Study of the JAK Inhibitor Ruxolitinib Administered Orally to Patients With Primary Myelofibrosis (PMF), Post-Polycythemia Vera-Myelofibrosis (PPV-MF) or Post-Essential Thrombocythemia-Myelofibrosis (PET-MF)

Study Overview
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Brief Summary
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This is a Phase IB, open-label, dose-finding study of the JAK 1 and 2 inhibitor ruxolitinib in patients with myelofibrosis (MF). The study consists of two periods: the core study period, comprising the dose escalation stage and the safety extension phase up to Week 24, then the extension study period beyond Week 24 and up to 3 years, to further characterize the safety and efficacy of ruxolitinib in this patient population. The dose escalation phase will enroll successive cohorts of patients who receive increasing doses of ruxolitinib until the maximum safe starting dose (MSSD) is determined. In the safety expansion phase, additional patients will be treated with ruxolitinib at the MSSD defined during dose escalation. The primary objective is to establish the MSSD of ruxolitinib in patients with MF and starting platelet counts < 100 x 10 ^9/L

Official Title
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A Phase Ib, Open-label, Dose-finding Study of the JAK Inhibitor INC424 Tablets Administered Orally to Patients With Primary Myelofibrosis (PMF), Post-polycythemia Veramyelofibrosis (PPV-MF) or Post-essentialthrombocythemia-myelofibrosis (PET-MF) and Baseline Platelet Counts ≥50 x109/L and <100 x109/L (EXPAND)

Conditions
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Myelofibrosis

Intervention / Treatment
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* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Require treatment for MF and classified at least as intermediate risk level 1 defined by the International Working Group. Platelet count < 100x10 ^9/L at screening or at Study Day 1. Exclusion Criteria: Received platelet transfusion within 14 days prior to Screening evaluations.

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stratum -1<br>Participants with baseline Platelet counts of 75-99 x10^9/L | Drug: Ruxolitinib<br>* Starting dose of ruxolitinib for cohort 1 in dose escalation phase - 5mg twice a day (BID) Doses will be increased a total of approximately 5mg for successive dosing cohorts based on baseline platelet count<br>* Other names: INCB018424;|
| Experimental: Stratum -2<br>Participants with baseline Platelet counts of 50-74 x10^9/L | Drug: Ruxolitinib<br>* Starting dose of ruxolitinib for cohort 1 in dose escalation phase - 5mg twice a day (BID) Doses will be increased a total of approximately 5mg for successive dosing cohorts based on baseline platelet count<br>* Other names: INCB018424;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities | DLT was defined as the occurrence of any of the following treatment-related toxicities, occurring through Day 28: Any grade ≥ 2 hemorrhagic event ; Any grade thrombocytopenia requiring PLT transfusion; PLT count < 25x109/L*; Grade 4 neutropenia (absolute neutrophil count < 0.5x109/L)*; Grade ≥ 3 febrile neutropenia*; Grade ≥ 2 total serum bilirubin with coincident direct bilirubin ≥ 0.5 mg/dL; Grade 3 non-hematologic toxicity for ≥ 7 consecutive days; Grade 4 non-hematologic toxicity. In the dose escalation stage in the core study period, the starting does in both strata was 5mg bid. Successive cohorts of newly enrolled patients received increasing doses of ruxolitinib until the Maximum Safe Starting Dose (MSSD) was determined. Initially, only patients with PLT counts 75-99 x10^9/L (stratum 1) were allowed to be enrolled. Once safety was established in stratum 1 at the first 2 dose cohorts, eligible population was further expanded to patients with PLT counts 50-74 x10^9/L (stratum 2). | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Treatment Emergent Adverse Events (TEAE's) | Adverse events reported for the first time or worsening of a pre-existing event after first dose of study drug/treatment. | approximately 4 years | 
| Number of Subjects Achieving ≥ 50% Reduction in Palpable Spleen Length | Participants achieving ≥ 50% reduction in palpable spleen length relative to study day 1 by treatment and stratum | 24 weeks | 
| Change in Spleen Length as Measure by Palpation Over Time | Defined as measurement of change in spleen length by palpation from baseline | Day 8, 15, 22, 29, 43, 57, 85, 113, 141, 168, 252, 336, 420, 504, 588, 672, 756, 1008, 1092 | 
| PK- C Reactive Protein Levels by PK Quartile (AUC0-12) | To define the PK and C Reactive Protein relationship using PK Quartiles (AUC 0-12, ng*h/mL) | 24 weeks | 
| PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12) | To define the PK and Interleukin 1 Receptor Antagonist relationship relationship using PK Quartiles (AUC 0-12, ng*h/mL) | 24 weeks | 
| PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12) | To define the PK and Tissue Necrosis Factor Receptor 2 relationship using PK Quartiles (AUC 0-12, ng*h/mL) | 24 weeks | 
| AUC 0-Inf | Area Under the Serum Concentration Versus Time Curve，Time 0 to Infinity | 0.25 to 0.75, 1 to 3, and 4 to 12 hours postdose on Day 1 and predose, 0.25 to 0.75 hours, and 1 to 3 hours postdose on Day 15, with a random sample on Days 29 and 57 |