A Study of INCB050465 in Combination With Ruxolitinib in Subjects With Myelofibrosis
- Conditions
- MPN (Myeloproliferative Neoplasms)
- Interventions
- Registration Number
- NCT02718300
- Lead Sponsor
- Incyte Corporation
- Brief Summary
The purpose of this study is to evaluate the safety, tolerability, and efficacy of the combination of parsaclisib and ruxolitinib in subjects with myelofibrosis.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 74
- 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
-
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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part 1: Ruxolitinib + Parsaclisib Parsaclisib Initial cohort dose of parsaclisib added to existing stable regimen of ruxolitinib, with subsequent cohort escalations based on protocol-specific criteria. Part 2: Ruxolitinib + Parsaclisib Parsaclisib Part 2 will compare 2 doses of parsaclisib . Part 4: Ruxolitinib + Parsaclisib Parsaclisib Part 4 will compare 2 different daily dosing strategies. Part 1: Ruxolitinib + Parsaclisib Ruxolitinib Initial cohort dose of parsaclisib added to existing stable regimen of ruxolitinib, with subsequent cohort escalations based on protocol-specific criteria. Part 2: Ruxolitinib + Parsaclisib Ruxolitinib Part 2 will compare 2 doses of parsaclisib . Part 3: Ruxolitinib + Parsaclisib Ruxolitinib Part 3 will compare 2 different long term dosing strategies. Part 4: Ruxolitinib + Parsaclisib Ruxolitinib Part 4 will compare 2 different daily dosing strategies. Part 3: Ruxolitinib + Parsaclisib Parsaclisib Part 3 will compare 2 different long term dosing strategies.
- Primary Outcome Measures
Name Time Method Number of Participants With Dose-limiting Toxicities (DLTs) up to Day 28 DLTs were defined as the occurrence of any protocol-defined toxicities occurring up to and including Day 28, except those with a clear alternative explanation (e.g., disease progression, other medications) or transient (≤ 72 hours) abnormal laboratory values without associated clinically significant signs or symptoms based on investigator determination. All DLTs were assessed by the investigator using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 criteria.
Change From Baseline in Spleen Volume Through Week 12 of the Initial Study Period as Measured by Magnetic Resonance Imaging (MRI) (or Computed Tomography [CT] Scan in Applicable Participants) Baseline; Week 12 Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Percent Change From Baseline in Spleen Volume Through Week 12 as Measured by MRI (or CT Scan in Applicable Participants) Baseline; Week 12 Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] / Baseline value) x 100.
- Secondary Outcome Measures
Name Time Method Change From Baseline in Spleen Volume Through Week 24 of the Initial Study Period as Measured by MRI (or CT Scan in Applicable Participants) Baseline; Week 24 Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Percent Change From Baseline in Spleen Volume Through Week 24 as Measured by MRI (or CT Scan in Applicable Participants ) Baseline; Week 24 Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] / Baseline value) x 100.
Change From Baseline in the Total Symptom Score (TSS) Through Week 12 as Measured by Myelofibrosis Symptom Assessment Form (MFSAF) Version 3.0 (v3.0) Symptom Diary Baseline; Week 12 The MFSAF v3.0 is comprised of 19 individual symptom scores, each collected daily using an 11-point scale. The daily TSS is composed of 6 of these individual symptom scores (nights sweats, itchiness, abdominal discomfort, pain under left ribs, early satiety, bone/muscle pain) collected on the same day. Participants scored each symptom using a scale from 0 (absent) to 10 (worst imaginable). The TSS was calculated as a sum of all 6 symptom scores; scores ranged from 0 to 60, with higher scores corresponding to more severe symptoms. The Baseline TSS was defined as the average of daily total scores from the last 7 days before the first dose of INCB050465. The Week 12 TSS was the average of the daily total scores from the last 7 consecutive days before the Week 12 visit. Change from Baseline was calculated as the post-Baseline score minus the Baseline score.
Percent Change From Baseline in the TSS Through Week 12 as Measured by MFSAF v3.0 Symptom Diary Baseline; Week 12 The MFSAF v3.0 is comprised of 19 individual symptom scores, each collected daily using an 11-point scale. The daily TSS is composed of 6 of these individual symptom scores (nights sweats, itchiness, abdominal discomfort, pain under left ribs, early satiety, bone/muscle pain) collected on the same day. Participants scored each symptom using a scale from 0 (absent) to 10 (worst imaginable). The TSS was calculated as a sum of all 6 symptom scores; scores ranged from 0 to 60, with higher scores corresponding to more severe symptoms. The Baseline TSS was defined as the average of daily total scores from the last 7 days before the first dose of INCB050465. The Week 12 TSS was the average of the daily total scores from the last 7 consecutive days before the Week 12 visit. Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] / Baseline value) x 100.
