Clinical Trials /

Dose-Finding Study of Pacritinib in Patients With Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis Previously Treated With Ruxolitinib

NCT03165734

Description:

This is a Bayesian adaptive dose-finding study in patients with primary or secondary myelofibrosis: 1. who have failed therapy with ruxolitinib on the basis of intolerance or loss of efficacy, 2. highly symptomatic (DIPSS risk score of Intermediate-1, Intermediate-2 or High Risk, and MPN-SAF TSS 2.0 of ≥10), 3. and have splenomegaly (assessed by physical examination). Condition or disease: Primary Myelofibrosis/Post-Polycythemia Vera Myelofibrosis/ Post-essential Thrombocythemia Myelofibrosis Intervention/treatment: Drug-Pacritinib Phase: Phase 2

Related Conditions:
  • Myelofibrosis Transformation in Essential Thrombocythemia
  • Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase
  • Primary Myelofibrosis
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Dose-Finding Study of Pacritinib in Patients With Thrombocytopenia and Primary Myelofibrosis, Post-polycythemia Vera Myelofibrosis, or Post-essential Thrombocythemia Myelofibrosis Previously Treated With Ruxolitinib
  • Official Title: Open-Label, Randomized, Phase2 Dose-Finding Study of Pacritinib in Patients With Thrombocytopenia and Primary Myelofibrosis, Post-polycythemia Vera Myelofibrosis, or Post-essential Thrombocythemia Myelofibrosis Previously Treated With Ruxolitinib

Clinical Trial IDs

  • ORG STUDY ID: PAC203
  • NCT ID: NCT03165734

Conditions

  • Primary Myelofibrosis
  • Post-polycythemia Vera Myelofibrosis
  • Post-essential Thrombocythemia Myelofibrosis

Interventions

DrugSynonymsArms
PacritinibPacritinib 100 mg QD

Purpose

This is a Bayesian adaptive dose-finding study in patients with primary or secondary myelofibrosis: 1. who have failed therapy with ruxolitinib on the basis of intolerance or loss of efficacy, 2. are thrombocytopenic (platelet count of ≤100,000/μL), 3. highly symptomatic (DIPSS risk score of Intermediate-1 to High Risk), 4. and have splenomegaly (assessed by physical examination). The study is designed to support a pacritinib dosage selection decision. Three dosages will be evaluated, with patients randomized 1:1:1 to pacritinib 100 mg quaque die (QD), pacritinib 100 mg bis in die (BID), or pacritinib 200 mg bis in die (BID). Assigned treatment will continue for 24 weeks unless the patient experiences progressive disease, intolerable AEs, withdraws consent, or until the assigned treatment arm is closed. 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 nonprotocol-directed anti-myelofibrosis treatment. The dosage selection process will be based on pre-specified efficacy and safety parameters, including model-based dose-response. The maximum duration of trial participation for an individual patient will be approximately 7 months. The estimated duration of the entire study is approximately 2 years if the maximum number of patients are enrolled.

Detailed Description

      The Sponsor will collect 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 will be collected on
      Day 1 (Baseline), Week 12, and Week 24 at 0 hours (predose).

      This study will utilize planned frequent monitoring by an Independent Data Monitoring
      Committee (IDMC). The first IDMC meeting will occur once 30 patients have been randomized and
      will meet approximately quarterly thereafter. To minimize the patient exposure to minimally
      effective dosages, an interim analysis of the primary efficacy and safety data will be
      performed to allow an earlier decision to discontinue an arm that is unlikely to achieve at
      least 10% SVR at Week 24. The interim analysis occurs when 15 patients from each arm have
      completed Week 12 evaluations and have evaluable spleen volume data by MRI or CT. IDMC will
      review efficacy and safety data, including interim analysis, and make recommendations on:

        1. Closing treatment arm(s) and expanding enrollment in remaining treatment arm(s)

        2. Pausing enrollment due to cardiac or hemorrhage adverse events

        3. Dosage for further clinical studies
    

Trial Arms

NameTypeDescriptionInterventions
Pacritinib 100 mg QDExperimentalPacritinib 100 mg (1 capsule) QD orally, at the same time of day, with or without food
  • Pacritinib
Pacritinib 100 mg BIDExperimentalPacritinib 100 mg (1 capsule) BID orally, at the same time of day, with or without food
  • Pacritinib
Pacritinib 200 mg BIDExperimentalPacritinib 200 mg (2 capsules) BID orally, at the same time of day, with or without food
  • Pacritinib

Eligibility Criteria

        Inclusion Criteria:

          1. Primary myelofibrosis, post-polycythemia vera myelofibrosis, or Post-essential
             thrombocythemia myelofibrosis

          2. Dynamic International Prognostic Scoring System (DIPSS) Intermediate-1, Intermediate
             -2, or High risk (Passamonti et al 2010)

          3. Prior ruxolitinib treatment failure or intolerance as defined by:

               1. Treatment for ≥6 months with inadequate efficacy response (any measure) in the
                  judgement of the investigator

               2. Treatment for ≥28 days complicated by either:

             i. Red Blood Cell transfusion ii. National Cancer Institute Common Terminology
             Criteria for Adverse Events (CTCAE) grade ≥3 AEs of thrombocytopenia, anemia,
             hematoma, and/or hemorrhage while being treated with a dosage of <20 mg BID

          4. Palpable splenomegaly ≥5 cm below the lower costal margin (LCM) in the midclavicular
             line as assessed by physical examination

          5. Platelet count of ≤100,000/μL at any time during the screening period and prior to
             first dose of pacritinib, including patients who are platelet transfusion-dependent

