MPN (Myeloproliferative Neoplasms)
Conditions
Keywords
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
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.
Interventions
DRUGParsaclisib
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.
DRUGRuxolitinib
The dose of ruxolitinib will be that which the subjects had been taking for at least 8 weeks before the first dose of parsaclisib.
Sponsors
Incyte Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Pre-assignment details
This study was conducted at 20 study centers in the United States. Participants who initially received weekly doses were given the option of transitioning to daily doses based on a preliminary analysis of data. All participants were analyzed according to their original treatment assignment in the Participant Flow and Baseline Characteristic module; those participants who transitioned from weekly to daily doses (n=8) were analyzed separately for specific outcome measures.
Participants by arm
| Arm | Count |
|---|---|
| TG5I/M Participants received at least 6 months of prior ruxolitinib therapy, including ruxolitinib administration at a stable dose of 5 milligrams (mg) twice a day (BID) to 25 mg BID for at least 8 weeks before randomization. From Day 1 to the end of Week 8, participants received oral parsaclisib 20 mg once daily (QD), followed by 5 mg QD until discontinuation criteria were met, in combination with the pre-Day 1 stable dose of ruxolitinib (5 to 25 mg BID). | 21 |
| TG5D Participants received at least 6 months of prior ruxolitinib therapy, including ruxolitinib administration at a stable dose of 5 mg BID to 25 mg BID for at least 8 weeks before randomization. From Day 1, participants received oral parsaclisib 5 mg QD until discontinuation criteria were met, in combination with the pre-Day 1 stable dose of ruxolitinib (5 to 25 mg BID). | 21 |
| TG10 + TG20: Daily/Weekly Dosing Participants received at least 6 months of prior ruxolitinib therapy, including ruxolitinib administration at a stable dose of 5 mg BID to 25 mg BID for at least 8 weeks before randomization. From Day 1 to the end of Week 8, participants in TG10 and TG20 received oral parsaclisib 10 mg or 20 mg QD, respectively, followed by the same dose weekly until discontinuation criteria were met, in combination with the pre-Day 1 stable dose of ruxolitinib (5 to 25 mg BID). | 32 |
| Total | 74 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 4 | 5 | 17 |
| Overall Study | Lost to Follow-up | 1 | 0 | 2 |
| Overall Study | Physician Decision | 1 | 0 | 2 |
| Overall Study | Study Terminated by Sponsor | 6 | 3 | 4 |
| Overall Study | Transitioned to Rollover Study or Pursued Allogenic Transplant | 9 | 9 | 4 |
| Overall Study | Withdrawal by Subject | 0 | 4 | 3 |
Baseline characteristics
| Characteristic | TG5I/M | TG5D | TG10 + TG20: Daily/Weekly Dosing | Total |
|---|---|---|---|---|
| Age, Continuous | 67.9 years STANDARD_DEVIATION 7.33 | 69.3 years STANDARD_DEVIATION 7.96 | 66.0 years STANDARD_DEVIATION 8.94 | 67.5 years STANDARD_DEVIATION 8.25 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 3 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 19 Participants | 27 Participants | 64 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 2 Participants | 3 Participants | 5 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Captured as Other in Database | 0 Participants | 2 Participants | 4 Participants | 6 Participants |
| Race/Ethnicity, Customized White | 20 Participants | 15 Participants | 25 Participants | 60 Participants |
| Sex: Female, Male Female | 11 Participants | 11 Participants | 17 Participants | 39 Participants |
| Sex: Female, Male Male | 10 Participants | 10 Participants | 15 Participants | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 14 | 11 / 18 | 4 / 21 | 5 / 21 | 26 / 74 | 3 / 8 |
| other Total, other adverse events | 13 / 14 | 18 / 18 | 20 / 21 | 20 / 21 | 71 / 74 | 8 / 8 |
| serious Total, serious adverse events | 2 / 14 | 11 / 18 | 7 / 21 | 6 / 21 | 26 / 74 | 3 / 8 |
Outcome results
Primary
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)
Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time frame: Baseline; Week 12
Population: Initial Safety Population: all enrolled participants who received at least 1 dose of study drug. Analysis was conducted on the Safety Population during the initial safety period. Only participants with available data were analyzed. Due to early termination of the study, per the Statistical Analysis Plan, daily and weekly dosing arms were combined for efficacy analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TG5I/M | 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 | 1779.0 centimeters cubed (cm^3) | Standard Deviation 1006.75 |
| TG5I/M | 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) | Change from Baseline at Week 12 | 383.3 centimeters cubed (cm^3) | Standard Deviation 2342.09 |
| TG5D | 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 | 2032.3 centimeters cubed (cm^3) | Standard Deviation 773.45 |
| TG5D | 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) | Change from Baseline at Week 12 | -276.9 centimeters cubed (cm^3) | Standard Deviation 226.11 |
| TG10 + TG20: Daily/Weekly Dosing | 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 | 2469.0 centimeters cubed (cm^3) | Standard Deviation 1208.9 |
| TG10 + TG20: Daily/Weekly Dosing | 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) | Change from Baseline at Week 12 | -54.3 centimeters cubed (cm^3) | Standard Deviation 312.69 |
Primary
Number of Participants With Dose-limiting Toxicities (DLTs)
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.
Time frame: up to Day 28
Population: Initial Safety Population: all participants who received at least 1 dose of study drug. Treatment groups were determined according to the actual treatment the participant received regardless of assigned study drug treatment. Analysis was conducted on the Safety Population during the initial safety period. Due to early termination of the study, per the Statistical Analysis Plan, daily and weekly dosing arms were combined for analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TG5I/M | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
| TG5D | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
| TG10 + TG20: Daily/Weekly Dosing | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
Primary
Percent Change From Baseline in Spleen Volume Through Week 12 as Measured by MRI (or CT Scan in Applicable Participants)
Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] / Baseline value) x 100.
Time frame: Baseline; Week 12
Population: Initial Safety Population. Analysis was conducted on the Safety Population during the initial safety period. Only participants with available data were analyzed. Due to early termination of the study, per the Statistical Analysis Plan, daily and weekly dosing arms were combined for efficacy analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TG5I/M | Percent Change From Baseline in Spleen Volume Through Week 12 as Measured by MRI (or CT Scan in Applicable Participants) | 9.2 percent change | Standard Deviation 104.37 |
| TG5D | Percent Change From Baseline in Spleen Volume Through Week 12 as Measured by MRI (or CT Scan in Applicable Participants) | -15.2 percent change | Standard Deviation 10.89 |
| TG10 + TG20: Daily/Weekly Dosing | Percent Change From Baseline in Spleen Volume Through Week 12 as Measured by MRI (or CT Scan in Applicable Participants) | -3.1 percent change | Standard Deviation 12.21 |
p-value: 0.4046Van Elteren test
Secondary
AUC0-4h of Parsaclisib
AUC0-4h was defined as the area under the plasma concentration-time curve from time = 0 to 4 hours post-dose.
