2-(3-(3,5-DIMETHYLTRIAZOL-4-YL)-5-((S)-OXAN-4-YL(PHENYL)METHYL)PYRIDO(3,2-B)INDOL-7-YL)PROPAN-2-OL for Myelofibrosis | Primary myelofibrosis | Post-polycythaemia vera myelofibrosis | Post-essential thrombocythaemia myelofibrosis

Inclusion criteria

• {"criterion_text":"- Males and females of ≥ 18 years of age at the time of signing the ICF"}
• {"criterion_text":"- In Part 1A, 2A1, and 2A3 -Ruxolitinib Combo cohorts: participants must not have been exposed to 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 ≥ 6 months, and on a stable dose ≥ 8 weeks prior to C1D1 with sub-optimal response defined as: (1) palpable spleen > 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."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Participant has an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2 at Screening."}
• {"criterion_text":"- Part 1A, 1B, and 2B participants at Screening must have a DIPSS Risk Score of Intermediate-1 with symptoms, Intermediate-2, or High."}
• {"criterion_text":"- Part 2A participants must have had a DIPSS Risk Score of Intermediate-2 or High"}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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 < 35% spleen volume reduction by MRI/CT scan."}
• {"criterion_text":"- In Part 1B Fedratinib Combo cohorts, Part 2B1-Fedratinib Combo arm, and Part 2B2-BMS-986158 Mono arm: Participant has been previously exposed to ruxolitinib, and must meet at least 1 of the following criteria (I and/or II): I) Treatment with ruxolitinib for ≥ 3 months with inadequate efficacy response (refractory) defined as < 10% spleen volume reduction by MRI/CT scan or regrowth (relapsed) to these parameters following an initial response II) Treatment with ruxolitinib for ≥ 28 days complicated by any of the following (intolerant): a) Development of a RBC transfusion requirement (at least 2 units/month for 2 months) or b) 2) Grade ≥ 3 AEs of thrombocytopenia, anemia, hematoma, and/or hemorrhage while on treatment with ruxolitinib"}
• {"criterion_text":"- Must not be a candidate for, or must have refused, allogenic SCT"}

Exclusion criteria

• {"criterion_text":"- Participant with previous splenectomy."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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)."}
• {"criterion_text":"- Participants with uncontrolled endocrine disorder including thyroid disease or inadequate thyroid function. Note: Subclinical hypothyroidism (thyroid-stimulating hormone< 10 mIU/mL) or controlledhypothyroidism on appropriate thyroid supplementation are acceptable. Physical and Laboratory Test Findings a) Absolute neutrophil count< 1.0 × 109/L b) Hgb < 8 g/dL (Screening Hgb ≥ 14 days after last RBC transfusions)only for non-TD participants) c) WBC count > 100 × 109/L d) Myeloblasts ≥ 10% in peripheral blood e) AST and ALT ≥ 3.0 × upper limit of normal (ULN) f) Serum amylase or lipase > 1.5 × ULN g) Serum total bilirubin ≥ 1.5 × ULN (participant's total bilirubin between 1.5 to 3.0 × ULN are eligible if the direct bilirubin fraction is < 25% of the total bilirubin) h) Creatinine clearance (CrCl) < 50 mL/min (calculated using the Cockroft-Gault formula) within 14 days prior to first dose of study treatment. i) Serum albumin < 3.0 g/dL j) Participant with abnormal blood coagulation parameters: Prothrombin time (PT) such that international normalized ratio (INR) is > 1.5 × ULN or a partial thromboplastin time > 1.2 × ULN. k) PLT < 100 × 109/L for participants in the ruxolitinib cohorts Parts 1A and 2A1, and PLT < 75 × 109/L for participants in fedratinib cohorts Parts 1B and 2B (combination and monotherapy arms), for participants in the ruxolitinib cohort Part 2A2 (add-on to Ruxo) and Part 2A3 (only if PLT is not > 99 × 109/L) (Screening PLT ≥ 7 days after last PLT transfusions)."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Participant with previous exposure to a BET inhibitor."}
• {"criterion_text":"- Prior organ allograft or allogenic hematopoietic stem cell transplantation."}
• {"criterion_text":"- Participant with diagnosis of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemochromatosis, non-alcoholic steatohepatitis)."}
• {"criterion_text":"- 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: QRS ≥ 120 msec or QTcF ≥ 460 msec"}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Participant 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."}

