| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Solid tumors and hematologic malignancies |
|
| E.1.1.1 | Medical condition in easily understood language |
| Solid tumors and hematologic cancers |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066481 |
| E.1.2 | Term | Hematological malignancy |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part 1: To assess the safety and tolerability and to define the dose limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D) of BMS-986158 as monotherapy for subjects with selected advanced solid tumors and hematologic malignancies.
Part 2: To assess the safety and tolerability and to define the DLT and RP2D of BMS-986158 in combination
with nivolumab for subjects with advanced solid tumors and hematologic malignancies. |
|
| E.2.2 | Secondary objectives of the trial |
To assess the preliminary antitumor activity of BMS-986158 monotherapy and in combination with nivolumab as measured by objective response rate (ORR), and response duration based on response evaluation criteria in solid tumors using criteria from RECIST v1.1, prostate cancers using PCWG3 criteria, or hematologic malignancies
using criteria from Lugano 2014.
To characterize pharmacokinetics of BMS-986158 and metabolite in monotherapy and in combination with nivolumab.
To assess the dose-response and exposure-response effect of BMS- 986158 monotherapy on the ECG (QT interval). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed Written IC
2. Target Population
a) Subjects must have a confirmed histologic or cytologic diagnosis of
one of the following malignancies for participation in the study:
Ovarian cancer
Triple negative breast cancer
Part 1 only: Small cell lung cancer
Part 2 only: Non-Small cell lung cancer
Part 2 only: Renal cell carcinoma
Part 2 only: Uveal melanoma
Part 2 only: Uterine carcinosarcoma
Part 2 only: Neuroendocrine prostate cancer
Part 2 only: Castration-resistant prostate cancer
Part 2 only: NUT-midline carcinoma
Part 2 only: Ewing sarcoma
Part 2 only: Burkitt's lymphoma/leukemia
Part 2 only: Double-hit lymphoma
Part 2 only: adolescent subjects with malignancies harboring genetic abnormalities likely sensitive to BET inhibition who have progressive disease with no effective therapeutic options
b) Subjects with controlled, treated brain metastasis
c) All subjects must have at least one measurable lesion at baseline
d) For Part 1, all subjects must have archival tumor tissue identified and available for correlative biomarker studies. For Part 2, 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 of study drug administration are excluded.
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
j) Subject Re-enrollment: This study permits the re-enrollment of a subject that has discontinued the study as a pre-treatment failure
k) Subjects with solid tumor types that are not included in the preferred target population may also be enrolled after a minimum of 2 subjects with the preferred tumor types have been enrolled at a single dose level during escalation
l) Androgen Receptor Deprivation (ARD) therapy is permitted for subjects with prostate cancer at doses defined by the investigator if the therapeutic agent is not a strong inducer or inhibitor of CYP3A4 activity.
m) If biomarker result from the Foundation Medicine Inc test is inconclusive, Foundation Medicine Inc will repeat the test. If there is not enough tumor material, the tumor biopsy must be repeated.
3. Previous Treatment
a) Prior anticancer therapy treatments such as chemotherapy, radiotherapy, biological immunotherapy, or investigational agents are permitted.
i) For cytotoxic agents, at least 4 weeks must have elapsed from last dose of prior cytotoxic anticancer therapy and the initiation of study drug administration.
ii) For non-cytotoxic agents, at least 4 weeks or 5 half-lives (whichever is shorter) must have elapsed from the last dose of prior non-cytotoxic anticancer therapy and the initiation of study drug administration.
b) All acute toxicities, from any prior therapy (radiotherapy, chemotherapy, or surgical procedures) must have resolved to Grade ≤ 1, NCI CTCAE, version 4.03 or to baseline if irreversible.
c) Concomitant therapy with bisphosphonates is acceptable as per American Society of Clinical Oncology (ASCO) guidelines. Doses of bisphosphonates must be stable for at least 30 days prior to treatment initiation, as per ASCO guidelines.