Time frame: Week 2 and Week 4: predose and 1, 2, and 4 hours post-dose
Population: PK Population. Only participants with available data were analyzed. To be able to form a meaningful statistical test with enough participants, participants across all treatment groups were combined according to the dose of parsaclisib received for analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| TG5I/M | AUC0-4h of Parsaclisib | Week 2 | 982 hours * nmol/L | Geometric Coefficient of Variation 39.4 |
| TG5I/M | AUC0-4h of Parsaclisib | Week 4 | 1080 hours * nmol/L | Geometric Coefficient of Variation 34.7 |
| TG5D | AUC0-4h of Parsaclisib | Week 2 | 2000 hours * nmol/L | Geometric Coefficient of Variation 30.5 |
| TG5D | AUC0-4h of Parsaclisib | Week 4 | 2140 hours * nmol/L | Geometric Coefficient of Variation 28 |
| TG10 + TG20: Daily/Weekly Dosing | AUC0-4h of Parsaclisib | Week 2 | 4560 hours * nmol/L | Geometric Coefficient of Variation 30.3 |
| TG10 + TG20: Daily/Weekly Dosing | AUC0-4h of Parsaclisib | Week 4 | 5070 hours * nmol/L | Geometric Coefficient of Variation 32.1 |
Comparison: Week 2p-value: 0.2873ANOVA
Comparison: Week 295% CI: [0.773, 1.336]
Comparison: Week 295% CI: [0.943, 1.429]
Comparison: Week 4p-value: 0.1601ANOVA
Comparison: Week 495% CI: [0.773, 1.274]
Comparison: Week 495% CI: [0.955, 1.452]
Secondary
AUC0-4h of Ruxolitinib
AUC0-4h was defined as the area under the plasma concentration-time curve from time = 0 to 4 hours post-dose.
Time frame: Day 1 and Week 4: predose and 1, 2, and 4 hours post-dose
Population: PK Population. Only participants with available data were analyzed. To be able to form a meaningful statistical test with enough participants, participants across all treatment groups were combined according to the pre-Day 1 stable dose of ruxolitinib received for analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| TG5I/M | AUC0-4h of Ruxolitinib | Day 1 | 440 hours x nmol/L | Geometric Coefficient of Variation 39.7 |
| TG5I/M | AUC0-4h of Ruxolitinib | Week 4 | 718 hours x nmol/L | Geometric Coefficient of Variation 67.9 |
| TG5D | AUC0-4h of Ruxolitinib | Day 1 | 1100 hours x nmol/L | Geometric Coefficient of Variation 25.5 |
| TG5D | AUC0-4h of Ruxolitinib | Week 4 | 1090 hours x nmol/L | Geometric Coefficient of Variation 29.5 |
| TG10 + TG20: Daily/Weekly Dosing | AUC0-4h of Ruxolitinib | Day 1 | 1310 hours x nmol/L | Geometric Coefficient of Variation 35.8 |
| TG10 + TG20: Daily/Weekly Dosing | AUC0-4h of Ruxolitinib | Week 4 | 1730 hours x nmol/L | Geometric Coefficient of Variation 38.9 |
| Ruxolitinib 20 mg | AUC0-4h of Ruxolitinib | Week 4 | 1910 hours x nmol/L | Geometric Coefficient of Variation 51 |
| Ruxolitinib 20 mg | AUC0-4h of Ruxolitinib | Day 1 | 1700 hours x nmol/L | Geometric Coefficient of Variation 52.4 |
| Ruxolitinib 25 mg | AUC0-4h of Ruxolitinib | Day 1 | 1890 hours x nmol/L | Geometric Coefficient of Variation 23.4 |
| Ruxolitinib 25 mg | AUC0-4h of Ruxolitinib | Week 4 | 2300 hours x nmol/L | Geometric Coefficient of Variation 34.2 |
Comparison: Day 1p-value: 0.1208ANOVA
Comparison: Day 195% CI: [0.832, 1.879]
Comparison: Day 195% CI: [0.649, 1.518]
Comparison: Day 195% CI: [0.645, 1.45]
Comparison: Day 195% CI: [0.548, 1.35]
Comparison: Week 4p-value: 0.3218ANOVA
Comparison: Week 495% CI: [0.482, 1.2]
Comparison: Week 495% CI: [0.506, 1.277]
Comparison: Week 495% CI: [0.432, 1.028]
Comparison: Week 495% CI: [0.39, 1.051]
Secondary
AUC0-t of Parsaclisib
AUC0-t was defined as the area under the plasma concentration-time curve from time =0 to the last measurable concentration at time = t.
Time frame: Week 2 and Week 4: predose and 1, 2, and 4 hours post-dose
Population: PK Population. Only participants with available data were analyzed. To be able to form a meaningful statistical test with enough participants, participants across all treatment groups were combined according to the dose of parsaclisib received for analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| TG5I/M | AUC0-t of Parsaclisib | Week 2 | 982 hours x nmol/L | Geometric Coefficient of Variation 39.4 |
| TG5I/M | AUC0-t of Parsaclisib | Week 4 | 1080 hours x nmol/L | Geometric Coefficient of Variation 34.7 |
| TG5D | AUC0-t of Parsaclisib | Week 2 | 2000 hours x nmol/L | Geometric Coefficient of Variation 30.5 |
| TG5D | AUC0-t of Parsaclisib | Week 4 | 2140 hours x nmol/L | Geometric Coefficient of Variation 28 |
| TG10 + TG20: Daily/Weekly Dosing | AUC0-t of Parsaclisib | Week 2 | 4560 hours x nmol/L | Geometric Coefficient of Variation 30.3 |
| TG10 + TG20: Daily/Weekly Dosing | AUC0-t of Parsaclisib | Week 4 | 5070 hours x nmol/L | Geometric Coefficient of Variation 32.1 |
Secondary
AUC0-t of Ruxolitinib
AUC0-t was defined as the area under the plasma concentration-time curve from time =0 to the last measurable concentration at time = t.
