To Assess the Safety, Tolerability and Efficacy of Itacitinib Immediate Release Tablets in Participants With Primary or Secondary Myelofibrosis Who Have Received Prior Ruxolitinib and/or Fedratinib Monotherapy (LIMBER-213)

Study Overview
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Brief Summary
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This is a 2-part study. In Part 1, participants will be dosed at 2 different dose levels in order to select the RP2D for Part 2 of the study.

Official Title
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A 2-Part, Phase 2, Open-Label Study of the Safety, Tolerability, and Efficacy of Itacitinib Immediate Release in Participants With Primary Myelofibrosis or Secondary Myelofibrosis (Post-Polycythemia Vera Myelofibrosis or Post-Essential Thrombocythemia Myelofibrosis) Who Have Received Prior Ruxolitinib and/or Fedratinib Monotherapy

Conditions
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Myelofibrosis, Polycythemia Vera, Thrombocythemia

Intervention / Treatment
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* Drug: itacitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of primary MF meeting the 2016 WHO criteria for overt PMF or secondary MF (PPV-MF or PET-MF) meeting the 2008 IWG-MRT criteria. At least Intermediate 1 risk MF according to the DIPSS. Prior treatment with ruxolitinib and/or fedratinib monotherapy Currently receiving ruxolitinib or fedratinib monotherapy for PMF or secondary MF. Splenomegaly defined as palpable spleen at least 5 cm below the left costal margin or volume ≥ 450 cm3 on imaging assessed during screening. Allogeneic stem cell transplant not planned. Platelet is greater than or equal to 50 × 109/L at screening. Ability to comprehend and willingness to sign a written ICF for the study. Willingness to avoid pregnancy or fathering children. Exclusion Criteria: Prior treatment with a JAK inhibitor other than ruxolitinib or fedratinib Record of ≥ 10% myeloid blasts in the peripheral blood (on peripheral blood smear) or bone marrow prior to or at the time of screening For participants on ruxolitinib or fedratinib, unable to be tapered from that treatment over the course of 14 days without corticosteroids, hydroxyurea, or other agents Treatment with ruxolitinib, fedratinib or other MF-directed therapy (approved or investigational) within 2 weeks of Day 1 Prior splenectomy or splenic irradiation within 6 months before receiving the first dose of itacitinib Unable or unwilling to undergo serial MRI or CT scans for spleen volume measurement Unable or unwilling to complete MFSAF v4.0 diary on a daily basis during the study ECOG performance status ≥ 3 Life expectancy less than 24 weeks Not willing to receive RBC or platelet transfusions Participants with laboratory values at screening outside of protocol defined ranges Significant concurrent, uncontrolled medical condition Participants with impaired cardiac function or clinically significant cardiac disease unless approved by medical monitor/sponsor History or presence of an abnormal ECG that, in the investigator's opinion, is clinically meaningful Chronic or current active infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment. Evidence of HBV or HCV infection or risk of reactivation Known HIV infection.

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 : Dose Escalation of itacitinib<br>Participants will be dosed at different dose levels with a maximum of up to 9 participants per dose level. | Drug: itacitinib<br>* itacitinb Immediate Release (IR) will be dosed orally twice a day<br>* Other names: INCB039110;|
| Experimental: Part 2 : Dose Expansion of itacitinib<br>Participants will be dosed at the recommended Phase 2 dose (RP2D) identified in Part 1. | Drug: itacitinib<br>* itacitinb Immediate Release (IR) will be dosed orally twice a day<br>* Other names: INCB039110;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 : Treatment Emergent Adverse Events (TEAE'S) | Defined as any adverse event either reported for the first time or worsening of a pre-existing event after first dose of study treatment up to 30 days after last dose of study treatment. | 24 Weeks | 
| Part 2 : Spleen Volume Reduction by MRI/CT Scan | Defined as the proportion of participants who have a reduction in spleen volume (by imaging) of at least 35 percent when compared with baseline. | 24 weeks | 
| Part 2 : Spleen Volume Reduction | Defined as the proportion of participants who have a reduction in spleen volume (by imaging) of at least 35% when compared with baseline. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2 : Treatment Emergent Adverse Events (TEAE'S) | Defined as any adverse event either reported for the first time or worsening of a pre-existing event after first dose of study treatment up to 30 days after last dose of study treatment. | 13 months | 
| Part 2 : Improvement in Total Symptom Score (TSS) | Defined as the proportion of participants who achieve at least 50% reduction in TSS over the 28 days immediately before the end of Week 24 compared with the 7 days immediately before the initiation of itacitinib IR (baseline). | 24 Weeks | 
| Part 2 : Improvement in quality of life. | Defined as the mean change in the 5 multi-item functional scale scores and the multi-item global health status scale score (EORTC QLQ-C30). | 24 weeks | 
| Part 2 : Improvement in Patient Global Impression of Change (PGIC) | Defined as percentage of participants who are categorized as improved | 24 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myelofibrosis, Post-PV Myelofibrosis, Post-ET Myelofibrosis, LIMBER, LIMBER-213, MF, Myeloproliferative Neoplasms