Primary endpoints

• {"endpoint_text":"- Incidence of Adverse Events (AEs), Serious Adverse Events (SAEs), Dose Limiting Toxicity (DLT), and AEs leading to discontinuation and death.","definition_or_measurement_approach":""}

Secondary endpoints

• {"endpoint_text":"- ≥ 35% reduction in Spleen Volume Response measured by MRI or CT at the end of cycle 6 as assessed by central reader","definition_or_measurement_approach":"Measured by MRI or CT and assessed by a central reader; threshold is ≥ 35% reduction in spleen volume at end of cycle 6."}
• {"endpoint_text":"- ≥ 25% reduction in Spleen Volume Response measured by MRI or CT at the end of cycle 3 and 6 as assessed by central reader","definition_or_measurement_approach":"Measured by MRI or CT and assessed by a central reader; threshold is ≥ 25% reduction in spleen volume at end of cycles 3 and 6."}
• {"endpoint_text":"- ≥ 50% reduction in Total Symptom Score measured by MF Symptom Assessment Form (MFSAF) at the end of cycle 6","definition_or_measurement_approach":"Measured by the MF Symptom Assessment Form (MFSAF); threshold is ≥ 50% reduction in total symptom score at end of cycle 6."}

France

Earliest CTIS Part Ii Submission Date

18-12-2023

Latest Decision Or Authorization Date

23-03-2026

Processing Time Days

826

Number Of Sites

5

Number Of Participants

30

Germany

Earliest CTIS Part Ii Submission Date

18-12-2023

Latest Decision Or Authorization Date

26-03-2026

Processing Time Days

829

Number Of Sites

3

Number Of Participants

25

Greece

Earliest CTIS Part Ii Submission Date

18-12-2023

Latest Decision Or Authorization Date

17-06-2024

Processing Time Days

182

Number Of Sites

2

Number Of Participants

3

Italy

Earliest CTIS Part Ii Submission Date

18-12-2023

Latest Decision Or Authorization Date

15-04-2025

Processing Time Days

484

Number Of Sites

1

Number Of Participants

12

Romania

Earliest CTIS Part Ii Submission Date

18-12-2023

Latest Decision Or Authorization Date

04-05-2026

Processing Time Days

868

Number Of Sites

1

Number Of Participants

12

Spain

Earliest CTIS Part Ii Submission Date

18-12-2023

Latest Decision Or Authorization Date

23-10-2024

Processing Time Days

310

Number Of Sites

6

Number Of Participants

8

Poland

Earliest CTIS Part Ii Submission Date

19-01-2024

Latest Decision Or Authorization Date

27-03-2026

Processing Time Days

798

Number Of Sites

3

Number Of Participants

18

Primary sponsor

Full Name

Bristol-Myers Squibb Services Unlimited Company

Organisation Type

Pharmaceutical company

Country Of Registered Address

Ireland

Third parties

• {"country":"India","full_name":"Accenture Solutions Private Limited","duties_or_roles":"Embarc operations; Pharmacovigilance duties: Medical review and Cases Data Entry","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Clario","duties_or_roles":"Collection of de-identified images; Imaging doc development (manuals, charters and reader training); Independent reader training; Transfer of analysis dataset; Transfer of images; Archival of study materials","organisation_type":"Health care"}
• {"country":"United States","full_name":"Greenphire LLC","duties_or_roles":"Provides electronic payments, travel arrangements,electronic study-related comunications to patients","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Signant Health Global LLC","duties_or_roles":"PRO/COA","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Labcorp Central Laboratory Services LP","duties_or_roles":"Main Asia Central Lab","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Biotel Research LLC","duties_or_roles":"Collection of de-identified images; Imaging doc development (manuals, charter and reading training); independent reader training; transfer of analysis dataset; transfer of images; archive study materials","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Y-Prime, Inc.","duties_or_roles":"IVRS30 – treatment randomisation, Core Technology Services","organisation_type":"Industry"}
• {"country":"United States","full_name":"Myriad RBM Inc.","duties_or_roles":"Exploratory Serum Biomarkers analysis","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Icon Laboratory Services Inc.","duties_or_roles":"Data entry of Local Laboratory Values","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"PPD Development LP","duties_or_roles":"Serum PK and serum immunogenicity analysis","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Azenta Germany GmbH","duties_or_roles":"biospecimen storage","organisation_type":"Pharmaceutical company"}