DIPSS-Intermediate or High Risk Myelofibrosis MedDRA version: 21.0 Level: LLT Classification code 10000879 Term: Acute myelofibrosis System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: PT Classification code 10028537 Term: Myelofibrosis System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: BET-Inhibitor
Product Code: BMS-986158
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: BET-Inhibitor
CAS Number: 1800340-40-2
Current Sponsor code: BET-Inhibitor
Other descriptiv
Sponsors
Bristol-Myers Squibb International Corporation
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1) Males and females of = 18 years of age at the time of signing the ICF 2)Participant has diagnosis of PMF according to the 2017 World Health Organization criteria (Appendix 12), or diagnosis of post-ET or post-PV MF according to the IWG-MRT 2007 criteria (Appendix 13), confirmed by the most recent local pathology report. 3) Participant has an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) = 2 at Screening. 4)Part 1A, 1B, and 2B participants at Screening must have a DIPSS Risk Score of Intermediate-1 with symptoms, Intermediate-2, or High. 5) Part 2A participants must have had a DIPSS Risk Score of Intermediate-2 or High 6) Participant has a measurable splenomegaly during the screening period as demonstrated by spleen volume of = 450 cm3 by MRI or computed tomography (CT) scan assessment. 7) Not Applicable per Protocol Amendment 03, replaced with 10). In Part 1A- and 2A1-Ruxolitinib Combo cohorts: participants must not have been treated with JAK2 inhibitors prior to the start of treatment with BMS- 986158 in combination with ruxolitinib. In Part 2A2 (add-on to Ruxo), Ruxolitinib Combo cohorts: participants must have been treated with ruxolitinib for = 3 months, and on a stable dose for = 8 weeks prior to Screening with sub-optimal response defined as > 10% but 10 cm below left costal margin (LCM) on physical examination at Screening, or (2) palpable spleen 5-10 cm below LCM on physical examination at Screening and the presence of active MF symptoms at screening as measured by MFSAF (Appendix 9) and defined as 1 symptom score = 5 or 2 symptom scores = 3 each. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 87 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range 161
Exclusion criteria
Exclusion criteria: 1) Participant with previous splenectomy. 2) In Part 1B-Fedratinib Combo cohorts, Part 2B1-Fedratinib Combo arm, and Part 2B2- BMS-986158 Mono arm: a) Participant with prior history of encephalopathy including WE. b) Participant with thiamine deficiency, defined as thiamine levels in whole blood below normal range according to institutional standard and not corrected prior to enrollment on the study (ie, C1D1). c) Participant who received ruxolitinib within 14 days prior to starting the treatment with BMS-986158 alone or in combination with fedratinib. Gradual tapering of ruxolitinib as per investigator’s discretion is recommended, and must be completed at the latest 14 days prior to C1D1. Use of systemic steroids = 10 mg/day prednisone or equivalent is allowed. d) Participant with previous exposure to JAK2 inhibitor(s) other than ruxolitinib. 3) Participant with previous exposure to a BET inhibitor. 4) Prior organ allograft or allogenic hematopoietic stem cell transplantation. 5) Participant with diagnosis of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemochromatosis, non-alcoholic steatohepatitis). 6) Participant has impaired cardiac function or clinically significant cardiac diseases: a) Any of the following on 12-lead ECG prior to study drug administration, confirmed by repeat and central ECG laboratory assessment: i) QRS ? 120 msec ii) QTcF ? 460 msec 7) Positive blood screen for hepatitis C antibody, hepatitis B surface antigen, or human immunodeficiency virus (HIV) 1 and 2 antibody a) Participants who are seropositive due to hepatitis B virus (HBV) vaccination are eligible. b) Participants who have no active viral infection and are under adequate prophylactics against HBV re-activation are eligible. c) Participants who are positive on anti-HCV IgG, but negative on viral RNA, and without morphologic changes in liver, are eligible. 8) 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/24 hours or repeated pulmonary hemorrhage. 9) Ppts with current or recent (within 1 month of study drug administration) GI disease such as symptomatic or uncontrolled ulcers (gastric or duodenal), particularly those with a history of and/or risk of perforation and GI tract hemorrhages, chronic or intermittent diarrhea, or uncontrolled disorders that increase the risk of diarrhea, such as inflammatory bowel disease. Non-chronic conditions (eg, infectious diarrhea) that are completely resolved for at least 2 weeks prior to starting study treatment are not exclusionary. 