4. Age and Reproductive Status
a) Males and Females, 12 years of age or greater at the time of informed consent.
i) For subjects < 18 years of age, age-adjusted normal ranges for all assessments shall be used, as appropriate, for inclusion, exclusion, and dose modification criteria. In addition, an alternate pediatric assessment (eg, left ventricular shortening fraction rather than left ventricular ejection fraction [LVEF]) with an institutionally defined normal range may be used as appropriate.
b) Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG)
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 plus 5 half-lives of study treatments plus 30 days (duration of ovulatory cycle) for a total of 5 months post-treatment completion. Female participants must be willing to refrain from donation of oocytes.
e) Sexually active Males with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study treatments plus 5 half-lives of study treatments plus 90 days for a total of 7 months post-treatment completion. In addition, male participants must be willing to refrain from sperm donation.
f) WOCBP who are continuously not heterosexually active are also exempt from contraceptive requirements, and still undergo pregnancy testing.
|
|
| E.4 | Principal exclusion criteria |
1. Medical History and Concurrent Diseases
a) Evidence of uncontrolled, active infection, requiring parenteral antibacterial, 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. Non-chronic conditions (eg, 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) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease.
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 New York Heart Association [NYHA] 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) History of and chronic hepatitis evidenced
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 halflives
(whichever is longer) or strong inducers of CYP3A4 or P-gp within 2 weeks or 5 half-lives (whichever is longer).
l) Current uncontrolled autoimmune pneumonitis
m) Use of non-oncology vaccines containing live virus for prevention of infectious diseases within 12 weeks prior to study treatment. The use of inactivated seasonal influenza vaccines, eg, Fluzone®, will be permitted on study without restriction.
n) Uncontrolled endocrine disorder including thyroid disease
o) Prior organ allograft or allogenic hematopoeitic stem cell transplantation (HSCT)
p) Participants with active, known or suspected autoimmune disease. Note the following exceptions: Participants with: vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, euthyroid participants with a history of Grave’s disease (participants with suspected autoimmune thyroid disorders must be negative for thyroglobulin and thyroid peroxidase antibodies and thyroid-stimulating immunoglobulin prior to first dose of study treatment), psoriasis not requiring systemic treatment, or conditions expected to recur in the absence of an external trigger are permitted to enroll.
2. Physical and Laboratory Test Findings
a) Inadequate bone marrow function
b) Abnormal blood coagulation parameters
c) Inadequate hepatic function
d) Inadequate renal function
e) Any of the following on 12-lead electrocardiogram (ECG) prior to study drug administration, confirmed by repeat.
i) QRS ≥ 120 msec, except right bundle branch block
ii) QTcF > 450 msec, except right bundle branch block
f) Inadequate thyroid function
Note: Subclinical hypothyroidism (thyroid-stimulating hormone < 10 mIU/mL) or controlled hypothyroidism on appropriate thyroid supplementation are acceptable if negative for .for thyroglobulin, thyroid peroxidase antibodies, and thyroid stimulating immunoglobulin.
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
d) Women who are pregnant
e) Adolescents who provide active dissent
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary objective (to assess the safety and tolerability and to define
the DLTs and MTD of BMS-986158) will be measured by the primary
endpoints of:
Incidence of AEs at their worst grade,
SAEs at their worst grade,
AEs leading to discontinuations, deaths, and 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 and 100 days after the last dose
of BMS-986158 monotherapy or BMS-986158 in combination with
nivolumab, respectively, or until resolution of any AE 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) |
| Efficacy, PK, biomarker (pharmacodynamic) and ECG objectives |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Disease assessment will occur every 8-9 weeks ±1 week from the start
of study therapy.
Plasma drug and metabolite concentrations will be collected at
predetermined times.
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Changes in QTcF, (ΔQTcF) from baseline, at selected times following
monotherapy treatment
with BMS-986158 will be measured, and association measures of QTc
changes with BMS-986158 PK exposure |
|
| 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 | 2 |
| 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 | 11 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 20 |
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