Phase 1b/2 Evaluation of BMS-986158 Alone and with Ruxolitinib or Fedratinib in DIPSS-Intermediate/High Risk Myelofibrosis Patients
- Trial ID
- 2023-509635-89-00
- Protocol
- CA011-023
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **safety** and tolerability of BMS-986158 in combination with ruxolitinib in previously untreated participants with DIPSS-Intermediate or High Risk **Myelofibrosis** (MF), and in combination with fedratinib in participants previously treated with ruxolitinib. Additionally, the study aims to determine the maximum tolerated dose and/or the recommended phase 2 dose (RP2D) of BMS-986158. This is clinically relevant as it seeks to establish a safe and effective dosage regimen for these combinations, potentially improving therapeutic outcomes for patients with MF.
Secondary objectives include:
- Assessing the preliminary efficacy based on the reduction of spleen volume, which is a significant clinical marker in MF management.
- Evaluating MF-associated symptoms, which can provide insights into the overall impact of the treatment on patient quality of life.
Participants
The clinical trial involves a total of **116 participants** diagnosed with **DIPSS-Intermediate or High Risk Myelofibrosis**. The study population includes both **males and females** aged **18 years and older**. Participants were selected based on specific inclusion criteria, including a diagnosis of primary myelofibrosis (PMF) or post-essential thrombocythemia (post-ET) or post-polycythemia vera (post-PV) myelofibrosis, confirmed by local pathology reports. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 or less, indicating a relatively stable general health status. Participants were required to have measurable splenomegaly and a DIPSS Risk Score of Intermediate-1 with symptoms, Intermediate-2, or High. The trial population includes individuals who have not been previously treated with JAK2 inhibitors or those who have been treated with ruxolitinib with sub-optimal response or intolerance. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, ensuring careful monitoring and ethical considerations throughout the study.
Plans and Procedures
The clinical trial is designed to evaluate the **safety** and tolerability of BMS-986158, both as a monotherapy and in combination with either **ruxolitinib** or **fedratinib**, in participants diagnosed with DIPSS-Intermediate or High Risk **myelofibrosis**. This is a Phase 1b/2 trial, structured as a randomized, double-blind, controlled study. The trial aims to determine the maximum tolerated dose and the recommended phase 2 dose of BMS-986158 in combination with ruxolitinib for previously untreated participants, and with fedratinib for those previously treated with ruxolitinib. The estimated duration of the trial is from March 2021 to December 2026.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age, prior treatment history, and **Eastern Cooperative Oncology Group (ECOG) Performance Status**. Following successful screening, participants will be enrolled and randomized into different treatment arms. The trial includes multiple follow-up visits to monitor the incidence of adverse events, serious adverse events, dose-limiting toxicity, and any adverse events leading to discontinuation or death. Secondary endpoints include the assessment of spleen volume reduction and symptom score improvement at specified cycles.
The expected length of participant involvement varies depending on the treatment arm and response to therapy, with regular assessments conducted throughout the trial period. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, non-compliance with the study protocol, or withdrawal of consent by the participant. The end-of-study visit will involve a comprehensive evaluation of the participant's health status and the collection of final data for analysis. The trial is conducted under strict ethical guidelines, ensuring the safety and well-being of all participants.
Treatment
The clinical trial involves the administration of several **experimental medications** and comparator treatments. The primary experimental medication is BMS-986158, a **BET-Inhibitor** with the chemical name 2-(3-(3,5-dimethyltriazol-4-yl)-5-((S)-oxan-4-yl(phenyl)methyl)pyrido(3,2-b)indol-7-yl)propan-2-ol. This medication is provided in capsule form and is administered orally. The frequency and dosage of administration are determined based on the study protocol, with the aim of assessing safety, tolerability, and determining the maximum tolerated dose or recommended phase 2 dose in participants with myelofibrosis.
