A Phase I/IIa Trial With BMS-986158, a Small Molecule Inhibitor of the Bromodomain and;Extra-Terminal (BET) Proteins, in Subjects with Selected Advanced Solid Tumors
- Conditions
- neoplasms, in addition to the above: small cell lung cancer, BRCA1/2 wild type ovarian canceradvanced solid tumourscancer10006291
- Registration Number
- NL-OMON46213
- Lead Sponsor
- Bristol-Myers Squibb
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Pending
- Sex
- Not specified
- Target Recruitment
- 12
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
1. Medical History and Concurrent Diseases
a) Evidence of uncontrolled, active infection, requiring parenteral anti-bacterial, anti-viral or anti-fungal therapy < 7 days prior to administration of study medication
b) Current or recent (within 3 months of study drug administration) gastrointestinal disease such as chronic or intermittent diarrhea, or disorders that increase the risk of diarrhea, such as inflammatory bowel disease. Non-chronic conditions (e.g. infectious diarrhea) that are completely resolved for at least 2 weeks prior to starting study treatment are not exclusionary
c) Subjects with concomitant second malignancies (except adequately treated non- melanomatous skin cancers or in situ bladder, breast or cervical cancers) are excluded unless a complete remission was achieved at least 3 years prior to study entry and no additional therapy is required or anticipated to be required during the study period
d) Conditions requiring chronic systemic glucocorticoid use, such as autoimmune disease or severe asthma
e) History of medically significant thromboembolic events or bleeding diathesis within the past 6 months, such as cerebrovascular accident (including transient ischemic attacks), pulmonary embolism, pulmonary hemorrhage > 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) < 1,500 cells/mm3;
ii) Platelet count < 100,000 cells/mm3;
iii) Hemoglobin < 8 g/dL
b) Abnormal blood coagulation parameters:
i) PT such that international normalized ratio (INR) is > 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.
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Primary Endpoints: Incidence of adverse events (AEs) at its worst grade,<br /><br>serious adverse events (SAEs) at its<br /><br>worst grade, adverse events leading to discontinuations, deaths, frequency of<br /><br>laboratory test toxicity grade shifting<br /><br>from baseline. Safety will be evaluated from the time that the subject signs<br /><br>the informed consent and for up to<br /><br>30 days after the last dose of study drug or until resolution of any adverse<br /><br>event for which alternative causes could<br /><br>not be identified resolve to <= Grade 1 or baseline or until the event has<br /><br>stabilized, whichever is longer.</p><br>
- Secondary Outcome Measures
Name Time Method