To Evaluate Efficacy and Safety of Parsaclisib and Ruxolitinib in Participants With Myelofibrosis Who Have Suboptimal Response to Ruxolitinib (LIMBER-304)

Study Overview
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Brief Summary
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The purpose of the study is to compare the efficacy and safety of parsaclisib when combined with ruxolitinb versus placebo combined with ruxolitinib in participants with myelofibrosis who have suboptimal response while receiving ruxolitinib monotherapy.

Detailed Description
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Prospective participants must be on stable doses of ruxolitinib ranging from 5 mg BID to 25 mg BID and will have been on that dose for at least the last 8 weeks prior to Day 1. At least 3 months duration of prior ruxolitinib is required. Participants must meet Protocol-defined criteria for suboptimal response to ruxolitinib monotherapy. 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 a participant has completed the week 24 assessments, the participant's treatment assignment will then be unblinded and if found to be placebo, the participant will have the opportunity to crossover to begin receiving parsaclisib, together with continued ruxolitinib, as long as hematology parameters are adequate.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Study of the PI3Kδ Inhibitor Parsaclisib Plus Ruxolitinib in Participants With Myelofibrosis Who Have Suboptimal Response to Ruxolitinib

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. Treated with ruxolitinib for ≥ 3 months with a stable dose for at least the last 8 weeks prior to Day 1 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 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 used for MF (whether for treatment of MF or another indication) with the exception of ruxolitinib, within 3 months of starting study drug, and/or lack of recovery from all toxicities from previous therapy (except ruxolitinib) to Grade 1 or better. 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 Unwillingness to receive RBC transfusions to treat low hemoglobin levels. Known hypersensitivity or severe reaction to parsaclisib or ruxolitinib or excipients of parsaclisib/matching placebo or ruxolitinib formulations.

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 : ruxolitinib +parsaclisib<br>Participants will receive parsaclisib starting from Day 1 for the duration of study, while continuing to receive the stable dose of ruxolitinib they were taking for the 8 weeks prior to Day 1. | 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 : ruxolitinib + placebo<br>Participants will receive placebo starting from Day 1 for the duration of study, while continuing to receive the stable dose of ruxolitinib they were taking for the 8 weeks prior to Day 1. | 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 108 | 
| 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 108 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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INCB050465, ruxolitinib, parsaclisib, LIMBER, LIMBER-304, MF, MPN, Myeloproliferative Neoplasm, Myelofibrosis, Myoproliferative Neoplasms