Time frame: Day 1 and Week 4: predose and 1, 2, and 4 hours post-dose
Population: PK Population. Only participants with available data were analyzed. To be able to form a meaningful statistical test with enough participants, participants across all treatment groups were combined according to the pre-Day 1 stable dose of ruxolitinib received for analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| TG5I/M | AUC0-t of Ruxolitinib | Day 1 | 440 hours x nmol/L | Geometric Coefficient of Variation 39.7 |
| TG5I/M | AUC0-t of Ruxolitinib | Week 4 | 718 hours x nmol/L | Geometric Coefficient of Variation 67.9 |
| TG5D | AUC0-t of Ruxolitinib | Day 1 | 1100 hours x nmol/L | Geometric Coefficient of Variation 25.5 |
| TG5D | AUC0-t of Ruxolitinib | Week 4 | 1090 hours x nmol/L | Geometric Coefficient of Variation 29.5 |
| TG10 + TG20: Daily/Weekly Dosing | AUC0-t of Ruxolitinib | Day 1 | 1310 hours x nmol/L | Geometric Coefficient of Variation 35.8 |
| TG10 + TG20: Daily/Weekly Dosing | AUC0-t of Ruxolitinib | Week 4 | 1730 hours x nmol/L | Geometric Coefficient of Variation 38.9 |
| Ruxolitinib 20 mg | AUC0-t of Ruxolitinib | Week 4 | 1910 hours x nmol/L | Geometric Coefficient of Variation 51 |
| Ruxolitinib 20 mg | AUC0-t of Ruxolitinib | Day 1 | 1700 hours x nmol/L | Geometric Coefficient of Variation 52.4 |
| Ruxolitinib 25 mg | AUC0-t of Ruxolitinib | Day 1 | 1890 hours x nmol/L | Geometric Coefficient of Variation 23.4 |
| Ruxolitinib 25 mg | AUC0-t of Ruxolitinib | Week 4 | 2300 hours x nmol/L | Geometric Coefficient of Variation 34.2 |
Secondary
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
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.
Time frame: Week 12 and every 12 weeks thereafter (up to 1494 days [EOT])
Population: Initial Safety Population. Analysis was conducted on the Safety Population during the initial safety period. Due to early termination of the study, per the Statistical Analysis Plan, daily and weekly dosing arms were combined for efficacy analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TG5I/M | 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 | 0.0 percentage of participants |
| TG5D | 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 | 9.5 percentage of participants |
| TG10 + TG20: Daily/Weekly Dosing | 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 | 9.4 percentage of participants |
Secondary
Change From Baseline in Spleen Volume Through Week 24 of the Initial Study Period as Measured by MRI (or CT Scan in Applicable Participants)
Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time frame: Baseline; Week 24
Population: Initial Safety Population. Analysis was conducted on the Safety Population during the initial safety period. Only participants with available data were analyzed. Due to early termination of the study, per the Statistical Analysis Plan, daily and weekly dosing arms were combined for efficacy analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TG5I/M | 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 | 1779.0 cm^3 | Standard Deviation 1006.75 |
| TG5I/M | Change From Baseline in Spleen Volume Through Week 24 of the Initial Study Period as Measured by MRI (or CT Scan in Applicable Participants) | Change from Baseline at Week 24 | -292.6 cm^3 | Standard Deviation 514.91 |
| TG5D | 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 | 2032.3 cm^3 | Standard Deviation 773.45 |
| TG5D | Change From Baseline in Spleen Volume Through Week 24 of the Initial Study Period as Measured by MRI (or CT Scan in Applicable Participants) | Change from Baseline at Week 24 | -335.9 cm^3 | Standard Deviation 204.19 |
| TG10 + TG20: Daily/Weekly Dosing | 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 | 2469.0 cm^3 | Standard Deviation 1208.9 |
| TG10 + TG20: Daily/Weekly Dosing | Change From Baseline in Spleen Volume Through Week 24 of the Initial Study Period as Measured by MRI (or CT Scan in Applicable Participants) | Change from Baseline at Week 24 | -37.5 cm^3 | Standard Deviation 432.02 |
Secondary
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
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.
Time frame: Baseline; Week 12
Population: Initial Safety Population. Analysis was conducted on the Safety Population during the initial safety period. Only participants with available data were analyzed. Due to early termination of the study, per the Statistical Analysis Plan, daily and weekly dosing arms were combined for efficacy analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TG5I/M | 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 | 17.6 scores on a scale | Standard Deviation 10.59 |
| TG5I/M | 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 | Change from Baseline at Week 12 | -6.0 scores on a scale | Standard Deviation 6.63 |
| TG5D | 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 | 16.3 scores on a scale | Standard Deviation 12.82 |
| TG5D | 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 | Change from Baseline at Week 12 | -5.0 scores on a scale | Standard Deviation 11.15 |
| TG10 + TG20: Daily/Weekly Dosing | 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 | 15.2 scores on a scale | Standard Deviation 12.94 |
| TG10 + TG20: Daily/Weekly Dosing | 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 | Change from Baseline at Week 12 | -2.1 scores on a scale | Standard Deviation 4.87 |
Secondary
Change From Baseline in the TSS Through Week 12 as Measured by Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF)
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.
Time frame: Baseline; Week 12
Population: Initial Safety Population. Analysis was conducted on the Safety Population during the initial safety period. Only participants with available data were analyzed. Due to early termination of the study, per the Statistical Analysis Plan, daily and weekly dosing arms were combined for efficacy analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TG5I/M | Change From Baseline in the TSS Through Week 12 as Measured by Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) | Baseline | 30.0 scores on a scale | Standard Deviation 17.88 |
| TG5I/M | Change From Baseline in the TSS Through Week 12 as Measured by Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) | Change from Baseline at Week 12 | -10.6 scores on a scale | Standard Deviation 12.63 |
| TG5D | Change From Baseline in the TSS Through Week 12 as Measured by Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) | Baseline | 27.7 scores on a scale | Standard Deviation 18.18 |
| TG5D | Change From Baseline in the TSS Through Week 12 as Measured by Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) | Change from Baseline at Week 12 | -12.6 scores on a scale | Standard Deviation 15.52 |
| TG10 + TG20: Daily/Weekly Dosing | Change From Baseline in the TSS Through Week 12 as Measured by Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) | Baseline | 29.2 scores on a scale | Standard Deviation 19.56 |
| TG10 + TG20: Daily/Weekly Dosing | Change From Baseline in the TSS Through Week 12 as Measured by Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) | Change from Baseline at Week 12 | -4.8 scores on a scale | Standard Deviation 9.78 |
Secondary
Change From Baseline in the TSS Through Week 24 as Measured by MFSAF v3.0 Symptom Diary
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.