10) Previous SARS-CoV-2 infection within 10 days prior to Cycle 1 Day 1 for mild or asymptomatic illness or within 20 days prior to Cycle 1 Day 1 for severe/critical illness. Note: Acute symptoms must have resolved and based on investigator assessment in consultation with the Sponsor's Medical Monitor, there are no sequelae that would place the participant at a higher risk of receiving study treatment. 11) In Parts 1A and 2A: Participant with treatment or use of pharmaceutical, herbal agents, or food known to be strong inducers of CYP3A4 within 2 week or 5 half-lives (whichever is longer), strong inhibitors of CYP3A4 or P-gp within 1 week or 5 half-lives (whichever is longer). 12) Ppts with uncontrolled endocrine disord
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Dose Escalation (Part 1) - To assess the safety tolerability, and to determine the MTD and/or RP2D of BMS-986158 in combination with ruxolitinib in previously untreated (1L) MF participants, and in combination with fedratinib in ruxolitinib-exposed (2L) MF participants. Dose Expansion (Part 2) - To further determine the safety and tolerability of BMS-986158 in combination with ruxolitinib in 1L or as an "add-on" to ruxolitinib in MF participants, and in combination with fedratinib, or as monotherapy, in 2L MF participants at the RP2Ds.;Secondary Objective: - To assess the preliminary efficacy of BMS-986158 in combination with ruxolitinib in 1L or as an "add-on" to ruxolitinib in MF participants or in combination with fedratinib, or as monotherapy, in 2L MF participants, based on SVR. -To assess the preliminary efficacy of BMS-986158 in Part 2A2 (add-on to ruxolitinib) participants based on SVR. - To evaluate MF-associated symptoms as measured by the MFSAF of participants treated with BMS-986158 monotherapy and in combination with either ruxolitinib or fedratinib in Part 2. - Improvement in anemia in Part 2 based on pre-defined changes in both TI participants and TD participants. - To characterize the PK of BMS-986158 in combination with ruxolitinib and in combination with fedratinib and in monotherapy - SDPFS of participants treated with BMS-986158 in combination with either ruxolitinib or fedratinib and in monotherapy.;Primary end point(s): •Incidence of AEs, SAEs, AEs meeting protocol-defined DLT criteria, AEs leading to discontinuation, and death. •Incidence of AEs, SAEs, AEs leading to discontinuation, and death. ;Timepoint(s) of evaluation of this end point: up to progressive disease, but it is expected to last from 12 months up to 24 months + 30-90 days. = up to 27 months | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1 SVR at end of Cycle 6 (and response rate defined as proportion of participants with SVR = 35%) by MRI (preferred) or CT (if MRI is contraindicated and if CT is allowed by local guidelines) assessed by BICR. 2 SVR at end of Cycle 3 and 6 (and response rate defined as proportion of participants with SVR = 25%) by MRI (preferred) or CT (if MRI is contraindicated and if CT is allowed by local guidelines) assessed by BICR 3 SRR and additional measures based on TSS measured by MFSAF; SRR is calculated at the end of Cycle 6 (and defined as the proportion of participants with = 50% reduction in TSS). 4 For TI, proportion of participants having = 2.0 g/dL Hgb increase over baseline, and for TD, proportion of participants becoming TI as measured by absence of RBC transfusions, ESA and hydroxyurea, over any consecutive 12-week period. 5 Summary of plasma concentrations and PK parameters of BMS- 986158 in combination with ruxolitinib in combination with fedratinib, and in BMS-986158 monotherapy. 6 Time from Dose 1, Day 1 to death due to any reason or disease progression (per modified IWG-MRT 2013) assessed by BICR; median SDPFS and SDPFS rates at 6 months and 12 months. ;Timepoint(s) of evaluation of this end point: 1 SVR – Up to cycle 6 2 SRR – up to cycle 6 3 SVR - Up to cycle 3 and 6 4 Improvement in Anemia OR "For TI, proportion of …" – the endpoint assessment timeframe can be aligned with the other secondary efficacy endpoints, such as SVR at Cycle 6, and repeated up to 24 months 5 PK – Up to 24 months 6 PK SDPFS – Up to 12 months | — |
Countries
Australia, France, Germany, Greece, Israel, Italy, Poland, Romania, Spain
Contacts
Public ContactGSM-CT
Bristol-Myers Squibb International Corporation
Outcome results
None listed