A Study to Assess the Safety and Tolerability of BMS-986158 Alone and in Combination With Either Ruxolitinib or Fedratinib in Participants With Blood Cancer (Myelofibrosis)

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety, tolerability, and efficacy of BMS-986158 alone and in combination with either Ruxolitinib or Fedratinib in participants with Dynamic International Prognostic Scoring System (DIPSS)-intermediate or high risk blood cancer. Part 1 consists of BMS-986158 in combination with either Ruxolitinib or Fedratinib and Part 2 consists of BMS-986158 in combination with either Ruxolitinib or Fedratinib and BMS-986158 alone.

Official Title
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A Phase 1b/2 Study of BMS-986158 Monotherapy and in Combination With Either Ruxolitinib or Fedratinib in Participants With DIPSS-Intermediate or High Risk Myelofibrosis

Conditions
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Myelofibrosis

Intervention / Treatment
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* Drug: BMS-986158
* Drug: Ruxolitinib
* Drug: Fedratinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of primary myelofibrosis (PMF), post-essential thrombocythemia (ET) or post-polycythemia vera (PV) myelofibrosis Treatment-related toxicities from prior therapy resolved to Grade 1 or pre-treatment baseline or determined to be irreversible prior to study treatment Must agree to follow specific methods of contraception, if applicable Exclusion Criteria: Women who are pregnant or breastfeeding at screening Any significant acute or uncontrolled chronic medical illness Other protocol-defined inclusion/exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1A: BMS-986158 + Ruxolitinib<br> | Drug: BMS-986158<br>* Specified dose on specified days<br>Drug: Ruxolitinib<br>* Specified dose on specified days<br>* Other names: Jakafi®;|
| Experimental: Part 1B: BMS-986158 + Fedratinib<br> | Drug: BMS-986158<br>* Specified dose on specified days<br>Drug: Fedratinib<br>* Specified dose on specified days<br>|
| Experimental: Part 2A1: BMS-986158 + Ruxolitinib<br> | Drug: BMS-986158<br>* Specified dose on specified days<br>Drug: Ruxolitinib<br>* Specified dose on specified days<br>* Other names: Jakafi®;|
| Experimental: Part 2B1: BMS-986158 + Fedratinib<br> | Drug: BMS-986158<br>* Specified dose on specified days<br>Drug: Fedratinib<br>* Specified dose on specified days<br>|
| Experimental: Part 2B2: BMS-986158 Mono and/or (BMS-986158 + Fedratinib), if applicable<br> | Drug: BMS-986158<br>* Specified dose on specified days<br>Drug: Fedratinib<br>* Specified dose on specified days<br>|
| Experimental: Part 2A2 Add-On: BMS-986158 + Ruxolitinib<br> | Drug: BMS-986158<br>* Specified dose on specified days<br>Drug: Ruxolitinib<br>* Specified dose on specified days<br>* Other names: Jakafi®;|
| Experimental: Part 2A3: BMS-986158 + Ruxolitinib<br> | Drug: BMS-986158<br>* Specified dose on specified days<br>Drug: Ruxolitinib<br>* Specified dose on specified days<br>* Other names: Jakafi®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (AEs) |  | Up to 52 months | 
| Incidence of serious adverse events (SAEs) |  | Up to 52 months | 
| Incidence of AEs meeting protocol-defined dose-limiting toxicity (DLT) criteria |  | Up to 26 months | 
| Incidence of AEs leading to discontinuation |  | Up to 52 months | 
| Incidence of death |  | Up to 52 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Spleen volume reduction (SVR) at end of Cycle 6 assessed by Blinded Independent Central Review (BICR) |  | Up to 175 days | 
| 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 |  | Up to 175 days | 
| SVR at end of Cycle 3 and 6 assessed by BICR |  | Up to 175 days | 
| 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 |  | Up to 175 days | 
| Symptom response rate (SRR) based on total symptom score (TSS) measured by Myelofibrosis Symptom Assessment Form (MFSAF) |  | Up to 175 days | 
| Additional measures based on TSS measured by MFSAF |  | Up to 175 days | 
| For transfusion independent (TI), proportion of participants having ≥ 2.0 g/dL hemoglobin (Hgb) increase over baseline |  | Up to 24 months | 
| For transfusion dependent (TD), proportion of participants becoming TI as measured by the absence of red blood cell (RBC) transfusions over any consecutive 12-week period |  | Up to 24 months | 
| For transfusion dependent (TD), proportion of participants becoming Tl as measured by the absence of erythropoiesis stimulating agents (ESA) over any consecutive 12-week period |  | Up to 24 months | 
| For transfusion dependent (TD), proportion of participants becoming Tl as measured by the absence of hydroxyurea over any consecutive 12-week period |  | Up to 24 months | 
| Summary of plasma concentrations pharmacokinetics (PK) parameters: maximum observed concentration (Cmax) |  | Up to 56 days | 
| Summary of plasma concentrations PK parameters: time of maximum observed concentration (Tmax) |  | Up to 56 days | 
| Summary of plasma concentrations PK parameters: area under the concentration-time curve from time zero to the time of the last quantifiable concentration ((AUC (0-T)) |  | Up to 56 days | 
| Time from Dose 1, Day 1 to death due to any reason or disease progression (per modified IWG-MRT 2013) assessed by BICR: SDPFS rates at 6 months and 12 months | International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Spleen and disease progression free survival (SDPFS) | 6 month and 12 month | 
| 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 at 6 months and 12 months |  | 6 month and 12 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BMS-986158, Fedratinib, Myelofibrosis, Ruxolitinib