Time frame: Baseline; Week 24
Population: Initial Safety Population. Analysis was conducted on the Safety Population during the initial safety period. Only participants with available data were analyzed. Due to early termination of the study, per the Statistical Analysis Plan, daily and weekly dosing arms were combined for efficacy analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TG5I/M | Change From Baseline in the TSS Through Week 24 as Measured by MFSAF v3.0 Symptom Diary | Baseline | 17.6 scores on a scale | Standard Deviation 10.59 |
| TG5I/M | Change From Baseline in the TSS Through Week 24 as Measured by MFSAF v3.0 Symptom Diary | Change from Baseline at Week 24 | -5.6 scores on a scale | Standard Deviation 8.97 |
| TG5D | Change From Baseline in the TSS Through Week 24 as Measured by MFSAF v3.0 Symptom Diary | Baseline | 16.3 scores on a scale | Standard Deviation 12.82 |
| TG5D | Change From Baseline in the TSS Through Week 24 as Measured by MFSAF v3.0 Symptom Diary | Change from Baseline at Week 24 | -3.9 scores on a scale | Standard Deviation 13.63 |
| TG10 + TG20: Daily/Weekly Dosing | Change From Baseline in the TSS Through Week 24 as Measured by MFSAF v3.0 Symptom Diary | Baseline | 15.2 scores on a scale | Standard Deviation 12.94 |
| TG10 + TG20: Daily/Weekly Dosing | Change From Baseline in the TSS Through Week 24 as Measured by MFSAF v3.0 Symptom Diary | Change from Baseline at Week 24 | -2.0 scores on a scale | Standard Deviation 7.15 |
Secondary
Change From Baseline in the TSS Through Week 24 as Measured by MPN-SAF
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.
Time frame: Baseline; Week 24
Population: Initial Safety Population. Analysis was conducted on the Safety Population during the initial safety period. Only participants with available data were analyzed. Due to early termination of the study, per the Statistical Analysis Plan, daily and weekly dosing arms were combined for efficacy analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TG5I/M | Change From Baseline in the TSS Through Week 24 as Measured by MPN-SAF | Baseline | 30.0 scores on a scale | Standard Deviation 17.88 |
| TG5I/M | Change From Baseline in the TSS Through Week 24 as Measured by MPN-SAF | Change from Baseline at Week 24 | -15.6 scores on a scale | Standard Deviation 9.95 |
| TG5D | Change From Baseline in the TSS Through Week 24 as Measured by MPN-SAF | Baseline | 27.7 scores on a scale | Standard Deviation 18.18 |
| TG5D | Change From Baseline in the TSS Through Week 24 as Measured by MPN-SAF | Change from Baseline at Week 24 | -12.6 scores on a scale | Standard Deviation 16.46 |
| TG10 + TG20: Daily/Weekly Dosing | Change From Baseline in the TSS Through Week 24 as Measured by MPN-SAF | Change from Baseline at Week 24 | -10.3 scores on a scale | Standard Deviation 11.88 |
| TG10 + TG20: Daily/Weekly Dosing | Change From Baseline in the TSS Through Week 24 as Measured by MPN-SAF | Baseline | 29.2 scores on a scale | Standard Deviation 19.56 |
Secondary
Clast of Parsaclisib
Clast was defined as the last quantifiable concentration.
Time frame: Week 2 and Week 4: predose and 1, 2, and 4 hours post-dose
Population: PK Population. Only participants with available data were analyzed. To be able to form a meaningful statistical test with enough participants, participants across all treatment groups were combined according to the dose of parsaclisib received for analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| TG5I/M | Clast of Parsaclisib | Week 2 | 224 nmol/L | Geometric Coefficient of Variation 31.6 |
| TG5I/M | Clast of Parsaclisib | Week 4 | 249 nmol/L | Geometric Coefficient of Variation 28.9 |
| TG5D | Clast of Parsaclisib | Week 2 | 419 nmol/L | Geometric Coefficient of Variation 24 |
| TG5D | Clast of Parsaclisib | Week 4 | 424 nmol/L | Geometric Coefficient of Variation 31.2 |
| TG10 + TG20: Daily/Weekly Dosing | Clast of Parsaclisib | Week 2 | 949 nmol/L | Geometric Coefficient of Variation 30.1 |
| TG10 + TG20: Daily/Weekly Dosing | Clast of Parsaclisib | Week 4 | 1060 nmol/L | Geometric Coefficient of Variation 33.5 |
Secondary
Clast of Ruxolitinib
Clast was defined as the last quantifiable concentration.
Time frame: Day 1 and Week 4: predose and 1, 2, and 4 hours post-dose
Population: PK Population. Only participants with available data were analyzed. To be able to form a meaningful statistical test with enough participants, participants across all treatment groups were combined according to the pre-Day 1 stable dose of ruxolitinib received for analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| TG5I/M | Clast of Ruxolitinib | Day 1 | 53.0 nmol/L | Geometric Coefficient of Variation 60.4 |
| TG5I/M | Clast of Ruxolitinib | Week 4 | 87.1 nmol/L | Geometric Coefficient of Variation 111 |
| TG5D | Clast of Ruxolitinib | Day 1 | 145 nmol/L | Geometric Coefficient of Variation 38.2 |
| TG5D | Clast of Ruxolitinib | Week 4 | 156 nmol/L | Geometric Coefficient of Variation 36.4 |
| TG10 + TG20: Daily/Weekly Dosing | Clast of Ruxolitinib | Day 1 | 213 nmol/L | Geometric Coefficient of Variation 64.1 |
| TG10 + TG20: Daily/Weekly Dosing | Clast of Ruxolitinib | Week 4 | 285 nmol/L | Geometric Coefficient of Variation 58.7 |
| Ruxolitinib 20 mg | Clast of Ruxolitinib | Week 4 | 270 nmol/L | Geometric Coefficient of Variation 87.3 |
| Ruxolitinib 20 mg | Clast of Ruxolitinib | Day 1 | 233 nmol/L | Geometric Coefficient of Variation 109 |
| Ruxolitinib 25 mg | Clast of Ruxolitinib | Day 1 | 235 nmol/L | Geometric Coefficient of Variation 38.8 |
| Ruxolitinib 25 mg | Clast of Ruxolitinib | Week 4 | 294 nmol/L | Geometric Coefficient of Variation 48.3 |
Secondary
Cmax of Parsaclisib
Cmax was defined as the maximum observed plasma concentration.
Time frame: Week 2 and Week 4: predose and 1, 2, and 4 hours post-dose
Population: Pharmacokinetic (PK) Population: all treated participants who contributed plasma PK samples. Only participants with available data were analyzed. To be able to form a meaningful statistical test with enough participants, participants across all treatment groups were combined according to the dose of parsaclisib received for analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| TG5I/M | Cmax of Parsaclisib | Week 2 | 350 nanomoles per Liter (nmol/L) | Geometric Coefficient of Variation 40.8 |
| TG5I/M | Cmax of Parsaclisib | Week 4 | 381 nanomoles per Liter (nmol/L) | Geometric Coefficient of Variation 35.9 |
| TG5D | Cmax of Parsaclisib | Week 2 | 734 nanomoles per Liter (nmol/L) | Geometric Coefficient of Variation 29.4 |
| TG5D | Cmax of Parsaclisib | Week 4 | 762 nanomoles per Liter (nmol/L) | Geometric Coefficient of Variation 29.2 |
| TG10 + TG20: Daily/Weekly Dosing | Cmax of Parsaclisib | Week 2 | 1620 nanomoles per Liter (nmol/L) | Geometric Coefficient of Variation 31.6 |
| TG10 + TG20: Daily/Weekly Dosing | Cmax of Parsaclisib | Week 4 | 1790 nanomoles per Liter (nmol/L) | Geometric Coefficient of Variation 30.5 |
Comparison: Week 2p-value: 0.3577ANOVA
Comparison: Week 295% CI: [0.791, 1.388]
Comparison: Week 295% CI: [0.936, 1.435]
Comparison: Week 4p-value: 0.1709ANOVA
Comparison: Week 495% CI: [0.78, 1.281]
Comparison: Week 495% CI: [0.955, 1.448]
Secondary
Cmax of Ruxolitinib
Cmax was defined as the maximum observed plasma concentration.
