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

Phase 3TerminatedNCT04551053

Incyte Corporation177 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

177

Conditions

Myelofibrosis Primary Myelofibrosis Post Essential Thrombocythemia Myelofibrosis Post Polycythemia Vera Myelofibrosis

Interventions

parsaclisibDRUG

parsaclisib will be administered QD orally

ruxolitinibDRUG

ruxolitinib will be administered BID orally

placeboDRUG

placebo will be administered QD orally

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (177)

Outcomes

Primary Outcomes

Percentage of Participants Achieving ≥25% Reduction in Spleen Volume From Baseline to Week 24 as Measured by Magnetic Resonance Imaging (MRI) (or Computed Tomography [CT] Scan in Applicable Participants)

Participants had an MRI of the upper and lower abdomen and pelvis to determine the spleen volume. A CT scan was substituted for participants who were not candidates for MRI or when MRI was not readily available.

Time frame: Baseline; Week 24

Secondary Outcomes

Percentage of Participants Who Have a ≥50% Reduction in Total Symptom Score (TSS) From Baseline to Week 24 as Measured by the Myelofibrosis Symptom Assessment Form v.4.0 (MFSAF v4.0) Diary

Symptoms of myelofibrosis were assessed using the MFSAF v4.0 diary. The MFSAF v4.0 is composed of 7 individual symptom scores (fatigue, night sweats, itchiness, abdominal discomfort, pain under left ribs, early satiety, bone pain), each collected daily using a 0- (no symptoms) to 10-point (worst imaginable symptoms) scale. The daily TSS (0 to 70) is the sum of the 7 individual symptom scores collected in a day. A higher TSS corresponds to more severe symptoms. The TSS was marked as missing if there were any missing individual scores. Observations with missing dates were excluded from the analysis. The Baseline/Week 24 total score was defined as the average of the daily total scores from the last 7 days before the first dose of parsaclisib, placebo, or ruxolitinib/the Week 24 visit. The Baseline/Week 24 total score was marked as missing if there were ≥4 out of the 7 daily TSSs missing.

Time frame: Baseline; Week 24

Change in TSS From Baseline to Week 24 as Measured by the MFSAF v4.0 Diary

Data from ClinicalTrials.gov

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