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

Study Overview
=================
Brief Summary
-----------------
This study (study ID PAC203 North America; PAC303 ex-North America) 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 399 patients in total will be enrolled, randomized 2:1 to either pacritinib (approximately 266 patients) or to P/C therapy (approximately 133 patients) Condition or disease: Primary Myelofibrosis/Post-Polycythemia Vera Myelofibrosis/ Post-essential Thrombocythemia Myelofibrosis Intervention/treatment: Drug-Pacritinib

Detailed Description
-----------------
The study is a randomized, controlled phase 3 study comparing the efficacy of pacritinib with P/C therapy 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 had no or limited exposure to any JAK2 inhibitor or are JAK2 inhibitor-naive, and who have severe thrombocytopenia (platelet count <50,000/µL). 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 previous 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, danazol, 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. 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. 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 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, initiates any non-protocol-directed anti-MF treatment, or the study is terminated. 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.

Official Title
-----------------
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)(PACIFICA)

Conditions
-----------------
Primary Myelofibrosis, Post-polycythemia Vera Myelofibrosis, Post-essential Thrombocythemia Myelofibrosis

Intervention / Treatment
-----------------
* Drug: Pacritinib
* Drug: Physician's Choice medications


Participation Criteria
=================
Eligibility Criteria
-----------------
Diagnosis and Inclusion Criteria PMF (including pre-fibrotic MF), PPV-MF, or PET-MF (Tefferi and Vandiman 2008) Average platelet count of <50,000/µL at Screening (Day -35 to Day -3) based on two measurements taken on different days; both measurements must be <50,000/µL DIPSS Intermediate-1, Intermediate-2, or High risk (Passamonti et al 2010) Palpable splenomegaly ≥5 cm below the lower costal margin (LCM) in the midclavicular line as assessed by physical examination TSS of ≥10 on the MPN-SAF TSS 2.0 or a single symptom score of ≥5 or two symptoms of ≥3, including only the symptoms of left upper quadrant pain, bone pain, itching, or night sweats If the patient has received prior JAK2 inhibitor treatment, this treatment must meet at least one of the following criteria: Prior treatment with any JAK2 inhibitor, irrespective of dose, with a duration of 90 days or less. The 90-day period starts on the date of first administration of JAK2 inhibitor therapy and continues for 90 calendar days, regardless of whether therapy is administered continuously or intermittently during that interval. Prior treatment with ruxolitinib, at no more than 10 mg total daily dose on any day, with a duration of 270 days or less. The 270-day period starts on the date of first ruxolitinib administration and continues for 270 calendar days, regardless of whether therapy is administered continuously or intermittently during that interval.The patient may not have received >10 mg of ruxolitinib on any day during that interval Age ≥18 years Eastern Cooperative Oncology Group performance status 0 to 2 Peripheral blast count of <10% throughout the Screening period and at baseline Absolute neutrophil count of ≥500/µL Left ventricular cardiac ejection fraction of ≥50% by echocardiogram or multigated acquisition (MUGA) scan Adequate liver and renal function, defined by liver transaminases (aspartate aminotransferase [AST]/serum glutamic-oxaloacetic transaminase [SGOT] and alanine aminotransferase [ALT]/serum glutamic pyruvic transaminase [SGPT]) ≤3 × the upper limit of normal (ULN) (AST/ALT ≤5 × ULN if transaminase elevation is related to MF), total bilirubin ≤4 x ULN (in cases where total bilirubin is elevated, direct bilirubin ≤4 × ULN, is required) and creatinine ≤2.5 mg/dL Adequate coagulation defined by prothrombin time/international normalized ratio and partial thromboplastin time ≤1.5 × ULN If fertile, willing to use effective birth control methods during the study Willing to undergo and able to tolerate frequent MRI or CT scan assessments during the study Able to understand and willing to complete symptom assessments using a patient-reported outcome instrument Provision of signed informed consent Exclusion Criteria Life expectancy <6 months Completed allogeneic stem cell transplant (allo-SCT) or are eligible for and willing to complete other approved available therapy including allo-SCT History of splenectomy or planning to undergo splenectomy Splenic irradiation within the last 6 months Previously treated with pacritinib Treatment with any MF-directed therapy within 14 days prior to treatment Day 1 Any prior treatment with more than one JAK2 inhibitor Treatment with an experimental therapy within 28 days prior to treatment Day 1 Systemic treatment with a strong CYP3A4 inhibitor or a strong cytochrome P450 (CYP450) inducer within 14 days prior to treatment Day 1. Shorter washout periods may be permitted with approval of the Medical Monitor, provided that the washout period is at least five half-lives of the drug prior to treatment Day 1 Significant recent bleeding history defined as National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grade ≥2 within 3 months prior to treatment Day 1, unless precipitated by an inciting event (e.g., surgery, trauma, or injury) Systemic treatment with medications that increase the risk of bleeding, including anticoagulants, antiplatelet agents (except for aspirin dosages of ≤100 mg per day), anti-vascular endothelial growth factor (anti-vascular endothelial growth factor [anti-VEGF]) agents, and daily use of cyclooxygenase-1 (COX-1) inhibiting