Change From Baseline in the TSS Through Week 24 as Measured by MFSAF v3.0 Symptom Diary Baseline; Week 24 The MFSAF v3.0 is comprised of 19 individual symptom scores, each collected daily using an 11-point scale. The daily TSS is composed of 6 of these individual symptom scores (nights sweats, itchiness, abdominal discomfort, pain under left ribs, early satiety, bone/muscle pain) collected on the same day. Participants scored each symptom using a scale from 0 (absent) to 10 (worst imaginable). The TSS was calculated as a sum of all 6 symptom scores; scores ranged from 0 to 60, with higher scores corresponding to more severe symptoms. The Baseline TSS was defined as the average of daily total scores from the last 7 days before the first dose of INCB050465. The Week 24 TSS was the average of the daily total scores from the last 7 consecutive days before the Week 24 visit. Change from Baseline was calculated as the post-Baseline score minus the Baseline score.
Percent Change From Baseline in the TSS Through Week 12 as Measured by MPN-SAF Baseline; Week 12 The MPN-SAF weekly total score is defined as the sum of 10 individual symptom scores (fatigue, nights sweats, itchiness, bone pain, fever, unintentional weight loss last 6 months, early satiety, abdominal discomfort, inactivity, problems with concentration) collected at the same visit using an 11-point scale. Participants scored each symptom using a scale from 0 (absent) to 10 (worst imaginable). The TSS was calculated as a sum of all 10 symptom scores; scores ranged from 0 to 100, with higher scores corresponding to more severe symptoms. Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] / Baseline value) x 100.
Change From Baseline in the TSS Through Week 24 as Measured by MPN-SAF Baseline; Week 24 The MPN-SAF weekly total score is defined as the sum of 10 individual symptom scores (fatigue, nights sweats, itchiness, bone pain, fever, unintentional weight loss last 6 months, early satiety, abdominal discomfort, inactivity, problems with concentration) collected at the same visit using an 11-point scale. Participants scored each symptom using a scale from 0 (absent) to 10 (worst imaginable). The TSS was calculated as a sum of all 10 symptom scores; scores ranged from 0 to 100, with higher scores corresponding to more severe symptoms. Change from Baseline was calculated as the post-Baseline score minus the Baseline score.
Percent Change From Baseline in the TSS Through Week 24 as Measured by MPN-SAF Baseline; Week 24 The MPN-SAF weekly total score is defined as the sum of 10 individual symptom scores (fatigue, nights sweats, itchiness, bone pain, fever, unintentional weight loss last 6 months, early satiety, abdominal discomfort, inactivity, problems with concentration) collected at the same visit using an 11-point scale. Participants scored each symptom using a scale from 0 (absent) to 10 (worst imaginable). The TSS was calculated as a sum of all 10 symptom scores; scores ranged from 0 to 100, with higher scores corresponding to more severe symptoms. Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] / Baseline value) x 100.
Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) Baseline; up to 1494 days (EOT) The PGIC questionnaire consists of a single question with 7 possible answers: "Since the start of treatment you've received in this study, your myelofibrosis symptoms are: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; 7, very much worse."
Mean PGIC Score at Week 12, Week 24, and the EOT up to 1494 days (EOT) The PGIC questionnaire consists of a single question with 7 possible answers: "Since the start of treatment you've received in this study, your myelofibrosis symptoms are: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; 7, very much worse."
