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

• ClinicalTrials.gov Identifier: NCT03165734
• Recruitment Status: Recruiting
• First Posted: May 24, 2017
• Last Update Posted: December 27, 2022
• Sponsor: CTI BioPharma
• Collaborator: PSI CRO
• Information provided by (Responsible Party): CTI BioPharma

Tracking Information

• First Submitted Date: May 17, 2017
• First Posted Date: May 24, 2017
• Last Update Posted Date: December 27, 2022
• Actual Study Start Date: June 26, 2017
• Estimated Primary Completion Date: June 30, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 22, 2022)

• Spleen volume [ Time Frame: From baseline at 24 weeks ]
  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
• Total Symptom Score (TSS) [ Time Frame: From baseline at Week 24 ]
  To compare the efficacy of pacritinib with 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)

Original Primary Outcome Measures (submitted: May 23, 2017)

Spleen volume [ Time Frame: 24 weeks ]

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

Current Secondary Outcome Measures (submitted: August 9, 2022)

• Overall Survival (OS) [ Time Frame: until 2.5 years after the date of randomization ]
  To compare the overall survival (OS) of patients treated with pacritinib versus those treated with P/C
• Patient Global Impression of Change (PGIC) assessed at Week 24 [ Time Frame: End of Week 12 to 2 years following Week 24 visit ]
  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
• To compare the safety of pacritinib versus P/C therapy [ Time Frame: Randomization through 30 after last treatment ]
  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.

Original Secondary Outcome Measures (submitted: May 23, 2017)

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 ]

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.

Current Other Pre-specified Outcome Measures (submitted: August 9, 2022)

• SVR of ≥35% [ Time Frame: Up to 24 Weeks ]
  Time to achievement of SVR of ≥35%
• Best response in SVR [ Time Frame: At 24 Weeks ]
  Best response in SVR by MRI or CT scan
• >25% SVR [ Time Frame: From baseline and at Week 24 ]
  Proportion of patients achieving >25% SVR
• Red blood cell (RBC) [ Time Frame: Baseline to End of Treatment ]
  Achievement of red blood cell (RBC) transfusion independence at Weeks 12 and 24
• hemoglobin level [ Time Frame: Weeks 12 and 24 ]
  Improvement in hemoglobin level without transfusion at Weeks 12 and 24
• platelet count [ Time Frame: Weeks 12 and 24 ]
  Improvement in platelet count at Weeks 12 and 24
• platelet transfusions [ Time Frame: Weeks 12 and 24 ]
  Frequency of platelet transfusions at Weeks 12 and 24
• PROMIS [ Time Frame: Baseline to Week 24 ]
  Improvement in fatigue as measured by Patient-Reported Outcomes Measurement Information System (PROMIS) v.1.0 - Fatigue from Baseline through Week 24
• Leukemia-free survival (LFS) [ Time Frame: Baseline to Week 24 ]
  Leukemia-free survival (LFS) of patients treated with pacritinib versus P/C therapy
• The percentage of red blood cell transfusion-independent patients achieving a 1 g/dL and a 2 g/dL increase in hemoglobin [ Time Frame: Baseline to 24 weeks ]
  The percentage of red blood cell transfusion-independent patients at baseline achieving a 1 g/dL and a 2 g/dL increase in hemoglobin at week 24
• The percentage of platelet transfusion-independent patients with improvement in grade of thrombocytopenia [ Time Frame: Baseline to 24 weeks ]
  The percentage of platelet transfusion-independent patients at baseline with improvement in grade of thrombocytopenia at week 24
• The percentage of transfusion-dependent patients achieving transfusion independence and achieving 50% reduction in transfusion rate [ Time Frame: Baseline to 24 weeks ]
  The percentage of transfusion-dependent patients at baseline achieving transfusion independence and achieving 50% reduction in transfusion rate at week 24
• Hemaglobin A1c [ Time Frame: Baseline to Week 24 ]
  Changes in hemoglobin A1c
• mutated allelic burden, gene expression, and pharmacodynamic (PD) biomarkers [ Time Frame: Baseline to up to 24 Weeks ]
  Changes in mutated allelic burden, gene expression, and pharmacodynamic (PD) biomarkers
• The proportion of patients who experience a major adverse cardiac event (MACE) [ Time Frame: Baseline to up to 24 Weeks ]
  MACE is a composite endpoint that is considered to occur if any of the following TEAEs occur:

  • cardiovascular death, defined as death due to acute myocardial infarction, sudden cardiac death, death due to heart failure, death due to stroke, death due to cardiovascular procedures, death due to cardiovascular hemorrhage, or death due to peripheral artery disease
  • non-fatal myocardial infarction
  • non-fatal stroke of any classification, including reversible focal neurological defects with imaging evidence of a new cerebral lesion consistent with ischemia or hemorrhage

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Phase 3 Study of Pacritinib in Patients With Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis
• 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)

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.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Outcomes Assessor); Primary Purpose: Treatment

