A Study of INCB050465 in Combination With Ruxolitinib in Subjects With Myelofibrosis

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, and efficacy of the combination of parsaclisib and ruxolitinib in subjects with myelofibrosis.

Official Title
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A Phase 2 Study of the Safety, Tolerability, and Efficacy of INCB050465 in Combination With Ruxolitinib in Subjects With Myelofibrosis

Conditions
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MPN (Myeloproliferative Neoplasms)

Intervention / Treatment
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* Drug: Parsaclisib
* Drug: Parsaclisib
* Drug: Ruxolitinib
* Drug: Parsaclisib
* Drug: Parsaclisib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis Palpable spleen of > 10 cm below the left subcostal margin on physical examination at the screening visit OR Palpable splenomegaly of 5 to 10 cm below left subcostal margin on physical exam AND active symptoms of MF at the screening visit as demonstrated by presence of 1 symptom score ≥ 5 or 2 symptom scores ≥ 3 using the Screening Symptom Form Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 Exclusion Criteria: Use of experimental drug therapy for myelofibrosis, or any other standard drug (eg, danazol, hydroxyurea, etc) with the exception of ruxolitinib within 6 months of starting study (combination) therapy 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 Unwillingness to be transfused with blood components Recent history of inadequate bone marrow reserve as demonstrated by the following: Platelet count < 50 × 10^9/L in the 4 weeks before screening or platelet transfusion(s) within 8 weeks before screening Absolute neutrophil count levels < 0.5 × 10^9/L in the 4 weeks before screening Subjects with peripheral blood blast count of > 10% at the screening or baseline hematology assessments Subjects who are not willing to receive red blood cell (RBC) transfusions to treat low hemoglobin levels Inadequate liver function at screening as demonstrated by the following: Direct bilirubin ≥ 2.0 × the upper limit of laboratory normal (ULN). (NOTE: direct bilirubin will only be determined if total bilirubin is ≥ 2.0 × ULN) alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 × ULN Inadequate renal function at screening as demonstrated by creatinine clearance < 50 mL/min or glomerular filtration rate < 50 mL/min/1.73 m^2

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Ruxolitinib + Parsaclisib<br>Initial cohort dose of parsaclisib added to existing stable regimen of ruxolitinib, with subsequent cohort escalations based on protocol-specific criteria. | Drug: Parsaclisib<br>* Up to 3 oral once a day (QD) doses of parsaclisib. Doses will be taken once daily for 8 weeks, followed by once weekly dosing at the same dose level.<br>* Other names: INCB050465;Drug: Ruxolitinib<br>* The dose of ruxolitinib will be that which the subjects had been taking for at least 8 weeks before the first dose of parsaclisib.<br>* Other names: Jakafi®;|
| Experimental: Part 2: Ruxolitinib + Parsaclisib<br>Part 2 will compare 2 doses of parsaclisib . | Drug: Parsaclisib<br>* Two recommended oral QD doses of parsaclisib. Once daily doses of parsaclisib will be taken for 8 weeks, followed by once weekly dosing at the same dose level.<br>* Other names: INCB050465;Drug: Ruxolitinib<br>* The dose of ruxolitinib will be that which the subjects had been taking for at least 8 weeks before the first dose of parsaclisib.<br>* Other names: Jakafi®;|
| Experimental: Part 3: Ruxolitinib + Parsaclisib<br>Part 3 will compare 2 different long term dosing strategies. | Drug: Ruxolitinib<br>* The dose of ruxolitinib will be that which the subjects had been taking for at least 8 weeks before the first dose of parsaclisib.<br>* Other names: Jakafi®;Drug: Parsaclisib<br>* 20 mg oral QD dose of parsaclisib for 8 weeks. After 8 weeks patients will take either 20 mg once weekly or 5 mg once daily.<br>* Other names: INCB050465;|
| Experimental: Part 4: Ruxolitinib + Parsaclisib<br>Part 4 will compare 2 different daily dosing strategies. | Drug: Ruxolitinib<br>* The dose of ruxolitinib will be that which the subjects had been taking for at least 8 weeks before the first dose of parsaclisib.<br>* Other names: Jakafi®;Drug: Parsaclisib<br>* 2 dose strategies will be compared: 5 mg parsaclisib beginning on Day 1 until end of treatment. 20 mg oral QD dose of parsaclisib for 8 weeks; after 8 weeks patients will take 5 mg once daily.<br>* Other names: INCB050465;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of Participants With Dose Limiting Toxicities (DLTs) |  | Baseline to Day 28 | 
| Part 2, Part 3 and Part 4: Change From Baseline in Spleen Volume at Week 12 as measured by MRI or CT scan |  | Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with adverse events (AEs) and changes in vital signs, ECGs, and laboratory parameters |  | Screening through up to 30 days after last dose of study drug, up to 25 months | 
| Change in total symptom score as measured by patient-reported myelofibrosis symptoms |  | Baseline through Week 12 or Week 24 | 
| Change From Baseline in Spleen Volume at Week 24 as measured by MRI or CT scan |  | Baseline to Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), post-essential thrombocythemia myelofibrosis (PET-MF), myeloproliferative neoplasms (MPNs), phosphoinositide 3-kinase (PI3K) inhibitor, Janus kinase (JAK) inhibitor