Study of the JAK Inhibitor Ruxolitinib Administered Orally to Patients With Primary Myelofibrosis (PMF), Post-Polycythemia Vera-Myelofibrosis (PPV-MF) or Post-Essential Thrombocythemia-Myelofibrosis (PET-MF)

Incyte Corporation69 enrolled

Overview

This is a Phase IB, open-label, dose-finding study of the JAK 1 and 2 inhibitor ruxolitinib in patients with myelofibrosis (MF). The study consists of two periods: the core study period, comprising the dose escalation stage and the safety extension phase up to Week 24, then the extension study period beyond Week 24 and up to 3 years, to further characterize the safety and efficacy of ruxolitinib in this patient population. The dose escalation phase will enroll successive cohorts of patients who receive increasing doses of ruxolitinib until the maximum safe starting dose (MSSD) is determined. In the safety expansion phase, additional patients will be treated with ruxolitinib at the MSSD defined during dose escalation. The primary objective is to establish the MSSD of ruxolitinib in patients with MF and starting platelet counts \< 100 x 10 \^9/L

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Myelofibrosis

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Require treatment for MF and classified at least as intermediate risk level 1 defined by the International Working Group. * Platelet count \< 100x10 \^9/L at screening or at Study Day 1. Exclusion Criteria: * Received platelet transfusion within 14 days prior to Screening evaluations.

Locations (18)

Unnamed facility

Winter Park, Florida, United States

Unnamed facility

Baltimore, Maryland, United States

Unnamed facility

Houston, Texas, United States

Unnamed facility

Vienna, Austria

Unnamed facility

Nanjing, Jiangsu, China

Unnamed facility

Chengdu, Sichuan, China

Unnamed facility

Hangzhou, Zhejiang, China

Unnamed facility

Beijing, China

Unnamed facility

Angers, France

Unnamed facility

Paris, France

...and 8 more locations

Outcomes

Primary Outcomes

Number of Participants With Dose Limiting Toxicities

DLT was defined as the occurrence of any of the following treatment-related toxicities, occurring through Day 28: Any grade ≥ 2 hemorrhagic event ; Any grade thrombocytopenia requiring PLT transfusion; PLT count \< 25x109/L\*; Grade 4 neutropenia (absolute neutrophil count \< 0.5x109/L)\*; Grade ≥ 3 febrile neutropenia\*; Grade ≥ 2 total serum bilirubin with coincident direct bilirubin ≥ 0.5 mg/dL; Grade 3 non-hematologic toxicity for ≥ 7 consecutive days; Grade 4 non-hematologic toxicity. In the dose escalation stage in the core study period, the starting does in both strata was 5mg bid. Successive cohorts of newly enrolled patients received increasing doses of ruxolitinib until the Maximum Safe Starting Dose (MSSD) was determined. Initially, only patients with PLT counts 75-99 x10\^9/L (stratum 1) were allowed to be enrolled. Once safety was established in stratum 1 at the first 2 dose cohorts, eligible population was further expanded to patients with PLT counts 50-74 x10\^9/L (stratum 2).

Time frame: 28 days

Secondary Outcomes

Number of Treatment Emergent Adverse Events (TEAE's)

Adverse events reported for the first time or worsening of a pre-existing event after first dose of study drug/treatment.

Time frame: approximately 4 years

Number of Subjects Achieving ≥ 50% Reduction in Palpable Spleen Length

Participants achieving ≥ 50% reduction in palpable spleen length relative to study day 1 by treatment and stratum

Time frame: 24 weeks

Change in Spleen Length as Measure by Palpation Over Time

Defined as measurement of change in spleen length by palpation from baseline

Time frame: Day 8, 15, 22, 29, 43, 57, 85, 113, 141, 168, 252, 336, 420, 504, 588, 672, 756, 1008, 1092

PK- C Reactive Protein Levels by PK Quartile (AUC0-12)

To define the PK and C Reactive Protein relationship using PK Quartiles (AUC 0-12, ng\*h/mL)

Time frame: 24 weeks

PK- Interleukin 1 Receptor Antagonist Levels by PK Quartile (AUC0-12)

To define the PK and Interleukin 1 Receptor Antagonist relationship relationship using PK Quartiles (AUC 0-12, ng\*h/mL)

Time frame: 24 weeks

PK- Tissue Necrosis Factor Receptor 2 Levels by PK Quartile (AUC0-12)

To define the PK and Tissue Necrosis Factor Receptor 2 relationship using PK Quartiles (AUC 0-12, ng\*h/mL)

Time frame: 24 weeks

AUC 0-Inf

Area Under the Serum Concentration Versus Time Curve，Time 0 to Infinity

Time frame: 0.25 to 0.75, 1 to 3, and 4 to 12 hours postdose on Day 1 and predose, 0.25 to 0.75 hours, and 1 to 3 hours postdose on Day 15, with a random sample on Days 29 and 57