Best Overall Response (Percentage of Participants With Complete Response [CR] or Partial Response [PR]) for Investigator-Reported International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Response Assessment Week 12 and every 12 weeks thereafter (up to 1494 days [EOT]) A participant was considered as a responder if the participant had a best overall response of CR or PR. CR: (a) bone marrow (BM): age-adjusted normocellularity (AAN); \< 5% blasts; ≤ grade 1 myelofibrosis (MF); (b) peripheral blood (PD): hemoglobin (Hg) ≥ 100 grams per Liter (g/L) and \< upper normal limit (UNL); neutrophils ≥ 1 × 10\^9/L and \< UNL; (c) platelets ≥ 100 × 10\^9/L and \< UNL; \< 2% immature myeloid cells (IMCs); (d) clinical: resolution of disease symptoms; spleen/liver not palpable; no extramedullary hematopoiesis (EMH). PR: (a) PB: Hg ≥ 100 g/L and \< UNL; neutrophils ≥ 1 × 10\^9/L and \< UNL; platelets ≥ 100 × 10\^9/L and \< UNL; \< 2% IMCs; (b) clinical: resolution of disease symptoms; spleen/liver not palpable; no EMH; (c) BM: AAN; \< 5% blasts; ≤ Grade 1 MF; and PB: Hg ≥ 85 g/L but \< 100 g/L and \< UNL; neutrophils ≥ 1 × 10\^9/L and \< UNL; platelets ≥ 50 × 10\^9/L but \< 100 × 10\^9/L and \< UNL; \< 2% IMCs.
Number of Participants With Any Treatment-emergent Adverse Event (TEAE) up to approximately 4 years An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, that occurred after a participant provided informed consent. Abnormal laboratory values or test results occurring after informed consent constituted AEs only if they induced clinical signs or symptoms, were considered clinically meaningful, required therapy (e.g., hematologic abnormality that required transfusion), or requird changes in the study drug(s). TEAEs were defined as AEs that began or worsened from Baseline after the first administration of study drug.
Percent Change From Baseline in the TSS Through Week 24 as Measured by MFSAF v3.0 Symptom Diary Baseline; Week 24 The MFSAF v3.0 is comprised of 19 individual symptom scores, each collected daily using an 11-point scale. The daily TSS is composed of 6 of these individual symptom scores (nights sweats, itchiness, abdominal discomfort, pain under left ribs, early satiety, bone/muscle pain) collected on the same day. Participants scored each symptom using a scale from 0 (absent) to 10 (worst imaginable). The TSS was calculated as a sum of all 6 symptom scores; scores ranged from 0 to 60, with higher scores corresponding to more severe symptoms. The Baseline TSS was defined as the average of daily total scores from the last 7 days before the first dose of INCB050465. The Week 24 TSS was the average of the daily total scores from the last 7 consecutive days before the Week 24 visit. Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] / Baseline value) x 100.
Change From Baseline in the TSS Through Week 12 as Measured by Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) Baseline; Week 12 The MPN-SAF weekly total score is defined as the sum of 10 individual symptom scores (fatigue, nights sweats, itchiness, bone pain, fever, unintentional weight loss last 6 months, early satiety, abdominal discomfort, inactivity, problems with concentration) collected at the same visit using an 11-point scale. Participants scored each symptom using a scale from 0 (absent) to 10 (worst imaginable). The TSS was calculated as a sum of all 10 symptom scores; scores ranged from 0 to 100, with higher scores corresponding to more severe symptoms. Change from Baseline was calculated as the post-Baseline score minus the Baseline score.
Number of Participants With Any TEAE During the Transition Period up to approximately 4 years An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, that occurred after a participant provided informed consent. Abnormal laboratory values or test results occurring after informed consent constituted AEs only if they induced clinical signs or symptoms, were considered clinically meaningful, required therapy (e.g., hematologic abnormality that required transfusion), or requird changes in the study drug(s). TEAEs were defined as AEs that began or worsened from Baseline after the first administration of study drug. Participants who had been assigned to dosing arms with weekly dosing beyond Week 8 had the opportunity to transition to all daily dosing at 5 mg if agreed upon by the participant and the Investigator.
Cmax of Parsaclisib Week 2 and Week 4: predose and 1, 2, and 4 hours post-dose Cmax was defined as the maximum observed plasma concentration.
Tmax of Parsaclisib Week 2 and Week 4: predose and 1, 2, and 4 hours post-dose tmax was defined as the time to the maximum concentration.
Cmin of Parsaclisib Week 2 and Week 4: predose and 1, 2, and 4 hours post-dose Cmin was defined as the minimum observed plasma concentration.
AUC0-4h of Parsaclisib Week 2 and Week 4: predose and 1, 2, and 4 hours post-dose AUC0-4h was defined as the area under the plasma concentration-time curve from time = 0 to 4 hours post-dose.