Time frame: Day 1 and Week 4: predose and 1, 2, and 4 hours post-dose
Population: PK Population. Only participants with available data were analyzed. To be able to form a meaningful statistical test with enough participants, participants across all treatment groups were combined according to the pre-Day 1 stable dose of ruxolitinib received for analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| TG5I/M | Cmax of Ruxolitinib | Day 1 | 202 nmol/L | Geometric Coefficient of Variation 39.5 |
| TG5I/M | Cmax of Ruxolitinib | Week 4 | 335 nmol/L | Geometric Coefficient of Variation 53.9 |
| TG5D | Cmax of Ruxolitinib | Day 1 | 491 nmol/L | Geometric Coefficient of Variation 26.3 |
| TG5D | Cmax of Ruxolitinib | Week 4 | 471 nmol/L | Geometric Coefficient of Variation 37.6 |
| TG10 + TG20: Daily/Weekly Dosing | Cmax of Ruxolitinib | Day 1 | 579 nmol/L | Geometric Coefficient of Variation 31.8 |
| TG10 + TG20: Daily/Weekly Dosing | Cmax of Ruxolitinib | Week 4 | 704 nmol/L | Geometric Coefficient of Variation 34.9 |
| Ruxolitinib 20 mg | Cmax of Ruxolitinib | Week 4 | 855 nmol/L | Geometric Coefficient of Variation 42.2 |
| Ruxolitinib 20 mg | Cmax of Ruxolitinib | Day 1 | 760 nmol/L | Geometric Coefficient of Variation 40.8 |
| Ruxolitinib 25 mg | Cmax of Ruxolitinib | Day 1 | 875 nmol/L | Geometric Coefficient of Variation 31.3 |
| Ruxolitinib 25 mg | Cmax of Ruxolitinib | Week 4 | 1050 nmol/L | Geometric Coefficient of Variation 36.8 |
Comparison: Day 1p-value: 0.083ANOVA
Comparison: Day 195% CI: [0.846, 1.753]
Comparison: Day 195% CI: [0.654, 1.399]
Comparison: Day 195% CI: [0.656, 1.354]
Comparison: Day 195% CI: [0.579, 1.298]
Comparison: Week 4p-value: 0.2402ANOVA
Comparison: Week 495% CI: [0.461, 1.069]
Comparison: Week 495% CI: [0.456, 1.073]
Comparison: Week 495% CI: [0.428, 0.951]
Comparison: Week 495% CI: [0.397, 0.99]
Secondary
Cmin of Parsaclisib
Cmin was defined as the minimum observed plasma concentration.
Time frame: Week 2 and Week 4: predose and 1, 2, and 4 hours post-dose
Population: PK Population. Only participants with available data were analyzed. To be able to form a meaningful statistical test with enough participants, participants across all treatment groups were combined according to the dose of parsaclisib received for analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| TG5I/M | Cmin of Parsaclisib | Week 2 | 38.3 nmol/L | Geometric Coefficient of Variation 64.7 |
| TG5I/M | Cmin of Parsaclisib | Week 4 | 32.6 nmol/L | Geometric Coefficient of Variation 112 |
| TG5D | Cmin of Parsaclisib | Week 2 | 44.7 nmol/L | Geometric Coefficient of Variation 106 |
| TG5D | Cmin of Parsaclisib | Week 4 | 69.2 nmol/L | Geometric Coefficient of Variation 53.8 |
| TG10 + TG20: Daily/Weekly Dosing | Cmin of Parsaclisib | Week 2 | 151 nmol/L | Geometric Coefficient of Variation 60.5 |
| TG10 + TG20: Daily/Weekly Dosing | Cmin of Parsaclisib | Week 4 | 196 nmol/L | Geometric Coefficient of Variation 75.3 |
Comparison: Week 2p-value: 0.0809ANOVA
Comparison: Week 295% CI: [0.342, 0.994]
Comparison: Week 295% CI: [0.658, 1.477]
Comparison: Week 4p-value: 0.1525ANOVA
Comparison: Week 495% CI: [0.604, 1.867]
Comparison: Week 495% CI: [0.937, 2.414]
Secondary
Cmin of Ruxolitinib
Cmin was defined as the minimum observed plasma concentration.
Time frame: Day 1 and Week 4: predose and 1, 2, and 4 hours post-dose
Population: PK Population. Only participants with available data were analyzed. To be able to form a meaningful statistical test with enough participants, participants across all treatment groups were combined according to the pre-Day 1 stable dose of ruxolitinib received for analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| TG5I/M | Cmin of Ruxolitinib | Day 1 | 9.23 nmol/L | Geometric Coefficient of Variation 141 |
| TG5I/M | Cmin of Ruxolitinib | Week 4 | 11.1 nmol/L | Geometric Coefficient of Variation 178 |
| TG5D | Cmin of Ruxolitinib | Day 1 | 23.5 nmol/L | Geometric Coefficient of Variation 122 |
| TG5D | Cmin of Ruxolitinib | Week 4 | 19.5 nmol/L | Geometric Coefficient of Variation 269 |
| TG10 + TG20: Daily/Weekly Dosing | Cmin of Ruxolitinib | Day 1 | 28.7 nmol/L | Geometric Coefficient of Variation 226 |
| TG10 + TG20: Daily/Weekly Dosing | Cmin of Ruxolitinib | Week 4 | 40.7 nmol/L | Geometric Coefficient of Variation 187 |
| Ruxolitinib 20 mg | Cmin of Ruxolitinib | Week 4 | 40.7 nmol/L | Geometric Coefficient of Variation 331 |
| Ruxolitinib 20 mg | Cmin of Ruxolitinib | Day 1 | 25.9 nmol/L | Geometric Coefficient of Variation 263 |
| Ruxolitinib 25 mg | Cmin of Ruxolitinib | Day 1 | 24.2 nmol/L | Geometric Coefficient of Variation 156 |
| Ruxolitinib 25 mg | Cmin of Ruxolitinib | Week 4 | 47.3 nmol/L | Geometric Coefficient of Variation 123 |
Comparison: Day 1p-value: 0.4287ANOVA
Comparison: Day 195% CI: [0.329, 4.914]
Comparison: Day 195% CI: [0.252, 4.251]
Comparison: Day 195% CI: [0.18, 2.731]
Comparison: Day 195% CI: [0.118, 2.348]
Comparison: Week 4p-value: 0.9788ANOVA
Comparison: Week 495% CI: [0.198, 3.896]
Comparison: Week 495% CI: [0.27, 5.56]
Comparison: Week 495% CI: [0.221, 3.821]
Comparison: Week 495% CI: [0.169, 4.299]
Secondary
Mean PGIC Score at Week 12, Week 24, and the 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.
