Safety and Tolerability Study of INCB057643 in Participants With Myelofibrosis and Other Advanced Myeloid Neoplasms

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, and preliminary efficacy of INCB057643 as monotherapy or combination with ruxolitinib for participants with myelofibrosis (MF) and other myeloid neoplasms.

Official Title
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A Phase 1, Open-Label, Safety and Tolerability Study of INCB057643 in Participants With Myelofibrosis and Other Advanced Myeloid Neoplasms

Conditions
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Myelofibrosis, Myelodysplastic Syndrome, Myelodysplastic/Myeloproliferative Neoplasm Overlap Syndrome, Myeloproliferative Neoplasm, Relapsed or Refractory Primary Myelofibrosis, Secondary Myelofibrosis (Post-Polycythemia Vera Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis)

Intervention / Treatment
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* Drug: INCB057643
* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years and older at the time of signing the informed consent. Part 1: Participants with relapsed or refractory MF, MDS, MDS/MPN, or ET who have received at least 1 prior line of therapy; are either refractory, relapsed, or intolerant to the last therapy; and there is no available therapy that would provide clinical benefit in the opinion of the investigator. •a. MF Primary MF or secondary MFs (post-PV MF and post-ET MF) that is histologically or cytologically confirmed, according to WHO 2016 criteria with measurable disease and risk category of intermediate-2 or high according to DIPSS. Measurable disease is defined: For dose escalation as having a palpable spleen of ≥ 5 cm below the left subcostal margin (ribs). -Must have received a JAK inhibitor(s), such as ruxolitinib. (Except for participants being enrolled in Cohorts C, H, and I). b. MDS Very low-, low-, intermediate-, or high risk MDS as per the IPSS-R criteria c. MDS/MPN Low-, intermediate-, or high-risk chronic myelomonocytic leukemia, atypical chronic myeloid leukemia, MDS/MPN with ring sideroblasts and thrombocytosis, and MDS/MPN unclassifiable as per the WHO 2016 criteria. Exception: Participants presenting with juvenile myelomonocytic leukemia will be excluded. d. ET Confirmed diagnosis of ET as per the WHO 2016 criteria. Participants should have disease refractory to hydroxyurea, are intolerant to hydroxyurea or for whom treatment with hydroxyurea is contraindicated as determined by the treating physician OR participants who have refused treatment with hydroxyurea due to side effects. Peripheral blood blast count < 1% at screening hematology assessment. Part 2: Combination with ruxolitinib a. Primary MF or secondary MFs (post-PV MF and post-ET MF), histologically or cytologically confirmed according to WHO 2016 criteria with measurable disease, either currently receiving ruxolitinib with suboptimal response or JAKi-naive. b. Part 2 dose escalation: Risk category of intermediate-2 or high according to DIPSS. c. Part 2 dose expansion: Risk category of intermediate-1, intermediate-2, or high. d. Part 2 dose expansion Cohorts D and E participants with chronic MF are defined as participants with bone marrow myeloblast percentage < 5% and no blasts detected/not persistent blast count in peripheral blood at screening or baseline, AND who are currently receiving ruxolitinib and having suboptimal response. e. Part 2 dose expansion Cohorts F and G participants with accelerated-phase MF are defined as having either a bone marrow myeloblast percentage ≥ 5% to < 20% or a myeloblast percentage ≥ 10% in peripheral blood on 2 occasions at least 2 weeks apart, AND are currently receiving ruxolitinib and have a suboptimal response. f. 2 dose expansion Cohorts H and I participants with JAKi-naive MF are eligible to receive ruxolitinib, with peripheral blood blast count of < 10% at the screening hematology assessment. Must not be a candidate for potentially curative therapy, including hematopoietic stem-cell transplantation. ECOG performance status 0 to 2. Life expectancy ≥ 24 weeks. Willingness to undergo a pretreatment bone marrow biopsy and/or aspirate at screening/baseline, or archival sample obtained since completion of most recent therapy. Willingness to avoid pregnancy or fathering children based on criteria. Exclusion Criteria: Prior receipt of a BET inhibitor. Note: For Part 1 monotherapy dose escalation, prior receipt of a BET inhibitor is allowed, as long as it is not within 5 half-lives of the compound and/or the participant has not experienced BET inhibitor-related AE(s) resulting in dose discontinuation. Concurrent anticancer therapy Participants who have received allogeneic hematopoietic stem cell transplantation within 6 months of enrollment Active HBV or HCV infection or at risk for HBV reactivation. Other protocol-defined Inclusion/Exclusion Criteria may 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: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: monotherapy and ruxoltinib combination