AUC0-t of Parsaclisib Week 2 and Week 4: predose and 1, 2, and 4 hours post-dose AUC0-t was defined as the area under the plasma concentration-time curve from time =0 to the last measurable concentration at time = t.
Clast of Parsaclisib Week 2 and Week 4: predose and 1, 2, and 4 hours post-dose Clast was defined as the last quantifiable concentration.
Tlast of Parsaclisib Week 2 and Week 4: predose and 1, 2, and 4 hours post-dose tlast was defined as the time of the last quantifiable concentration.
Cmax of Ruxolitinib Day 1 and Week 4: predose and 1, 2, and 4 hours post-dose Cmax was defined as the maximum observed plasma concentration.
Tmax of Ruxolitinib Day 1 and Week 4: predose and 1, 2, and 4 hours post-dose tmax was defined as the time to the maximum concentration.
Cmin of Ruxolitinib Day 1 and Week 4: predose and 1, 2, and 4 hours post-dose Cmin was defined as the minimum observed plasma concentration.
AUC0-4h of Ruxolitinib Day 1 and Week 4: predose and 1, 2, and 4 hours post-dose AUC0-4h was defined as the area under the plasma concentration-time curve from time = 0 to 4 hours post-dose.
AUC0-t of Ruxolitinib Day 1 and Week 4: predose and 1, 2, and 4 hours post-dose AUC0-t was defined as the area under the plasma concentration-time curve from time =0 to the last measurable concentration at time = t.
Clast of Ruxolitinib Day 1 and Week 4: predose and 1, 2, and 4 hours post-dose Clast was defined as the last quantifiable concentration.
Tlast of Ruxolitinib Day 1 and Week 4: predose and 1, 2, and 4 hours post-dose tlast was defined as the time of the last quantifiable concentration.
Trial Locations
- Locations (39)
California Cancer Associates For Research and Excellence
🇺🇸Fresno, California, United States
Baylor Scott and White Research Institute
🇺🇸Dallas, Texas, United States
University of Chicago Medical Center
🇺🇸Chicago, Illinois, United States
Indiana Blood and Marrow Transplantation
🇺🇸Indianapolis, Indiana, United States
Md Anderson Cancer Center
🇺🇸Houston, Texas, United States
Oncology Hematology Care, Inc.
🇺🇸Cincinnati, Ohio, United States
Cancer Care Centers of South Texas
🇺🇸San Antonio, Texas, United States
Rush University Medical Center
🇺🇸Nashville, Tennessee, United States
Va Salt Lake City Health Care System
🇺🇸Salt Lake City, Utah, United States
UCLA School of Medicine
🇺🇸Los Angeles, California, United States
Birmingham Hematology & Oncolgy Associates Llc
🇺🇸Birmingham, Alabama, United States
McFarland Clinic
🇺🇸Ames, Iowa, United States
Cancer Center For Blood Disorders
🇺🇸Bethesda, Maryland, United States
University of Southern California
🇺🇸Los Angeles, California, United States
Emory University
🇺🇸Atlanta, Georgia, United States
University of Kansas Cancer Center
🇺🇸Westwood, Kansas, United States
Saint Agnes Hospital
🇺🇸Baltimore, Maryland, United States
Shands Hospital
🇺🇸Gainesville, Florida, United States
Summit Medical Group
🇺🇸Florham Park, New Jersey, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Norton Cancer Institute
🇺🇸Louisville, Kentucky, United States
Mount Sinai School of Medicine
🇺🇸New York, New York, United States
Roswell Park Cancer Institute
🇺🇸Buffalo, New York, United States
Renovatio Clinical Consultants Llc
🇺🇸The Woodlands, Texas, United States
Alta Bates Medical Center
🇺🇸Berkeley, California, United States
Mayo Clinic Arizona
🇺🇸Scottsdale, Arizona, United States
Georgetown University Hospital
🇺🇸Washington, District of Columbia, United States
California Cancer Assoc. for Research and Excellence
🇺🇸San Marcos, California, United States
Pcr Oncology
🇺🇸Pismo Beach, California, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
New Mexico Cancer Care Alliance
🇺🇸Albuquerque, New Mexico, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
Oregon Health & Science University
🇺🇸Portland, Oregon, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Vista Oncology Inc Ps
🇺🇸Olympia, Washington, United States
City of Hope National Medical Center
🇺🇸Duarte, California, United States
Montefiore Medical Center
🇺🇸Bronx, New York, United States