To Evaluate the Efficacy and Safety of Parsaclisib and Ruxolitinib in Participants With Myelofibrosis (LIMBER-313)

Study Overview
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Brief Summary
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The purpose of the study is to compare the efficacy of parsaclisib when combined with ruxolitinb versus placebo combined with ruxolitinib in participants with myelofibrosis.

Detailed Description
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This is a Phase 3, randomized, double-blind study of the combination of the PI3Kδ inhibitor parsaclisib or matching placebo and the JAK1/2 inhibitor ruxolitinib in participants with PMF or secondary MF (PPV-MF or PET-MF) with DIPSS risk category of intermediate or high. Prospective participants must have not received prior MF therapy with a JAK inhibitor or a PI3K inhibitor. After participants have been determined to be eligible for the study and completed the baseline symptom diary assessment for 7 days, they will be randomized to 1 of 2 treatment groups, with stratification for platelet count (≥ 100 × 10^9/L vs 50 to < 100 × 10^9/L inclusive) and DIPSS risk category (high vs intermediate-2 vs intermediate-1). Once all enrolled participants completed the week 24 assessments the study will be unblinded and and participants randomized to placebo will have the opportunity to cross over to begin receiving parsaclisib, together with continued ruxolitinib, as long as hematology parameters are adequate.

Official Title
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A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Combination of PI3Kδ Inhibitor Parsaclisib and Ruxolitinib in Participants With Myelofibrosis

Conditions
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Myelofibrosis, Primary Myelofibrosis, Post Essential Thrombocythemia Myelofibrosis, Post Polycythemia Vera Myelofibrosis

Intervention / Treatment
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* Drug: parsaclisib
* Drug: ruxolitinib
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of PMF, PPV-MF, or PET-MF. DIPSS risk category of intermediate-1, intermediate-2, or high. Palpable spleen of ≥ 5 cm below the left costal margin on physical examination at the screening visit. Active symptoms of MF at the screening visit, as demonstrated by the presence of a TSS of ≥ 10 using the Screening Symptom Form. Participants with an ECOG performance status score of 0, 1, or 2. Screening bone marrow biopsy specimen and pathology report(s) available that was obtained within the prior 2 months or willingness to undergo a bone marrow biopsy at screening/baseline; willingness to undergo bone marrow biopsy at Week 24 and every 24 weeks there after. Screening/baseline biopsy specimen must show diagnosis of MF. Life expectancy of at least 24 weeks. Willingness to avoid pregnancy or fathering children. Exclusion Criteria: Prior use of any JAK inhibitor. Prior therapy with any drug that inhibits PI3K (examples of drugs targeting this pathway include but are not limited to INCB040093, idelalisib, duvelisib, buparlisib, copanlisib, and umbralisib). Use of experimental drug therapy for MF or any other standard drug (eg, danazol, hydroxyurea) used for MF within 3 months of starting study drug and/or lack of recovery from all toxicities from previous therapy to ≤ Grade 1. Inability to swallow food or any condition of the upper gastrointestinal tract that precludes administration of oral medications. Recent history of inadequate bone marrow reserve. Inadequate liver and renal function at screening. Active bacterial, fungal, parasitic, or viral infection that requires therapy. Active HBV or HCV infection that requires treatment or at risk for HBV reactivation. Known HIV infection. Uncontrolled, severe, or unstable cardiac disease that in the investigator's opinion may jeopardize the safety of the participant or compliance with the Protocol. Active invasive malignancy over the previous 2 years. Splenic irradiation within 6 months before receiving the first dose of study drug. Concurrent use of any prohibited medications. Active alcohol or drug addiction that would interfere with the ability to comply with the study requirements. Use of any potent CYP3A4 inhibitors or inducers within 14 days or 5 half lives(whichever is longer) before the first dose of study drug or anticipated during the study. Inadequate recovery from toxicity and/or complications from a major surgery before starting therapy. Currently breastfeeding or pregnant. Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the participant; or interfere with interpretation of study data. History of Grade 3 or 4 irAEs from prior immunotherapy. Receipt of any live vaccine within 30 days of the first dose of study drug

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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A : parsaclisib + ruxolitinib<br>Participants will receive parsaclisib and ruxolitinib starting from Day 1 for the duration of study, ruxolitinib dose will be determined by baseline platelet count. | Drug: parsaclisib<br>* parsaclisib will be administered QD orally<br>* Other names: INCB050465;Drug: ruxolitinib<br>* ruxolitinib will be administered BID orally<br>* Other names: Jakavi;|
| Placebo Comparator: Group B : placebo + ruxolitinib<br>Participants will receive placebo and ruxolitinib starting from Day 1 for the duration of study, ruxolitinib dose will be determined by baseline platelet count. | Drug: ruxolitinib<br>* ruxolitinib will be administered BID orally<br>* Other names: Jakavi;Drug: placebo<br>* placebo will be administered QD orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants achieving targeted reduction in spleen volume | Reduction in spleen volume is measured by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT). | Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants who have a targeted reduction in Total Symptom Score (TSS) | Reduction in TSS is measured by Myelofibrosis Symptom Assessment Form (MFSAF) v4.0. | Baseline to Week 24 | 
| Change in TSS | Change in TSS is measured by Myelofibrosis Symptom Assessment Form (MFSAF) v4.0. | Baseline to Week 24 | 
| Time to the first ≥ 50% reduction in TSS | Reduction in TSS is measured by Myelofibrosis Symptom Assessment Form (MFSAF) v4.0. | Baseline to Week 24 | 
| Overall Survival (OS) | OS is defined as randomization date to death due to any cause. | Up to approximately 36 months | 
| Number of Treatment Emergent Adverse Events (TEAE) | Defined as any adverse event either reported for the first time or worsening of a pre-existing event after first dose of study drug up to 35 days after last dose of study drug. | Up to approximately 36 months | 
| Time of onset of targeted reduction in spleen volume | Reduction in spleen volume is measured by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT). | Baseline to Week 144 | 
| Duration of maintenance of targeted reduction in spleen volume | Reduction in spleen volume is measured by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT). | Baseline to Week 144 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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INCB050465, ruxolitinib, parsaclisib, LIMBER, MF, Myelofibrosis, Myeloproliferative Neoplasms, Myoproliferative Neoplasms