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

Phase 2TerminatedNCT02718300

Incyte Corporation74 enrolled

Overview

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

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

MPN (Myeloproliferative Neoplasms)

Interventions

ParsaclisibDRUG

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.

ParsaclisibDRUG

Two recommended oral QD doses of parsaclisib. Once daily doses of parsaclisib will be taken for 8 weeks, followed by once weekly dosing at the same dose level.

RuxolitinibDRUG

The dose of ruxolitinib will be that which the subjects had been taking for at least 8 weeks before the first dose of parsaclisib.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (39)

Outcomes

Primary Outcomes

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

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

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

Secondary Outcomes

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

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

Data from ClinicalTrials.gov

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20 mg oral QD dose of parsaclisib for 8 weeks. After 8 weeks patients will take either 20 mg once weekly or 5 mg once daily.

ParsaclisibDRUG

2 dose strategies will be compared: 1. 5 mg parsaclisib beginning on Day 1 until end of treatment. 2. 20 mg oral QD dose of parsaclisib for 8 weeks; after 8 weeks patients will take 5 mg once daily.

Birmingham Hematology & Oncolgy Associates Llc

Birmingham, Alabama, United States

Mayo Clinic Arizona

Scottsdale, Arizona, United States

Alta Bates Medical Center

Berkeley, California, United States

City of Hope National Medical Center

Duarte, California, United States

California Cancer Associates For Research and Excellence

Fresno, California, United States

University of Southern California

Los Angeles, California, United States

UCLA School of Medicine

Los Angeles, California, United States

Pcr Oncology

Pismo Beach, California, United States

California Cancer Assoc. for Research and Excellence

San Marcos, California, United States

Georgetown University Hospital

Washington D.C., District of Columbia, United States

...and 29 more locations

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

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

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

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

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

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

Change From Baseline in the TSS Through Week 24 as Measured by MPN-SAF

Time frame: Baseline; Week 24

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

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)

Mean PGIC Score at Week 12, Week 24, and the EOT

Time frame: up to 1494 days (EOT)

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])

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

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

Cmax of Parsaclisib

Cmax was defined as the maximum observed plasma concentration.