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. 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

Conditions

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Inclusion Criteria

  1. PMF, PPV-MF, or PET-MF (as defined by Tefferi and Vardiman 2008)
  2. DIPSS Intermediate-1, Intermediate -2, or High risk (Passamonti et al 2010)
  3. Prior ruxolitinib treatment with failure to benefit or intolerance as defined by at least one of the following:
  4. Treatment for ≥3 months with inadequate efficacy response defined as <10% spleen volume reduction by MRI or <30% decrease from baseline in spleen length by physical examination or regrowth to these parameters following an initial response; and/or
  5. Treatment for ≥28 days complicated by either

i. Development of a red blood cell transfusion requirement (at least 2 units/month for 2 months)

ii. National Cancer Institute (NCI) 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 in the midclavicular line as assessed by physical examination

5. TSS of ≥10 on the MPN-SAF TSS 2.0 or patients with 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. Age ≥18 years old

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

8. Peripheral blast count of <10%

9. Absolute neutrophil count of >500/µL

10. 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), direct bilirubin ≤4× ULN, and creatinine ≤2.5 mg/dL

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

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

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

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

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

16. Provision of 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 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 anticoagulation or antiplatelet agents, except for aspirin dosages of ≤100 mg per day, within the last 2 weeks
  7. Treatment with a strong CYP3A4 inhibitor or a strong cytochrome P450 inducer within the last 2 weeks
  8. Treatment with medications that can prolong the QTc interval within the last 2 weeks
  9. Treatment with an experimental therapy within the last 28 days
  10. Significant recent bleeding history defined as NCI CTCAE grade ≥2 within the last 3 months, unless precipitated by an inciting event (e.g., surgery, trauma, injury)
  11. Any history of 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.
  12. New York Heart Association Class II, III, or IV congestive heart failure
  13. Any history of CTCAE grade ≥2 cardiac dysrhythmias within the last 6 months. 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.
  14. 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/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)
  15. Any gastrointestinal or metabolic condition that could interfere with absorption of oral medication
  16. Inflammatory or chronic functional bowel disorder such as Crohn's Disease, inflammatory bowel disease, chronic diarrhea, or constipation
  17. 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
  18. 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
  19. Known seropositivity for human immunodeficiency virus
  20. Known active hepatitis A, B, or C virus infection
  21. Women who are pregnant or lactating
  22. Concurrent enrollment in another interventional trial

Study Design

Phase
Phase 2
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
Single (Outcomes Assessor)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Pacritinib 100 mg QD
Pacritinib 100 mg (1 capsule) QD orally, at the same time of day, with or without food
  • 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 capsules contains 146 mg of pacritinib citrate, which is equivalent to 100 mg pacritinib free base
Experimental
Pacritinib 100 mg BID
Pacritinib 100 mg (1 capsule) BID orally, at the same time of day, with or without food
  • 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 capsules contains 146 mg of pacritinib citrate, which is equivalent to 100 mg pacritinib free base
Experimental
Pacritinib 200 mg BID
Pacritinib 200 mg (2 capsules) BID orally, at the same time of day, with or without food
  • 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 capsules contains 146 mg of pacritinib citrate, which is equivalent to 100 mg pacritinib free base

Recruiting Locations

Vanderbilt-Ingram Cancer Center
Nashville, Tennessee 37232

More Details

NCT ID
NCT03165734
Status
Recruiting
Sponsor
CTI BioPharma

Study Contact

Debra Jones
206-282-7100
djones@ctibiopharma.com

Detailed Description

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 QD, pacritinib 100 mg BID, or pacritinib 200 mg BID. Randomization will be stratified by baseline platelet count (≤50,000/µL; >50,000/µL and ≤100,000/µL; and >100,000/µL). Assigned treatment will continue until the patient experiences progressive disease, intolerable AEs, withdraws consent, or until the assigned treatment arm is closed. No study treatment crossover will be 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 will be approximately 36 months. The Following the Week 24 assessment, patients who are benefiting from therapy and who have not experienced progressive disease will be allowed to continue receiving pacritinib at the original randomized dose or following the dose recommendations of the Independent Data Monitoring Committee (IDMC), and will be followed for survival, efficacy and safety for up to 2.5 years.

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). DNA samples will also be collected for analysis of mutations associated with myelofibrosis at baseline and Week 24.

This study will utilize planned frequent monitoring by an IDMC. The first meeting will occur once 18 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 will be performed when 6 patients per arm have completed the 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

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.