Time frame: up to 1494 days (EOT)
Population: Initial Safety Population. Analysis was conducted on the Safety Population during the initial safety period. Only participants with available data were analyzed. Due to early termination of the study, per the Statistical Analysis Plan, daily and weekly dosing arms were combined for efficacy analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TG5I/M | Mean PGIC Score at Week 12, Week 24, and the EOT | Week 24 | 2.6 scores on a scale | Standard Deviation 0.91 |
| TG5I/M | Mean PGIC Score at Week 12, Week 24, and the EOT | Week 12 | 3.2 scores on a scale | Standard Deviation 1.11 |
| TG5I/M | Mean PGIC Score at Week 12, Week 24, and the EOT | EOT | 3.6 scores on a scale | Standard Deviation 1.09 |
| TG5D | Mean PGIC Score at Week 12, Week 24, and the EOT | Week 24 | 2.8 scores on a scale | Standard Deviation 1.01 |
| TG5D | Mean PGIC Score at Week 12, Week 24, and the EOT | Week 12 | 3.0 scores on a scale | Standard Deviation 0.94 |
| TG5D | Mean PGIC Score at Week 12, Week 24, and the EOT | EOT | 3.3 scores on a scale | Standard Deviation 1.24 |
| TG10 + TG20: Daily/Weekly Dosing | Mean PGIC Score at Week 12, Week 24, and the EOT | Week 12 | 3.2 scores on a scale | Standard Deviation 1.28 |
| TG10 + TG20: Daily/Weekly Dosing | Mean PGIC Score at Week 12, Week 24, and the EOT | EOT | 3.8 scores on a scale | Standard Deviation 1.85 |
| TG10 + TG20: Daily/Weekly Dosing | Mean PGIC Score at Week 12, Week 24, and the EOT | Week 24 | 2.4 scores on a scale | Standard Deviation 0.96 |
Secondary
Number of Participants With Any TEAE During the Transition Period
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.
Time frame: up to approximately 4 years
Population: Transition Safety Population. AEs were reported in the initial randomization group (TG10, TG20) if the start of the AEs occurred before transitioning to TG5D. If the start of the AEs occurred after transitioning to TG5D, they were reported in the TG5D Transition arm.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TG5I/M | Number of Participants With Any TEAE During the Transition Period | 8 Participants |
Secondary
Number of Participants With Any Treatment-emergent Adverse Event (TEAE)
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.
Time frame: up to approximately 4 years
Population: Initial Safety Population. Analysis was conducted on the Safety Population during the initial safety period. Due to early termination of the study, per the Statistical Analysis Plan, daily and weekly dosing arms were combined for analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TG5I/M | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 20 Participants |
| TG5D | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 20 Participants |
| TG10 + TG20: Daily/Weekly Dosing | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 31 Participants |
Secondary
Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (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.
Time frame: Baseline; up to 1494 days (EOT)
Population: Initial Safety Population. Analysis was conducted on the Safety Population during the initial safety period. Due to early termination of the study, per the Statistical Analysis Plan, daily and weekly dosing arms were combined for efficacy analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| TG5I/M | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 12, very much worse | 0 Participants |
| TG5I/M | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 12, much improved | 4 Participants |
| TG5I/M | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 12, minimally improved | 5 Participants |
| TG5I/M | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 12, no change | 6 Participants |
| TG5I/M | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 12, minimally worse | 2 Participants |
| TG5I/M | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 12, much worse | 0 Participants |
| TG5I/M | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 12, very much improved | 1 Participants |
| TG5I/M | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 12, not reported | 3 Participants |
| TG5I/M | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 24, very much improved | 1 Participants |
| TG5I/M | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 24, much improved | 7 Participants |
| TG5I/M | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 24, minimally improved | 4 Participants |
| TG5I/M | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 24, no change | 3 Participants |
| TG5I/M | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 24, minimally worse | 0 Participants |
| TG5I/M | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 24, much worse | 0 Participants |
| TG5I/M | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 24, very much worse | 0 Participants |
| TG5I/M | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 24, not reported | 6 Participants |
| TG5I/M | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | EOT, very much improved | 0 Participants |
| TG5I/M | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | EOT, much improved | 2 Participants |
| TG5I/M | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | EOT, minimally improved | 7 Participants |
| TG5I/M | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | EOT, no change | 4 Participants |
| TG5I/M | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | EOT, minimally worse | 2 Participants |
| TG5I/M | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | EOT, much worse | 1 Participants |
| TG5I/M | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | EOT, very much worse | 0 Participants |
| TG5I/M | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | EOT, not reported | 5 Participants |
| TG5D | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | EOT, much worse | 1 Participants |
| TG5D | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 12, very much improved | 1 Participants |
| TG5D | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 24, minimally worse | 1 Participants |
| TG5D | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | EOT, very much improved | 0 Participants |
| TG5D | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 12, much improved | 4 Participants |
| TG5D | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 24, minimally improved | 6 Participants |
| TG5D | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | EOT, minimally worse | 1 Participants |
| TG5D | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 12, minimally improved | 6 Participants |
| TG5D | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 24, much worse | 0 Participants |
| TG5D | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | EOT, very much worse | 0 Participants |
| TG5D | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 12, no change | 6 Participants |
| TG5D | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 24, much improved | 4 Participants |
| TG5D | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | EOT, much improved | 6 Participants |
| TG5D | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 12, minimally worse | 0 Participants |
| TG5D | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 24, very much worse | 0 Participants |
| TG5D | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 24, no change | 1 Participants |
| TG5D | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 12, much worse | 0 Participants |
| TG5D | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 24, very much improved | 1 Participants |
| TG5D | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | EOT, not reported | 5 Participants |
| TG5D | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 12, very much worse | 0 Participants |
| TG5D | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 24, not reported | 8 Participants |