nonsteroidal anti- inflammatory drugs (NSAIDs) within 14 days prior to treatment Day 1 Systemic treatment with medications that can prolong the QT interval within 14 days prior to treatment Day 1. Shorter washout periods may be permitted with approval of the Medical Monitor, provided that the washout period is at least five half-lives of the drug prior to treatment Day 1 Any history of CTCAE grade ≥2 non-dysrhythmia cardiac conditions within 6 months prior to treatment Day 1. Patients with asymptomatic grade 2 non- dysrhythmia cardiovascular conditions may be considered for inclusion, with the approval of the Medical Monitor, if stable and unlikely to affect patient safety. Any history of CTCAE grade ≥2 cardiac dysrhythmias within 6 months prior to treatment Day 1. Patients with non-QTc 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. QT corrected by the Fridericia method (QTcF) prolongation >450 ms or other factors that increase the risk for QT interval prolongation (e.g., hypokalemia [defined as serum potassium <3.0 mEq/L that is persistent and refractory to correction], or history of long QT interval syndrome New York Heart Association Class II, III, or IV congestive heart failure Any active gastrointestinal or metabolic condition that could interfere with absorption of oral medication Active or uncontrolled inflammatory or chronic functional bowel disorder such as Crohn's Disease, inflammatory bowel disease, chronic diarrhea, or chronic constipation Other malignancy within 3 years prior to treatment Day 1. The following patients may be eligible despite having had a malignancy within the prior 3 years: patients with curatively treated squamous or basal cell carcinoma of the skin; patients with curatively treated non-invasive cancers; patients with organ-confined prostate cancer with prostate-specific antigen (PSA) <20 ng/mL and National Comprehensive Cancer Network risk of Very Low, Low, or Favorable Intermediate; and patients with curatively treated non-metastatic prostate cancer with negative PSA. Uncontrolled intercurrent illness, including, but not limited to, ongoing active infection, psychiatric illness, or social situation that, in the judgment of the treating physician, would limit compliance with study requirements Known seropositivity for human immunodeficiency virus Known active hepatitis A, B, or C virus infection Women who are pregnant or lactating Concurrent enrollment in another interventional trial Severe thrombocytopenia due to vitamin B12 deficiency, folate deficiency, or viral infection in the opinion of the investigator Known hypersensitivity to pacritinib or any of the following inactive ingredients: microcrystalline cellulose, polyethylene glycol, and magnesium stearate; any contraindication to the physician's choice medicinal product selected by the investigator to be used as the comparator or to loperamide or equivalent antidiarrheal medication.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pacritinib 200 mg BID<br>To receive pacritinib 200 mg twice daily (BID) orally, at the same time of day, with or without food | Drug: Pacritinib<br>* Oral administration. Supplied in capsules containing 100 mg (as the free base) in red cap/gray body size 0 opaque hard gelatin capsules. The inactive ingredients are microcrystalline cellulose, magnesium stearate, and polyethylene glycol 8000. Each capsule contains 146 mg of pacritinib citrate, which is equivalent to 100 mg pacritinib free base<br>|
| Active Comparator: Physician's Choice (P/C) therapy<br>The Physician's Choice (P/C) therapy (limited to single drugs from the following list: corticosteroids, hydroxyurea, danazol, or low-dose ruxolitinib). The proposed P/C regimen for a patient must be selected prior to randomization. | Drug: Physician's Choice medications<br>* Physician's Choice medications will be selected and administered according to the investigator's judgement. Investigators can select individual P/C agents but cannot combine agents or give them sequentially.<br>* Other names: low-dose ruxolitinib;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Spleen volume | To compare the efficacy of pacritinib with that of physician's choice (P/C) therapy, as assessed by the proportion of patients achieving a ≥35% spleen volume reduction (SVR) as measured by magnetic resonance imaging (MRI, preferred) or computed tomography (CT) scans | From baseline at 24 weeks | 
| Total Symptom Score (TSS) (excluding tiredness) | To compare the efficacy of pacritinib compared to P/C therapy, as assessed by the proportion of patients achieving a ≥50% reduction in Total Symptom Score (TSS). The TSS is the sum of the individual symptom scores for tiredness, early satiety, abdominal discomfort, night sweats, pruritus, bone pain, and pain under ribs on the left side. Symptoms are ranked 0 (absent) to 10 (worst imaginable) | From baseline at Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | To compare the overall survival (OS) of patients treated with pacritinib versus those treated with P/C | until 2.5 years after the date of randomization | 
| Patient Global Impression of Change (PGIC) assessed at Week 24 | To compare the percentage of patients who self-assess as very much improved or much improved as measured by the Patient Global Impression of Change (PGIC) in patients treated with pacritinib versus those treated with P/C | End of Week 12 to 2 years following Week 24 visit | 
| To compare the safety of pacritinib versus P/C therapy | Safety will be assessed based on the incidence and severity (according to the Common Terminology Criteria for Adverse Events) of treatment emergent adverse events from the time of randomization until 30 days after completion of treatment with pacritinib and/or physician's choice therapy. | Randomization through 30 after last treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
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