1178 in Patients With Advanced Solid Tumor and HR+/HER2- Breast Cancer
  • Official Title: A Phase 1/2a Study to Evaluate the Tolerability, Safety, Pharmacokinetics and Efficacy of BPI-1178 Alone in Advanced Solid Tumor and of BPI-1178 in Combination With Endocrine Therapy in Advanced HR+/HER2- Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: BPI-1178-2019-001
  • NCT ID: NCT04282031

Conditions

  • Advanced Solid Tumor
  • Breast Neoplasms

Interventions

DrugSynonymsArms
BPI-1178phase 1 (dose escalation)
Fulvestrantphase 2b cohort A
Letrozolephase 2b cohort B

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
phase 1 (dose escalation)ExperimentalParticipants 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.
  • BPI-1178
phase 2b cohort AExperimentalParticipants 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.
  • BPI-1178
  • Fulvestrant
phase 2b cohort BExperimentalParticipants 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.
  • BPI-1178
  • Letrozole

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:phase 1 and 2a: Number of subjects with dose limiting toxicity (DLT)
Time Frame:Up to Day 28 of Cycle 1 (28 days/cycle)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:phase 1 and 2a: Number of subjects with adverse events
Time Frame:Up to 30 days after the last dose of BPI-1178
Safety Issue:
Description:
Measure:phase 1: Objective response rate (ORR)
Time Frame:Up to approximately 18 months
Safety Issue:
Description:
Measure:Phase 1 and 2a: Maximum plasma concentration (Cmax) of BPI-1178 and its main metabolites
Time Frame:From single dosing in phase 1 or from baseline in phase 2a to the end of Cycle 1 (28 days/cycle)
Safety Issue:
Description:
Measure:Phase 1 and 2a: Peak Plasma Time (Tmax) of BPI-1178 and its main metabolites
Time Frame:From single dosing in phase 1 or from baseline in phase 2a to the end of Cycle 1 (28 days/cycle)
Safety Issue:
Description:
Measure:Phase 1 and 2a: Area under the plasma concentration versus time curve (AUC) of BPI-1178 and its main metabolites
Time Frame:From single dosing in phase 1 or from baseline in phase 2a to the end of Cycle 1 (28 days/cycle)
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Beta Pharma (Suzhou) Co., Ltd.

Last Updated

February 20, 2020