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

Phase 3

Terminated

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

Interventions: Drug: parsaclisib
Drug: placebo
Drug: ruxolitinib

Registration Number: NCT04551066

Lead Sponsor: Incyte Corporation

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 252

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group B : placebo + ruxolitinib	placebo	Participants will receive placebo and ruxolitinib starting from Day 1 for the duration of study, ruxolitinib dose will be determined by baseline platelet count.
Group A : parsaclisib + ruxolitinib	parsaclisib	Participants will receive parsaclisib and ruxolitinib starting from Day 1 for the duration of study, ruxolitinib dose will be determined by baseline platelet count.
Group A : parsaclisib + ruxolitinib	ruxolitinib	Participants will receive parsaclisib and ruxolitinib starting from Day 1 for the duration of study, ruxolitinib dose will be determined by baseline platelet count.
Group B : placebo + ruxolitinib	ruxolitinib	Participants will receive placebo and ruxolitinib starting from Day 1 for the duration of study, ruxolitinib dose will be determined by baseline platelet count.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Achieving ≥35% Reduction in Spleen Volume From Baseline to Week 24 as Measured by Magnetic Resonance Imaging [MRI] (or Computed Tomography [CT] Scan in Applicable Participants)	Baseline; Week 24	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. Determination of spleen length below the left costal margin was measured by palpation, using a flexible ruler provided by the sponsor.

Secondary Outcome Measures

Name	Time	Method
Time to the First ≥50% Reduction in TSS as Measured by the MFSAF v4.0 Diary	Baseline; up to Week 24	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 on the same day. Higher TSS indicate more severe symptoms. The TSS was 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 scores was missing if there were ≥4 missing out of the 7 daily total scores.
Overall Survival	up to 749 days	Overall survival was defined as the interval between the randomization date and the date of death due to any cause.
Percentage of Participants Who Had a ≥50% Reduction in Total Symptom Score (TSS) From Baseline to Week 24 as Measured by the Myelofibrosis Symptom Assessment Form v4.0 (MFSAF v4.0) Diary	Baseline; Week 24	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 on the same day. Higher TSS indicate more severe symptoms. The TSS was 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 scores was missing if there were ≥4 missing out of the 7 daily total scores.
Change in TSS From Baseline to Week 24 as Measured by the MFSAF v4.0 Diary	Baseline; Week 24	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 on the same day. Higher TSS indicate more severe symptoms. The TSS was 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 scores was missing if there were ≥4 missing out of the 7 daily total scores. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Number of Participants With Any Treatment-emergent Adverse Event (TEAE)	up to 749 days	An adverse event (AE) is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it is considered drug related. An AE could therefore be any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. A TEAE is defined as any AE either reported for the first time or the worsening of a pre-existing event after the first dose of study drug until 30 to 35 days after the last dose of parsaclisib/matching placebo or ruxolitinib.
Number of Participants With Any Grade 3 or Higher TEAE	up to 749 days	An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it is considered drug related. A TEAE is defined as any AE either reported for the first time or the worsening of a pre-existing event after the first dose of study drug until 30 to 35 days after the last dose of parsaclisib/matching placebo or ruxolitinib. The severity of AEs was assessed using Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Grades 1 through 5. Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: moderate; minimal, local or noninvasive intervention indicated; limiting instrumental activities of daily living (ADL). Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4: life-threatening urgent intervention indicated. Grade 5: death related to AE.
Time of Onset of a ≥35% Reduction in Spleen Volume	up to 749 days	The time to the first ≥35% reduction in spleen volume is defined as the time from randomization to the first time participants had ≥35% reduction in spleen volume.
Duration of Maintenance of a ≥35% Reduction in Spleen Volume	up to 749 days	The duration of ≥35% reduction from Baseline in spleen volume was defined as the interval between the first spleen volume measurement that was a ≥35% reduction from Baseline and the date of the first measurement that was no longer a ≥35% reduction from Baseline.

Trial Locations

Locations (175): Alaska Oncology and Hematology
🇺🇸
Anchorage, Alaska, United States
Mayo Clinic Rochester
🇺🇸
Phoenix, Arizona, United States
Sutter Health Alta Bates Summit Medical Center Absmc Alta Bates Summit Comprehensive Cancer Center
🇺🇸
Berkeley, California, United States
CCARE
🇺🇸
Fresno, California, United States
California Research Institute (Cri)
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Los Angeles, California, United States
UCLA School of Medicine
🇺🇸
Los Angeles, California, United States
Scripps Clinic
🇺🇸
San Diego, California, United States
Coastal Integrated Cancer Care-Cicc
🇺🇸
San Luis Obispo, California, United States
Stamford Hospital-Medical Oncology Hematology
🇺🇸
Stamford, Connecticut, United States
Georgetown University
🇺🇸
Washington, District of Columbia, United States
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Alaska Oncology and Hematology
🇺🇸Anchorage, Alaska, United States