A Phase 2/3 Study of Pacritinib in Patients With Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis

Official Title

A Phase 2/3 Study of Pacritinib An Open-Label, Randomized, Phase 2 Dose-Finding Study of Pacritinib in Patients With Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis Previously Treated With Ruxolitinib Phase 3 Study (PACIFICA):A Randomized, Controlled Phase 3 Study of Pacritinib Versus Physician's Choice in Patients With Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis With Severe Thrombocytopenia (Platelet Count <50,000/μL)

Summary:

Phase 3 of this study is evaluating 200 mg BID of pacritinib compared to physician's choice (P/C) therapy in patients with MF and severe thrombocytopenia (platelet count <50,000/μL). Approximately 180 patients in total will be enrolled, randomized 2:1 to either pacritinib (approximately 120 patients) or to P/C therapy (approximately 60 patients) Phase 2 was an open-label, randomized, dose-ranging study designed to identify the most appropriate dosage of pacritinib for future studies based on risk/benefit profile. Patients were randomized 1:1:1 to three dosage arms: 100mg QD, 100mg BID or 200mg BID. A total of 164 patients were randomized in the phase 2 portion of Study PAC203, and 161 (98.2%) patients received any treatment with pacritinib. Condition or disease: Primary Myelofibrosis/Post-Polycythemia Vera Myelofibrosis/ Post-essential Thrombocythemia Myelofibrosis Intervention/treatment: Drug-Pacritinib

Trial Description

Primary Outcome:

  • Spleen volume
Secondary Outcome:
  • Total Symptom Score (TSS)
  • Overall Survival (OS)
  • Patient Global Impression of Change (PGIC) assessed at Week 24
The Phase 3 portion 1of the study is a randomized, controlled study in patients with PMF, PPV-MF, or PET-MF (Dynamic International Prognostic Scoring System [DIPSS] risk score of Intermediate-1 to High-Risk), who have had up to 90 days (from the date of the first dose) of prior treatment with a JAK2 inhibitor or are JAK2 inhibitor-naive, and who have severe thrombocytopenia (platelet count <50,000/µL). The Phase 3 portion of this study was designed to use the pacritinib 200 mg BID dose, which was determined to be the optimal dose based on dose- and exposure-response analyses conducted using all available data, including the dosing data from the Phase 2 portion of this study. Patients will be randomized 2:1 to receive pacritinib 200 mg BID or the P/C therapy (limited to single drugs from the following list: corticosteroids, hydroxyurea, thalidomide, lenalidomide, or low-dose ruxolitinib). The proposed P/C regimen for a patient must be selected prior to randomization. Randomization will be stratified by prior JAK2 inhibitor therapy (yes/no) and P/C therapy selected prior to randomization. For the purposes of stratification, thalidomide and lenalidomide will be considered as being in the same group. Prior JAK2 inhibitor therapy will be defined as any duration of treatment with a JAK2 inhibitor, such as ruxolitinib, fedratinib, or momelotinib. To be eligible, patients are not allowed to have been treated with more than one JAK2 inhibitor, with duration of therapy limited to no more than 90 days from the first day of administration. Assigned treatment will continue until the patient experiences progressive disease or intolerable AEs, withdraws consent, or initiates new MF-directed therapy. No study treatment crossover will be allowed at any time. All patients should complete all visit procedures through Week 24, including patients who stop the pacritinib treatment or have protocol-defined progressive disease prior to Week 24, unless the patient withdraws consent for study procedures, dies, undergoes splenic irradiation or splenectomy, or initiates any non-protocol-directed anti-MF treatment. In addition to the above, patients will be considered to have discontinued treatment if pacritinib or P/C therapy is held for >28 consecutive days due to treatment toxicity, or if treatment is discontinued for lack of efficacy, or at the request of the principal investigator or the patient. Following the Week 24 assessment, patients who are benefiting from therapy will be allowed to continue receiving the assigned treatment (pacritinib or P/C) until the patient experiences progressive disease, intolerable AEs, withdraws consent, or initiates new MF-directed therapy. All randomized patients will be followed for survival for 2.5 years from the date of randomization unless consent for follow-up is withdrawn. The Phase 2 portion of the study was designed to support a pacritinib dosage selection decision. Three dosages were evaluated, with patients randomized 1:1:1 to pacritinib 100 mg QD, pacritinib 100 mg BID, or pacritinib 200 mg BID. Randomization was stratified by baseline platelet count (≤50,000/µL; >50,000/µL and ≤100,000/µL; and >100,000/µL). Assigned treatment continued until the patient experienced progressive disease, intolerable AEs, withdrew consent, or until the assigned treatment arm was closed. No study treatment crossover was allowed. All patients should complete all visit procedures through Week 24, including patients who stop pacritinib treatment or have protocol-defined progressive disease prior to Week 24, unless patient withdraws consent, dies, undergoes splenic irradiation or splenectomy, or initiates any non-protocol-directed anti-myelofibrosis treatment. The maximum duration of trial participation for an individual patient was approximately 36 months. Following the Week 24 assessment, patients who were benefiting from therapy and who have not experienced progressive disease were allowed to continue receiving pacritinib at the original randomized dose or following the dose recommendations of the Independent Data Monitoring Committee (IDMC), and were followed for survival, efficacy and safety for up to 2.5 years. The Sponsor collected PK samples from all patients in each dosing arm at the end of Week 12 and Week 24 at the following timepoints: 0 hours (predose), 4 hours postdose (±10 minutes), and 8 hours postdose (±15 minutes). In addition, PD samples were collected on Day 1 (Baseline), Week 12, and Week 24 at 0 hours (predose). DNA samples were also collected for analysis of mutations associated with myelofibrosis at baseline and Week 24.

View this trial on ClinicalTrials.gov

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