Another experimental medication used in the trial is **Ruxolitinib**, marketed under the name Jakavi. It is available in tablet form with dosages of 5 mg, 10 mg, and 15 mg. Ruxolitinib is administered orally, and the dosing schedule is tailored to the individual participant's needs as per the study protocol. The medication is used in combination with BMS-986158 to evaluate its efficacy and safety in previously untreated myelofibrosis participants.
The trial also includes the use of **Fedratinib** as a comparator treatment. Fedratinib is provided in hard capsule form and is administered orally. It is used in combination with BMS-986158 for participants who have previously been treated with Ruxolitinib. The objective is to assess the combination's safety and efficacy in this specific participant group.
All medications in the trial are of chemical origin, and participant compliance is monitored through regular assessments and adherence checks as outlined in the study protocol. The trial aims to provide comprehensive data on the safety and efficacy of these treatments in participants with DIPSS-Intermediate or High Risk **Myelofibrosis**.
Efficacy
Efficacy in this clinical trial will be assessed using several key endpoints. The primary efficacy endpoint is the incidence of adverse events (AEs), serious adverse events (SAEs), dose-limiting toxicity (DLT), and AEs leading to discontinuation and death. Secondary efficacy endpoints include a reduction in spleen volume and symptom scores. Specifically, a ≥ 35% reduction in spleen volume response will be measured by MRI or CT at the end of cycle 6, and a ≥ 25% reduction will be assessed at the end of cycles 3 and 6. Additionally, a ≥ 50% reduction in total symptom score will be evaluated using the Myelofibrosis Symptom Assessment Form (MFSAF) at the end of cycle 6.
The efficacy parameters will be measured and collected at specified timepoints, with MRI or CT scans being utilized to assess spleen volume changes. The MFSAF will be employed to quantify symptom improvement. These assessments will be conducted by a central reader to ensure consistency and accuracy in the evaluation of the trial's outcomes. The trial aims to determine the maximum tolerated dose and/or the recommended phase 2 dose (RP2D) of BMS-986158 in combination with **ruxolitinib** or **fedratinib** in participants with myelofibrosis, focusing on those with DIPSS-Intermediate or high-risk profiles.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Males and females of ≥ 18 years of age at the time of signing the ICF
- 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.
- Participant has an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2 at Screening.
- Part 1A, 1B, and 2B participants at Screening must have a DIPSS Risk Score of Intermediate-1 with symptoms, Intermediate-2, or High.
- Part 2A participants must have had a DIPSS Risk Score of Intermediate-2 or High
- 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.
- 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.
- 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
- Must not be a candidate for, or must have refused, allogenic SCT
- 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.
Exclusion Criteria
- Participant with previous splenectomy.
- 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.
- Participant with previous exposure to a BET inhibitor.
- Prior organ allograft or allogenic hematopoietic stem cell transplantation.
- Participant with diagnosis of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemochromatosis, non-alcoholic steatohepatitis).
- 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
- 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.
- 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.
- 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.
- 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.
- 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).
- 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).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 22 Mar 2021 | 30 |
 Germany | Not Recruiting | 22 Mar 2021 | 25 |
 Greece | Not Recruiting | 22 Mar 2021 | 3 |
 Italy | Not Recruiting | 22 Mar 2021 | 12 |
 Poland | Not Recruiting | 22 Mar 2021 | 18 |
 Romania | Not Recruiting | 22 Mar 2021 | 12 |
 Spain | Not Recruiting | 22 Mar 2021 | 8 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
BET-Inhibitor | Test | CAPSULE | ORAL USE | — | — | PRD10498773 |
Jakavi 5 mg tablets | Comparator | TABLETS | ORAL | — | — | PRD3949635 |
Jakavi 10 mg tablets | Comparator | TABLETS | ORAL | — | — | PRD2387737 |
Jakavi 15 mg tablets | Comparator | TABLETS | ORAL | — | — | PRD3949619 |
FEDRATINIB | Test | — | ORAL USE | — | — | SUB126288 |