| TG5D | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | EOT, minimally improved | 3 Participants |
| TG5D | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 12, not reported | 4 Participants |
| TG5D | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | EOT, no change | 5 Participants |
| TG10 + TG20: Daily/Weekly Dosing | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 12, not reported | 8 Participants |
| TG10 + TG20: Daily/Weekly Dosing | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 24, very much improved | 3 Participants |
| TG10 + TG20: Daily/Weekly Dosing | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 24, much improved | 9 Participants |
| TG10 + TG20: Daily/Weekly Dosing | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 24, minimally improved | 4 Participants |
| TG10 + TG20: Daily/Weekly Dosing | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | EOT, no change | 3 Participants |
| TG10 + TG20: Daily/Weekly Dosing | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 24, no change | 3 Participants |
| TG10 + TG20: Daily/Weekly Dosing | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | EOT, very much worse | 1 Participants |
| TG10 + TG20: Daily/Weekly Dosing | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 24, minimally worse | 0 Participants |
| TG10 + TG20: Daily/Weekly Dosing | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 24, much worse | 0 Participants |
| TG10 + TG20: Daily/Weekly Dosing | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | EOT, minimally worse | 2 Participants |
| TG10 + TG20: Daily/Weekly Dosing | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 24, very much worse | 0 Participants |
| TG10 + TG20: Daily/Weekly Dosing | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | EOT, not reported | 18 Participants |
| TG10 + TG20: Daily/Weekly Dosing | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 24, not reported | 13 Participants |
| TG10 + TG20: Daily/Weekly Dosing | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 12, very much improved | 1 Participants |
| TG10 + TG20: Daily/Weekly Dosing | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 12, much improved | 8 Participants |
| TG10 + TG20: Daily/Weekly Dosing | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | EOT, very much improved | 1 Participants |
| TG10 + TG20: Daily/Weekly Dosing | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 12, minimally improved | 5 Participants |
| TG10 + TG20: Daily/Weekly Dosing | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | EOT, much worse | 2 Participants |
| TG10 + TG20: Daily/Weekly Dosing | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 12, no change | 6 Participants |
| TG10 + TG20: Daily/Weekly Dosing | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 12, minimally worse | 3 Participants |
| TG10 + TG20: Daily/Weekly Dosing | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | EOT, much improved | 4 Participants |
| TG10 + TG20: Daily/Weekly Dosing | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 12, much worse | 1 Participants |
| TG10 + TG20: Daily/Weekly Dosing | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | Week 12, very much worse | 0 Participants |
| TG10 + TG20: Daily/Weekly Dosing | Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT) | EOT, minimally improved | 1 Participants |
Secondary
Percent Change From Baseline in Spleen Volume Through Week 24 as Measured by MRI (or CT Scan in Applicable Participants )
Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] / Baseline value) x 100.
Time frame: Baseline; Week 24
Population: Initial Safety Population. Analysis was conducted on the Safety Population during the initial safety period. Only participants with available data were analyzed. Due to early termination of the study, per the Statistical Analysis Plan, daily and weekly dosing arms were combined for efficacy analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TG5I/M | Percent Change From Baseline in Spleen Volume Through Week 24 as Measured by MRI (or CT Scan in Applicable Participants ) | -21.9 percent change | Standard Deviation 24.1 |
| TG5D | Percent Change From Baseline in Spleen Volume Through Week 24 as Measured by MRI (or CT Scan in Applicable Participants ) | -19.0 percent change | Standard Deviation 11.23 |
| TG10 + TG20: Daily/Weekly Dosing | Percent Change From Baseline in Spleen Volume Through Week 24 as Measured by MRI (or CT Scan in Applicable Participants ) | -4.9 percent change | Standard Deviation 18.81 |
p-value: 0.7802Van Elteren test
Secondary
Percent Change From Baseline in the TSS Through Week 12 as Measured by MFSAF v3.0 Symptom Diary
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.
Time frame: Baseline; Week 12
Population: Initial Safety Population. Analysis was conducted on the Safety Population during the initial safety period. Only participants with available data were analyzed. Due to early termination of the study, per the Statistical Analysis Plan, daily and weekly dosing arms were combined for efficacy analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TG5I/M | Percent Change From Baseline in the TSS Through Week 12 as Measured by MFSAF v3.0 Symptom Diary | -37.0 percent change | Standard Deviation 30.93 |
| TG5D | Percent Change From Baseline in the TSS Through Week 12 as Measured by MFSAF v3.0 Symptom Diary | -17.7 percent change | Standard Deviation 57.81 |
| TG10 + TG20: Daily/Weekly Dosing | Percent Change From Baseline in the TSS Through Week 12 as Measured by MFSAF v3.0 Symptom Diary | 10.1 percent change | Standard Deviation 118.94 |
p-value: 0.6856Van Elteren test
Secondary
Percent Change From Baseline in the TSS Through Week 12 as Measured by MPN-SAF
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.
Time frame: Baseline; Week 12
Population: Initial Safety Population. Analysis was conducted on the Safety Population during the initial safety period. Only participants with available data were analyzed. Due to early termination of the study, per the Statistical Analysis Plan, daily and weekly dosing arms were combined for efficacy analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TG5I/M | Percent Change From Baseline in the TSS Through Week 12 as Measured by MPN-SAF | -28.7 percent change | Standard Deviation 42.48 |
| TG5D | Percent Change From Baseline in the TSS Through Week 12 as Measured by MPN-SAF | -38.1 percent change | Standard Deviation 44.76 |
| TG10 + TG20: Daily/Weekly Dosing | Percent Change From Baseline in the TSS Through Week 12 as Measured by MPN-SAF | -20.1 percent change | Standard Deviation 40.88 |
p-value: 0.4005Van Elteren test
Secondary
Percent Change From Baseline in the TSS Through Week 24 as Measured by MFSAF v3.0 Symptom Diary
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.
Time frame: Baseline; Week 24
Population: Initial Safety Population. Analysis was conducted on the Safety Population during the initial safety period. Only participants with available data were analyzed. Due to early termination of the study, per the Statistical Analysis Plan, daily and weekly dosing arms were combined for efficacy analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TG5I/M | Percent Change From Baseline in the TSS Through Week 24 as Measured by MFSAF v3.0 Symptom Diary | -29.2 percent change | Standard Deviation 41.08 |
| TG5D | Percent Change From Baseline in the TSS Through Week 24 as Measured by MFSAF v3.0 Symptom Diary | -16.7 percent change | Standard Deviation 76.27 |
| TG10 + TG20: Daily/Weekly Dosing | Percent Change From Baseline in the TSS Through Week 24 as Measured by MFSAF v3.0 Symptom Diary | 11.1 percent change | Standard Deviation 80.23 |
p-value: 0.3385Van Elteren test
Secondary
Percent Change From Baseline in the TSS Through Week 24 as Measured by MPN-SAF
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.
