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.
Brief Title
To Evaluate the Efficacy and Safety of Parsaclisib and Ruxolitinib in Participants With Myelofibrosis (LIMBER-313)
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.
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.
Categories
Completion Date
Completion Date Type
Actual
Conditions
Myelofibrosis
Primary Myelofibrosis
Post Essential Thrombocythemia Myelofibrosis
Post Polycythemia Vera Myelofibrosis
Eligibility Criteria
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
* 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
Inclusion Criteria
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.
* 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.
Gender
All
Gender Based
false
Keywords
INCB050465
ruxolitinib
parsaclisib
LIMBER
MF
Myelofibrosis
Myeloproliferative Neoplasms
Myoproliferative Neoplasms
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT04551066
Org Class
Industry
Org Full Name
Incyte Corporation
Org Study Id
INCB 50465-313/LIMBER-313
Overall Status
Terminated
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Combination of PI3Kδ Inhibitor Parsaclisib and Ruxolitinib in Participants With Myelofibrosis
Primary Outcomes
Outcome Description
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.
Outcome Measure
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)
Outcome Time Frame
Baseline; Week 24
Secondary Outcomes
Outcome Description
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.
Outcome Time Frame
Baseline; Week 24
Outcome Measure
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
Outcome Description
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.
Outcome Time Frame
Baseline; Week 24
Outcome Measure
Change in TSS From Baseline to Week 24 as Measured by the MFSAF v4.0 Diary
Outcome Description
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.
Outcome Time Frame
Baseline; up to Week 24
Outcome Measure
Time to the First ≥50% Reduction in TSS as Measured by the MFSAF v4.0 Diary
Outcome Description
Overall survival was defined as the interval between the randomization date and the date of death due to any cause.
Outcome Time Frame
up to 749 days
Outcome Measure
Overall Survival
Outcome Description
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.
Outcome Time Frame
up to 749 days
Outcome Measure
Number of Participants With Any Treatment-emergent Adverse Event (TEAE)
Outcome Description
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.
Outcome Time Frame
up to 749 days
Outcome Measure
Number of Participants With Any Grade 3 or Higher TEAE
Outcome Description
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.
Outcome Time Frame
up to 749 days
Outcome Measure
Time of Onset of a ≥35% Reduction in Spleen Volume
Outcome Description
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.
Outcome Time Frame
up to 749 days
Outcome Measure
Duration of Maintenance of a ≥35% Reduction in Spleen Volume
See Also Links
Url
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Swati Goel
Investigator Email
swgoel@montefiore.org
Investigator Phone
718-920-6310 / 718-920-4137
Categories Mesh Debug
Blood & Bone Marrow Cancers --- MYELOPROLIFERATIVE DISORDERS
Blood & Bone Marrow Cancers --- BONE MARROW DISEASES
Blood Disorders --- HEMATOLOGIC DISEASES
Blood & Bone Marrow Cancers --- HEMATOLOGIC DISEASES
MeSH Terms
PRIMARY MYELOFIBROSIS
MYELOPROLIFERATIVE DISORDERS
BONE MARROW DISEASES
HEMATOLOGIC DISEASES
HEMIC AND LYMPHATIC DISEASES
PARSACLISIB
RUXOLITINIB
COUNTERFEIT DRUGS
SUBSTANDARD DRUGS
PHARMACEUTICAL PREPARATIONS