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 : INCB057643 Monotherapy<br>INCB057643 dose escalation and dose expansion | Drug: INCB057643<br>* INCB057643 dose escalation and dose expansion.<br>|
| Experimental: Part 2 : INCB057643 Combination with Ruxolitinib<br>Combination arm in dose escalation and dose expansion | Drug: INCB057643<br>* INCB057643 dose escalation and dose expansion.<br>Drug: Ruxolitinib<br>* Ruxolitinib will be administered twice a day using the dose designated as the stable dose at the time of the screening visit for each subject. Acceptable doses are 5 mg BID to 25 mg BID.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of treatment-emergent adverse events | Defined as adverse events reported for the first time or worsening of a pre-existing event after first dose of study drug monotherapy and in combination with ruxolitinib. | Up to approximately 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Spleen Volume Response (MF only) | Defined as achieving a protocol defined reduction at Week 24 relative to baseline as measured by MRI or CT scan. | Week 24 | 
| Duration of Spleen Response (MF only) | Defined as the time from spleen response to progressive disease based on splenomegaly as defined by disease-specific criteria. | Up to approximately 9 months | 
| Duration of a Spleen Volume Response from baseline (MF only) | Defined as the interval between the first spleen volume measurement and the date of the first measurement that no longer achieves the protocol defined criteria. | Up to approximately 9 months | 
| Bone Marrow (BM) Blast Complete Remission (MF, myelodysplastic syndrome (MDS), and MDS/myeloproliferative neoplasm (MPN)) | Defined as BM blasts achieving the protocol defined criteria at baseline. | Up to approximately 9 months | 
| BM Blast Partial Remission (MF, MDS, and MDS/MPN) | Defined as BM blasts decreased by the protocol defined criteria. | Up to approximately 9 months | 
| Peripheral Blast Complete Remission (MF, MDS, and MDS/MPN) | Defined as peripheral blasts achieving the protocol defined criteria. | Up to approximately 9 months | 
| Peripheral Blast Partial Remission (MF, MDS, and MDS/MPN) | Defined as peripheral blast achieving the protocol defined criteria. | Up to approximately 9 months | 
| Durable Blast Complete or Partial remission (MF, MDS, and MDS/MPN) | Defined as achieving the protocol defined criteria. | Up to approximately 9 months | 
| Symptom Response Rate (MF or ET) | Defined as the proportion of participants who achieve a protocol defined reduction in Total Symptomatic Score (TSS) relative to baseline as measured by the MPN-symptom assessment form (SAF) TSS. | Week 24 | 
| Anemia Response (MF only) | A hemoglobin increase of 1.5 g/dL relative to baseline for any rolling 12-week period during the study treatment period, if transfusion independent (TI) at baseline or Achieving TI for any rolling 12-week period during the study treatment period, if transfusion dependent (TD) at baseline. | Up to approximately 9 months | 
| Duration of Anemia Response (MF only) | The interval from the first onset of anemia response to the earliest date of loss of anemia response that persists for at least 4 weeks or death from any cause for the TI participants at baseline or duration of RBC-TI period for participants achieving RBC-TI for at least 12 consecutive weeks during the study treatment period for the TD participants at baseline. | Up to approximately 9 months | 
| Changes in hemoglobin value from baseline (MF only) | Defined as the mean change from baseline in the hemoglobin value over 12-week treatment periods. | Up to approximately 9 months | 
| Red Blood Cell (RBC) Transfusion Burden (MF only) | Defined as the average number of RBC units per participant-month through Weeks 12, 24, and 48. | Up to approximately 9 months | 
| Transfusion Dependence before study enrollment (MF only) | Defined as transfusions achieving the protocol defined criteria in the 8 weeks before study enrollment. | Up to approximately 9 months | 
| Baseline hemoglobin (Hgb) (MF only) | Baseline Hgb will be measured at the protocol defined visits. The baseline Hgb defined as the average of all eligible Hgb assessments. | Up to approximately 9 months | 
| Overall response (ET only) | Defined as proportion of participants with complete response or partial response and hematological improvement/response as per definition for ET. | Up to approximately 9 months | 
| Duration of platelet count reduction or White Blood Cell (WBC) count reduction (ET only) | Defined as platelet count reduction or WBC count reduction lasting ≥ 12 weeks. | Up to approximately 9 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LIMBER, Myelofibrosis, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasm overlap syndrome, myeloproliferative neoplasm, BET protein inhibitor, relapsed primary myelofibrosis, refractory primary myelofibrosis, secondary myelofibrosis, post-polycythemia vera myelofibrosis, post-essential thrombocythemia myelofibrosis