| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Serious ovarian cancer with wild-type BRCA1/2, triple negative breast cancer and small cell lung cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Ovarian cancer, breast cancer and small cell lung cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10041067 |
| E.1.2 | Term | Small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10075566 |
| E.1.2 | Term | Triple negative breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033128 |
| E.1.2 | Term | Ovarian cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the safety and tolerability and to define the dose limiting toxicities (DLT) and maximum tolerated dose (MTD) of BMS-986158 as monotherapy for subjects with selected advanced solid tumors. |
|
| E.2.2 | Secondary objectives of the trial |
-) To assess the preliminary anti-tumor activity of BMS-986158 as measured by objective response rate (ORR), and response duration based on RECIST v1.1.
-) To characterize pharmacokinetics of BMS-986158 and metabolite in monotherapy.
-) To assess pharmacodynamic changes in the expression of selected BET regulated genes in peripheral blood.
-) To assess the dose-response and exposure-response effect on the ECG (QT interval) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed Written Informed Consent
2. Target Population
a) Subjects with 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 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
(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
iii) Small cell lung cancer
(1) Histologically or cytologically documented SCLC.
(2) Received at least one prior Platinum Based Therapy 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 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 pretreatment 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.
g) Subjects who have undergone any major surgery within 4 weeks are excluded. Subjects must have recovered from the effects of major surgery at least 14 days before first dose.
h) Prophylactic anticoagulation for venous access devices with low-dose heparin or similar (e.g. heparin catheter flush) will be permitted.
i) For antiplatelet agents, prophylactic doses are permitted (e.g. aspirin < 300 mg daily, clopidogrel < 75 mg daily)
j) This study permits the re-enrollment of a subject that has discontinued the study as a pre treatment failure. If re-enrolled, the subject must re-consent.
3. Previous Treatment
a) Prior anti-cancer treatments [therapeutic or diagnostic] are permitted.
b) All acute toxicities, from any prior therapy must have resolved to Grade ≤ 1, NCI CTCAE, version 4.03 or to baseline if irreversible.
c) Concomitant therapy with biophosphates is acceptable
4. Age and Reproductive Status
a) Males and Females, ages 18 years of age or greater
b) Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test during screening and within 24 hours prior to the start of study drug.
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug (s) BMS-986158 plus 30 days (duration of ovulatory cycle) for a total of 30 days post-treatment completion.
e) Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug (s) BMS-986158 plus 90 days (duration of sperm turnover) for a total of 90 days posttreatment completion.
f) Azoospermic males are exempt from contraceptive requirements. |
|
| E.4 | Principal exclusion criteria |
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. 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 nonmelanomatous
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
f) Uncontrolled or significant cardiovascular disease including:
i) Congestive heart failure NYHA (New York Heart Association) Class 3 or greater within 3 months.
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).
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 drugadministration, confirmed by repeat.
i) QRS ≥ 120 msec, except right bundle branch block
ii) QTcF > 450 msec
3. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
c) Inability to comply with restrictions and prohibited activities/treatments as listed in protocol.
d) Women who are pregnant.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study subjects and that the results of the study can be used. It is imperative that subjects fully meet all eligibility criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary objective which is to assess the safety and tolerability and to define the dose limiting
toxicity and MTD of BMS-986158) will be measured by the primary endpoint(s) of: 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.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 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 ≤ Grade 1 or baseline or until the event has stabilized, whichever is longer. |
|
| E.5.2 | Secondary end point(s) |
The endpoint(s) used to measure efficacy, PK, biomarker (pharmacodynamic) and ECG objectives are described below:
1) Efficacy will be based on RECIST v1.1 for solid tumors using the following secondary endpoints:
Best overall response (BOR),
Objective Response Rate (ORR),
Duration of Response,
Progression Free Survival (PFS)
Progression Free Survival Rate (PFSR) at week ‘t’: defined as the proportion of subjects who
remain progression free and surviving at ‘t’ weeks (t=12, 24).
2) Pharmacokinetics
Pharmacokinetics of BMS-986158 (parent and metabolite, as data permits) will be derived from
plasma concentration versus time
3) Pharmacodynamic Biomarkers
Summary changes from baseline in the expression of BET regulated genes
4) ECG/QTc
Changes in QTcF, (ΔQTcF) from baseline, at selected times. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
PK and QTc: Tables 5.5.1-4, 5.5.1-5 and 5.5.1-6 (pages 108-110 of protocol) detail time points
PD: Tables 5.6.4, 5.6.5 and 5.6.6 (pages 115-118 of protocol) detail time points
Treatment Arm A of Part 1A and Part 2A:
-CT scans done every 8 weeks ± 1 week
Treatment Arm B of Part 1A and Part 2A:
-CT scans done every 9 weeks ± 1 week
Treatment Arm C of Part 1A and Part 2A:
-CT scans done every 9 weeks ± 1 week
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belgium |
| Canada |
| Netherlands |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of the study will occur after the last treated subject completes their Clinical Follow-up, unless if a subject discontinues prematurely.
The Clinical Follow-Up visits will occur approximately 30 days after the subject discontinues study treatment.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 23 |
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