neoplasms, in addition to the above: small cell lung cancer, BRCA1/2 wild type ovarian cancer advanced solid tumours cancer
Conditions
Interventions
Study Drug: includes Investigational [Medicinal] Products (IP/IMP) as listed:
BMS-986158 is formulated as a hard gelatin capsule partially filled with a
white to off-white waxy, semi-solid to
solid d
advanced solid tumours
Sponsors
Bristol-Myers Squibb
Eligibility
Age
18 Years to 64 Years
Inclusion criteria
Inclusion criteria: 1. Signed Written Informed Consent a) The subject must sign the informed consent form prior to the performance of any study related procedures that are not considered part of standard of care. 2. Target Population a) Subjects must have a confirmed histologic/cytologic diagnosis of one of the following preferred malignancies for participation in the study and meet the other criteria listed (a specific exception for disease diagnosis criteria is noted in inclusion criteria k) i) Ovarian cancer (1) Histological or cytological documented epithelial ovarian cancer, primary peritoneal carcinoma, or fallopian tube cancer. (2) Received at least one prior Platinum Based Therapy (PBT) regimen. (3) Have platinum-resistant/refractory disease, be intolerant of platinum-containing compounds, and/or have hypersensitivity to platinum-containing compounds. (4) For Part 2A Expansion only: All subjects must have serous histology and have germline wild-type BRCA1 and BRCA2 ii) Triple negative breast cancer (TNBC) (1) Women with histological or cytological confirmed triple negative breast carcinoma as defined by ASCO/CAP guidelines. (2) Had progression or refractory disease during or after at least 1 chemotherapy regimen for the treatment of metastatic or locally advanced disease. iii) Small cell lung cancer (SCLC) ;(1) Histologically or cytologically documented SCLC, limited or extensive stage disease. (2) Received at least one prior Platinum Based Therapy (PBT) regimen.;b) Subjects with controlled, treated brain metastasis fulfilling all the following criteria may be screened: no radiographic progression for at least 2 weeks following radiation and/or surgical treatment, off steroids for at least 2 weeks, without new or progressing neurological signs or symptoms. c) All subjects must have at least one measurable lesion at baseline by CT or MRI as per RECIST v1.1 d) All subjects must have archival tumor tissue identified and available for correlative biomarker studies (if slides are provided, a minimum of 10 (ten) unstained slides with at least 5 micron thick tissue sections are required) unless a fresh biopsy is provided. All subjects not providing a fresh biopsy must consent to provide tumor blocks or slides to the sponsor and the availability of the tissue must be confirmed prior to subjects receiving study medication. If an archived tumor specimen is unavailable or unsuitable for correlative biomarker studies, subjects may consent to a pre-treatment fresh tumor biopsy to be eligible for this study if it can be performed at minimal acceptable clinical risk as judged by the Investigator and if it does not include a target lesion or lesion in an area treated with prior radiation therapy. For the first 25 ovarian subjects enrolled in dose expansion Part 2A, both a pre- treatment and on-treatment fresh biopsy must be provided. e) Subjects must have a life expectancy of at least 3 months. f) Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1 (Appendix 5) g) Subjects who have undergone any major surgery within 4 weeks of study drug administration are excluded. Subjects must have recovered from the effects of major surgery at least 14 days before the first dose of the study drug. h) Prophylactic anticoagulation for venous access devices with low-dose heparin or similar (e.g. heparin catheter flush) will be permitted. i) For anti
Exclusion criteria
Exclusion criteria: 1. Medical History and Concurrent Diseases a) Evidence of uncontrolled, active infection, requiring parenteral anti-bacterial, anti-viral or anti-fungal therapy 2 teaspoonfuls/24hrs or repeated pulmonary hemorrhage, gastrointestinal hemorrhage requiring transfusion or procedural intervention f) Uncontrolled or significant cardiovascular disease including: i) Congestive heart failure NYHA (New York Heart Association) Class 3 or greater within 3 months (Appendix 6). ;ii) History of congenital long QT syndrome or clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation or Torsade de Pointes). Controlled atrial fibrillation is not an exclusion criterion. iii) Active coronary artery disease, unstable or newly diagnosed angina or myocardial infarction in the past 6 months. g) Inability to tolerate oral medication. h) HIV-related disease or known positivity for human immunodeficiency virus (HIV). i) Past or active hepatitis B or C infection. j) Any other sound medical, psychiatric and/or social reason as determined by the investigator. k) Use of strong inhibitors of CYP3A4 or P-gp within 1 week or 5 half-lives (whichever is longer) or strong inducers of CYP3A4 or P-gp within 2 weeks or 5 half-lives (whichever is longer). See Appendix 3;2. Physical and Laboratory Test Findings a) Inadequate bone marrow function defined as: i) Absolute neutrophil count (ANC) 1.5x ULN (or > 2.5 x baseline, if a subject is on a stable dose of therapeutic warfarin) or a PTT > 1.2x upper limit of normal (ULN). c) Inadequate hepatic function defined as: i) Aspartate aminotransferase (AST) > 3x ULN ii) Alanine aminotransferase (ALT) > 3x ULN iii) Total bilirubin > 1.5 x ULN (except known Gilbert*s syndrome, direct bilirubin > 1.5x ULN); d) Inadequate renal function defined as: i) Creatinine clearance (CrCl) <= 50 mL/minute (either measured or calculated using a standard formula such as Cockcroft and Gault) within 14 days prior to randomization e) Any of the following on 12-lead electrocardiogram (ECG) prior to study drug administration, confirmed by repeat.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary Endpoints: Incidence of adverse events (AEs) at its worst grade, serious adverse events (SAEs) at its worst grade, adverse events leading to discontinuations, deaths, frequency of laboratory test toxicity grade shifting from baseline. Safety will be evaluated from the time that the subject signs the informed consent and for up to 30 days after the last dose of study drug or until resolution of any adverse event for which alternative causes could not be identified resolve to | — |
Secondary
| Measure | Time frame |
|---|---|
| - Pharmacokinetics: Select PK parameters including Cmax, Cmin, Tmax, AUC (TAU), AUC(0-T), will be derived from parent (BMS-986158) and metabolite plasma concentration versus time data for all schedules. In addition parameters specific to single dose only, if data permits, (T-HALF, AUC(INF), CLT/F, Vz/F) or multiple dose only (Cmin, Ctau, Ctrough, DF, Swing, AI and T-HALFeff) will be calculated derived from parent (BMS-986158) and metabolite plasma concentration versus time data. The metabolite to parent ratios (MR) will also be calculated for Cmax, AUC(0-T), AUC(INF) and AUC(TAU). - Efficacy: Objective response rate (ORR), Duration of response (DOR), and Progression Free Survival Rate (PFSR) at select times are efficacy endpoints. ORR is defined as the total number of subjects who*s best overall response (BOR) is either a CR or PR, divided by the total number of subjects in the population of interest. Overall survival rate at select times is an exploratory efficacy endpoint. - ECG: Changes in QTcF (ΔQTcF) from baseline at selected times. - Biomarkers for pharmacodynamic assessments: Summary changes from baseline in the expression of BET- regulated genes will be assessed in blood collected at multiple time points after BMS-986158 administration on the first day of dosing and then following multiple dosing schedules. | — |
Countries
The Netherlands
Outcome results
None listed