E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary Myelofibrosis, Post-essential thrombocythemia myelofibrosis, Post polycythaemia vera myelofibrosis |
|
E.1.1.1 | Medical condition in easily understood language |
Primary or Secondary Myelofibrosis (MF) |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10077161 |
E.1.2 | Term | Primary myelofibrosis |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10074692 |
E.1.2 | Term | Post essential thrombocythaemia myelofibrosis |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10074691 |
E.1.2 | Term | Post polycythaemia vera myelofibrosis |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028537 |
E.1.2 | Term | Myelofibrosis |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
● To determine a recommended dosage of pacritinib for further clinical studies |
|
E.2.2 | Secondary objectives of the trial |
● To examine the dose–response relationship for efficacy, as measured by spleen volume reduction (SVR) using MRI (preferred) or CT and TSS using the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score version 2.0 (MPN-SAF TSS 2.0)
● To examine the dose–response relationship for safety with a focus on AEs of interest
● To further characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of pacritinib
● To evaluate the long term efficacy and safety of pacritinib treatment |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. PMF, PPV-MF, or PET-MF (as defined by Tefferi and Vardiman 2008, Appendix 4)
2. DIPSS Intermediate-1, Intermediate -2, or High risk (Passamonti et al. 2010, Appendix 3)
3. Prior ruxolitinib treatment with failure to benefit or intolerance as defined by at least one of the following:
a. 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 to these parameters following an initial response; and/or
b. 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. 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 (LCM) in the midclavicular line as assessed by physical examination
5. TSS of ≥10 on the MPN-SAF TSS 2.0 patients with a single symptom score of ≥5 or two symptoms ≥3 including only the symptoms of left upper quadrant pain, bone pain, itching or night sweats (Appendix 3)
6. Age ≥18 years old
7. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 (Appendix 6)
8. Peripheral blast count of <10% throughout the screening period
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 (LVEF) 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 |
|
E.4 | Principal exclusion criteria |
1. Life expectancy <6 months
2. Completed 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. Patients receiving high-dose ruxolitinib (more than 10 mg BID or 20
mg QD) who cannot tolerate tapering down ruxolitinib to 10 mg BID or
less prior to the first dose of pacritinib
7. Treatment with anticoagulation or antiplatelet agents, except for aspirin dosages of ≤100 mg per day, within the last 2 weeks
8. Treatment with a strong CYP3A4 inhibitor or a strong cytochrome P450 (CYP450) inducer within the last 2 weeks
9. Treatment with medications that can prolong the QTc interval within the last 2 weeks
10. Treatment with an experimental therapy within the last 28 days
11. 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)
12. 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.
13. New York Heart Association Class II, III, or IV congestive heart failure
14. 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.
15. 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)
16. Any active gastrointestinal or metabolic condition that could interfere with absorption of oral medication
17. Active or uncontrolled Inflammatory or chronic functional bowel disorder such as Crohn’s Disease, inflammatory bowel disease, chronic diarrhea, or constipation
18. 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
19. 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
20. Known seropositivity for human immunodeficiency virus
21. Known active hepatitis A, B, or C virus infection
22. Women who are pregnant or lactating
23. Concurrent enrollment in another interventional trial |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy variable for dosage selection is the percent reduction in spleen volume from baseline.
The primary safety measure for dosage selection is the percentage of patients with CTCAE grade ≥3 cardiac AEs (Standardized MedDRA Query [SMQ]), CTCAE grade ≥3 hemorrhage AEs (SMQ), CTCAE grade ≥4 thrombocytopenia toxicity (central laboratory based), or CTCAE grade ≥4 anemia toxicity (central laboratory based). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint is measured at Weeks 12 and 24. |
|
E.5.2 | Secondary end point(s) |
Other supportive measures for evaluation as part of the dose–response relationship include: the percentage of patients who achieve at least 35% reduction in spleen volume; % TSS reduction from baseline; and the percentage of patients with at least 50% reduction in TSS.
All other safety data including AEs, death and clinical laboratory measures will be used as supportive measures for evaluation of pacritinib dose-safety relationship and for long term safety evaluation.
Long term efficacy is evaluated using percent reduction in spleen volume from baseline as measured by MRI or CT, percent reduction in TSS from baseline, percent reduction in spleen length by physical exam and the patient global impression assessment.
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary endpoint is measured at Weeks 12 and 24.
To evaluate the long term efficacy and safety of pacritinib treatment follow up will continue every 3 months up to 2.5 years (with the exception of MRI/CT spleen assessment, which will only be followed up to 2 years and TSS assessment, which will only be followed up to 48 weeks). |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
France |
Germany |
Hungary |
Israel |
Italy |
Korea, Republic of |
Netherlands |
Poland |
Romania |
Spain |
Sweden |
United Kingdom |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 21 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 11 |