Condition

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

Intervention

• Drug: Pacritinib
  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
• Drug: Physician's Choice medications
  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.
  Other Names:

  • corticosteroids
  • hydroxyurea
  • danazol
  • low-dose ruxolitinib

Study Arms

• Experimental: Pacritinib 200 mg BID
  To receive pacritinib 200 mg twice daily (BID) orally, at the same time of day, with or without food
  Intervention: Drug: Pacritinib
• Active Comparator: Physician's Choice (P/C) therapy
  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.
  Intervention: Drug: Physician's Choice medications

• Publications *: Gerds AT, Savona MR, Scott BL, Talpaz M, Egyed M, Harrison CN, Yacoub A, Vannucchi A, Mead AJ, Kiladjian JJ, O'Sullivan J, Garcia-Gutierrez V, Bose P, Rampal RK, Miller CB, Palmer J, Oh ST, Buckley SA, Mould DR, Ito K, Tyavanagimatt S, Smith JA, Roman-Torres K, Devineni S, Craig AR, Mascarenhas JO. Determining the recommended dose of pacritinib: results from the PAC203 dose-finding trial in advanced myelofibrosis. Blood Adv. 2020 Nov 24;4(22):5825-5835. doi: 10.1182/bloodadvances.2020003314.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 9, 2022): 399
• Original Estimated Enrollment (submitted: May 23, 2017): 105
• Estimated Study Completion Date: December 31, 2025
• Estimated Primary Completion Date: June 30, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Diagnosis and Inclusion Criteria

1. PMF (including pre-fibrotic MF), PPV-MF, or PET-MF (Tefferi and Vandiman 2008)
2. 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
3. DIPSS Intermediate-1, Intermediate-2, or High risk (Passamonti et al 2010)
4. Palpable splenomegaly ≥5 cm below the lower costal margin (LCM) in the midclavicular line as assessed by physical examination
5. 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

6. If the patient has received prior JAK2 inhibitor treatment, this treatment must meet at least one of the following criteria:

   1. 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.
   2. 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
7. Age ≥18 years
8. Eastern Cooperative Oncology Group performance status 0 to 2
9. Peripheral blast count of <10% throughout the Screening period and at baseline
10. Absolute neutrophil count of ≥500/µL
11. Left ventricular cardiac ejection fraction of ≥50% by echocardiogram or multigated acquisition (MUGA) scan
12. 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
13. Adequate coagulation defined by prothrombin time/international normalized ratio and partial thromboplastin time ≤1.5 × ULN
14. If fertile, willing to use effective birth control methods during the study
15. Willing to undergo and able to tolerate frequent MRI or CT scan assessments during the study
16. Able to understand and willing to complete symptom assessments using a patient-reported outcome instrument
17. Provision of signed informed consent

Exclusion Criteria

1. Life expectancy <6 months
2. Completed allogeneic stem cell transplant (allo-SCT) or are eligible for and willing to complete other approved available therapy including allo-SCT
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 any MF-directed therapy within 14 days prior to treatment Day 1
7. Any prior treatment with more than one JAK2 inhibitor
8. Treatment with an experimental therapy within 28 days prior to treatment Day 1
9. 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
10. 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)
11. 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
12. 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
13. 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.
14. 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.
15. 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
16. New York Heart Association Class II, III, or IV congestive heart failure
17. Any active gastrointestinal or metabolic condition that could interfere with absorption of oral medication
18. Active or uncontrolled inflammatory or chronic functional bowel disorder such as Crohn's Disease, inflammatory bowel disease, chronic diarrhea, or chronic constipation
19. 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.
20. 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
21. Known seropositivity for human immunodeficiency virus
22. Known active hepatitis A, B, or C virus infection
23. Women who are pregnant or lactating
24. Concurrent enrollment in another interventional trial
25. Severe thrombocytopenia due to vitamin B12 deficiency, folate deficiency, or viral infection in the opinion of the investigator
26. 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Simran Bedi Singh; 206-272-4454; ssingh@ctibiopharma.com

Contact: John Volpone; 1-206-272-4652; jvolpone@ctibiopharma.com

• Listed Location Countries: Australia, Belarus, Bulgaria, Canada, Czechia, France, Georgia, Germany, Hungary, Israel, Italy, Korea, Republic of, Poland, Russian Federation, Serbia, Spain, Ukraine, United Kingdom, United States
• Removed Location Countries: Sweden

Administrative Information

• NCT Number: NCT03165734
• Other Study ID Numbers: PAC203/PAC303; PAC303 ( Other Identifier: CTI BioPharma )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: CTI BioPharma
• Original Responsible Party: Same as current
• Current Study Sponsor: CTI BioPharma
• Original Study Sponsor: Same as current
• Collaborators: PSI CRO

Investigators

• Study Director: Simran Bedi Singh; CTI BioPharma

• PRS Account: CTI BioPharma
• Verification Date: December 2022