          6. Total Symptom Score (TSS) of ≥10 on the Myeloproliferative Neoplasm Symptom Assessment
             Form Total Symptom Score (MPN-SAF TSS 2.0)

          7. Age ≥18 years old

          8. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2

          9. Peripheral blast count of <10%

         10. Absolute neutrophil count of >500/μL

         11. Adequate liver and renal function, defined by liver transaminases (aspartate
             aminotransferase/serum glutamic oxaloacetic transaminase and alanine
             aminotransferase/serum glutamic pyruvic transaminase [SGPT]), ≤3 × the upper limit of
             normal (ULN) (AST/ALT ≤5 × ULN if transaminase elevation is related to MF), direct
             bilirubin ≤4× ULN, and creatinine ≤2.5 mg/dL

         12. Adequate coagulation function, defined by prothrombin time PT)/international
             normalized ratio (INR), partial thromboplastin time (PTT), or thrombin time (TT) of
             ≤1.5 × ULN

         13. Left ventricular cardiac ejection fraction of ≥45% by echocardiogram or multigated
             acquisition (MUGA) scan

         14. QTc interval of <450 ms as assessed by ECG and corrected by the Fridericia method

         15. If fertile, willing to use effective birth control methods during the study

         16. Willing to undergo and able to tolerate frequent MRI or CT assessments during the
             study

         17. Able to understand and willing to complete symptom assessments using a
             patient-reported outcomes instrument

         18. Provision of informed consent

        Exclusion Criteria:

          1. Life expectancy <6 months

          2. Completed allogeneic stem cell transplantation (ASCT) or are eligible for and willing
             to complete Completed allogeneic stem cell transplantation (ASCT)

          3. History of splenectomy or planning to undergo splenectomy

          4. Splenic irradiation within the last 6 months

          5. Previously treated with pacritinib

          6. Treatment with anticoagulation or antiplatelet agents, except for aspirin dosages of
             ≤100 mg per day, within the last 2 weeks

          7. Treatment with a potent cytochrome P450 (CYP450) inducer within the last 2 weeks

          8. Treatment with medications that can prolong the QTc interval within the last 2 weeks

          9. Significant recent bleeding history defined as National Cancer Institute Common
             Terminology Criteria for Adverse Events (NCI CTCAE) grade ≥2 within the last 3 months,
             unless precipitated by an inciting event (e.g., surgery, trauma, injury)

         10. Any history of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥2
             non-dysrhythmia cardiac conditions within the last 6 months. Patients with
             asymptomatic grade 2 non-dysrhythmia cardiac conditions may be considered for
             inclusion, with the approval of the medical monitor, if stable and unlikely to affect
             patient safety.

         11. New York Heart Association Class II, III, or IV congestive heart failure

         12. Any history of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥2 cardiac
             dysrhythmias within the last 6 months. Patients with non-QTc Common Terminology
             Criteria for Adverse Events (CTCAE) grade 2 cardiac dysrhythmias may be considered for
             inclusion, with the approval of the medical monitor, if the dysrhythmias are stable,
             asymptomatic, and unlikely to affect patient safety.

         13. QTc prolongation >450 ms or other factors that increase the risk for QT interval
             prolongation (e.g., heart failure, hypokalemia [defined as serum potassium <3.0
             mEq(milliequivalent)/L that is persistent and refractory to correction], family
             history of long QT interval syndrome, or concomitant use of medications that may
             prolong QT interval)

         14. Any gastrointestinal or metabolic condition that could interfere with absorption of
             oral medication

         15. Inflammatory or chronic functional bowel disorder such as Crohn's Disease,
             inflammatory bowel disease, chronic diarrhea, or constipation

         16. Other malignancy within the last 3 years, other than curatively treated basal cell or
             squamous cell skin cancer, carcinoma in situ of the cervix, organ-confined or treated
             nonmetastatic prostate cancer with negative prostate-specific antigen, in situ breast
             carcinoma after complete surgical resection, or superficial transitional cell bladder
             carcinoma

         17. Uncontrolled intercurrent illness, including, but not limited to, ongoing active
             infection or psychiatric illness or social situation that, in the judgment of the
             treating physician, would limit compliance with study requirements

         18. Known seropositivity for human immunodeficiency virus

         19. Known active hepatitis A, B, or C virus infection

         20. Women who are pregnant or lactating
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Spleen volume
Time Frame:24 weeks
Safety Issue:
Description:The primary efficacy variable for dosage selection is the percent reduction in spleen volume from baseline as measured by MRI or CT. For evaluation as part of the dose-response relationship will include the percentage of patients who achieve at least 35% reduction in spleen volume

Secondary Outcome Measures

Measure:Percentage of patients with CTCAE grade ≥3 cardiac AEs, CTCAE grade ≥3 hemorrhage AEs, CTCAE grade ≥4 thrombocytopenia toxicity, or CTCAE grade ≥4 anemia toxicity
Time Frame:Day 0 through the patient's last day of study participation, approximately 8 months
Safety Issue:
Description:The safety population is defined as all randomized patients who received at least one dose of study treatment. For screened patients who are not randomized, only SAEs occurring between the time of informed consent and determination of screen failure are to be reported.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:CTI BioPharma

Trial Keywords

  • myelofibrosis
  • pacritinib
  • Post-polycythemia Vera Myelofibrosis
  • Post-essential Thrombocythemia Myelofibrosis
  • Ruxolitinib
  • Bone Marrow Disease
  • Hematologic Diseases
  • Blood Platelet Disorders
  • Hemorrhagic Disorders
  • Splenomegaly
  • Anemia
  • Spleen volume
  • Spleen

Last Updated

September 6, 2017