Time frame: Baseline; Week 24
Population: Initial Safety Population. Analysis was conducted on the Safety Population during the initial safety period. Only participants with available data were analyzed. Due to early termination of the study, per the Statistical Analysis Plan, daily and weekly dosing arms were combined for efficacy analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TG5I/M | Percent Change From Baseline in the TSS Through Week 24 as Measured by MPN-SAF | -63.4 percent change | Standard Deviation 28.14 |
| TG5D | Percent Change From Baseline in the TSS Through Week 24 as Measured by MPN-SAF | -44.7 percent change | Standard Deviation 38.07 |
| TG10 + TG20: Daily/Weekly Dosing | Percent Change From Baseline in the TSS Through Week 24 as Measured by MPN-SAF | -35.9 percent change | Standard Deviation 40.43 |
p-value: 0.3138Van Elteren test
Secondary
Tlast of Parsaclisib
tlast was defined as the time of the last quantifiable concentration.
Time frame: Week 2 and Week 4: predose and 1, 2, and 4 hours post-dose
Population: PK Population. Only participants with available data were analyzed. To be able to form a meaningful statistical test with enough participants, participants across all treatment groups were combined according to the dose of parsaclisib received for analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| TG5I/M | Tlast of Parsaclisib | Week 2 | 3.89 hours | Geometric Coefficient of Variation 3.87 |
| TG5I/M | Tlast of Parsaclisib | Week 4 | 3.87 hours | Geometric Coefficient of Variation 2.94 |
| TG5D | Tlast of Parsaclisib | Week 2 | 3.96 hours | Geometric Coefficient of Variation 1.58 |
| TG5D | Tlast of Parsaclisib | Week 4 | 3.98 hours | Geometric Coefficient of Variation 2.27 |
| TG10 + TG20: Daily/Weekly Dosing | Tlast of Parsaclisib | Week 2 | 3.94 hours | Geometric Coefficient of Variation 2.55 |
| TG10 + TG20: Daily/Weekly Dosing | Tlast of Parsaclisib | Week 4 | 3.94 hours | Geometric Coefficient of Variation 2.93 |
Secondary
Tlast of Ruxolitinib
tlast was defined as the time of the last quantifiable concentration.
Time frame: Day 1 and Week 4: predose and 1, 2, and 4 hours post-dose
Population: PK Population. Only participants with available data were analyzed. To be able to form a meaningful statistical test with enough participants, participants across all treatment groups were combined according to the pre-Day 1 stable dose of ruxolitinib received for analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| TG5I/M | Tlast of Ruxolitinib | Day 1 | 3.97 hours | Geometric Coefficient of Variation 2.72 |
| TG5I/M | Tlast of Ruxolitinib | Week 4 | 3.94 hours | Geometric Coefficient of Variation 2.06 |
| TG5D | Tlast of Ruxolitinib | Day 1 | 3.92 hours | Geometric Coefficient of Variation 4.04 |
| TG5D | Tlast of Ruxolitinib | Week 4 | 3.92 hours | Geometric Coefficient of Variation 1.87 |
| TG10 + TG20: Daily/Weekly Dosing | Tlast of Ruxolitinib | Day 1 | 3.89 hours | Geometric Coefficient of Variation 4.63 |
| TG10 + TG20: Daily/Weekly Dosing | Tlast of Ruxolitinib | Week 4 | 3.95 hours | Geometric Coefficient of Variation 3.57 |
| Ruxolitinib 20 mg | Tlast of Ruxolitinib | Week 4 | 3.93 hours | Geometric Coefficient of Variation 2.66 |
| Ruxolitinib 20 mg | Tlast of Ruxolitinib | Day 1 | 3.99 hours | Geometric Coefficient of Variation 1.27 |
| Ruxolitinib 25 mg | Tlast of Ruxolitinib | Day 1 | 3.99 hours | Geometric Coefficient of Variation 1.2 |
| Ruxolitinib 25 mg | Tlast of Ruxolitinib | Week 4 | 3.89 hours | Geometric Coefficient of Variation 3.68 |
Secondary
Tmax of Parsaclisib
tmax was defined as the time to the maximum concentration.
Time frame: Week 2 and Week 4: predose and 1, 2, and 4 hours post-dose
Population: PK Population. Only participants with available data were analyzed. To be able to form a meaningful statistical test with enough participants, participants across all treatment groups were combined according to the dose of parsaclisib received for analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| TG5I/M | Tmax of Parsaclisib | Week 2 | 1.0 hours |
| TG5I/M | Tmax of Parsaclisib | Week 4 | 1.0 hours |
| TG5D | Tmax of Parsaclisib | Week 2 | 1.0 hours |
| TG5D | Tmax of Parsaclisib | Week 4 | 1.0 hours |
| TG10 + TG20: Daily/Weekly Dosing | Tmax of Parsaclisib | Week 2 | 1.0 hours |
| TG10 + TG20: Daily/Weekly Dosing | Tmax of Parsaclisib | Week 4 | 1.0 hours |
Comparison: Week 2p-value: 0.6693Kruskal-Wallis
Comparison: Week 4p-value: 0.1521Kruskal-Wallis
Secondary
Tmax of Ruxolitinib
tmax was defined as the time to the maximum concentration.
Time frame: Day 1 and Week 4: predose and 1, 2, and 4 hours post-dose
Population: PK Population. Only participants with available data were analyzed. To be able to form a meaningful statistical test with enough participants, participants across all treatment groups were combined according to the pre-Day 1 stable dose of ruxolitinib received for analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| TG5I/M | Tmax of Ruxolitinib | Day 1 | 1.1 hours |
| TG5I/M | Tmax of Ruxolitinib | Week 4 | 1.0 hours |
| TG5D | Tmax of Ruxolitinib | Day 1 | 1.0 hours |
| TG5D | Tmax of Ruxolitinib | Week 4 | 1.0 hours |
| TG10 + TG20: Daily/Weekly Dosing | Tmax of Ruxolitinib | Day 1 | 1.0 hours |
| TG10 + TG20: Daily/Weekly Dosing | Tmax of Ruxolitinib | Week 4 | 1.0 hours |
| Ruxolitinib 20 mg | Tmax of Ruxolitinib | Week 4 | 1.0 hours |
| Ruxolitinib 20 mg | Tmax of Ruxolitinib | Day 1 | 1.0 hours |
| Ruxolitinib 25 mg | Tmax of Ruxolitinib | Day 1 | 1.0 hours |
| Ruxolitinib 25 mg | Tmax of Ruxolitinib | Week 4 | 1.0 hours |
Comparison: Day 1p-value: 0.0756Kruskal-Wallis
Comparison: Week 4p-value: 0.0866Kruskal-Wallis