| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary Myelofibrosis, Post-essential thrombocythemia myelofibrosis with Severe Thrombocytopenia (Platelet Counts <50,000/μL), 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] - Cardiovascular Diseases [C14] |
| 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 | 21.1 |
| 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 | 21.0 |
| 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.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- The primary objective of the study is to compare the efficacy of pacritinib with that of P/C therapy, as assessed by the proportion of patients achieving a ≥35% SVR from baseline at Week 24 as measured by MRI (preferred) or CT scans.
- 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)from baseline at Week 24 |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are as follow:
1. 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.
2. To compare the overall survival (OS) of patients treated with pacritinib versus those treated with P/C
3. To compare the safety of pacritinib versus P/C therapy
|
|
| 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 1)
2.Platelet count of <50,000/μL at Screening (Day -35 to Day -3)
3.DIPSS Intermediate-1, Intermediate-2, or High Risk (Passamonti et al 2010, appendix 2)
4.Palpable splenomegaly ≥5 cm below the lower costal margin (LCM) in the midclavicular line asassessed 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. The TSS criteria need only to be met on a single day.
6.Age ≥18 years
7.Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
8.Peripheral blast count of <10% throughout the Screening period and prior to randomization
9.Absolute neutrophil count of ≥500/μL
10.Left ventricular cardiac ejection fraction of ≥50% by echocardiogram or multigated acquisition scan
11.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 × ULN (in cases where total bilirubin is elevated, direct bilirubin ≤4 × ULN is required )and creatinine ≤2.5 mg/dL
12.Adequate coagulation defined by prothrombin time (PT)/international normalized ratio (INR) and PTT ≤1.5 × ULN
13.If fertile, willing to use highly effective birth control methods during the study (see Section 7.1.2.5 for acceptable birth control methods).
14.Willing to undergo and able to tolerate frequent MRI or CT scan assessments during the study
15.Able to understand and willing to complete symptom assessments using a patient-reported outcome instrument
16.Provision of informed consent |
|
| E.4 | Principal exclusion criteria |
1. Life expectancy <6 months
2. Completed allogeneic SCT, or are eligible for and willing to complete other approved available therapy including allogeneic 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. Prior treatment with more than one JAK2 inhibitor
8. Prior treatment with ruxolitinib, if BOTH of the following conditions are met: i. exposure to higher-dose ruxolitinib (>10 mg daily) within 120 days prior to treatment Day 1 and
ii. total duration of treatment with higher-dose ruxolitinib (>10 mg
daily) was >90 days, from first to last exposure (i.e., this 90-day period starts on the date of first administration of ruxolitinib at a total daily dose of >10 mg and continues for 90 calendar days, regardless of whether higher-dose ruxolitinib is administered continuously or intermittently).
9. Prior treatment with any JAK2 inhibitor other than ruxolitinib,
irrespective of dose, with a duration of >90 days. 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.
10.Treatment with an experimental therapy, including MF-directed experimental therapies within 28 days prior to treatment Day 1
11.Systemic treatment with a strong P450 3A4 (CYP3A4) inhibitor or a strong CYP3A4 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 (Appendix 5 and Appendix 6, respectively).
12.Significant recent bleeding history defined as NCI CTCAE grade ≥2
within 3 months prior to treatment Day 1, unless precipitated by an
inciting event (e.g., surgery, trauma, or injury)
13.Systemic treatment with medications that increase the risk of
bleeding, including anticoagulants, antiplatelet agents (except for
aspirin dosages of ≤100 mg per day) and daily use of COX-1 inhibiting Nonsteroidal anti-inflammatory drugs (NSAIDs) within 14 days prior to treatment Day 1. Treatment with systemic anti-vascular endothelial growth factor (anti-VEGF) agents within 28 days prior to treatment Day 1.
14.Systemic treatment with medications that can prolong the QT intervalwithin 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 (Appendix 8).
15.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
16.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
17.QT corrected by the Fridericia method (QTcF) prolongation >450 ms or other factors that increase the risk for QT interval prolongation
(hypokalemia [defined as serum potassium <3.0 mEq/L that is persistent and refractory to correction], or history of long QT interval
syndrome)
18.New York Heart Association Class II, III, or IV congestive heart
failure (Appendix 7).
19.Any active GI or metabolic condition that could interfere with
absorption of oral medication
20.Active or uncontrolled inflammatory or chronic functional bowel
disorder such as Crohn's disease, inflammatory bowel disease, chronic diarrhea, or chronic constipation
21.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.
22. 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
23.Known seropositivity for human immunodeficiency (HIV) virus. For patients in Czech, France and Italy only: testing for HIV is required during Screening. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- The co primary efficacy endpoint of SVR is the spleen volume reduction response rate defined as the percentage of patients who achieve at least 35% reduction in spleen volume from baseline as measured by MRI (preferred) or CT scan at Week 24. Patients who do not have a Week 24 spleen assessment will be included as non-responders in this analysis
- The co primary efficacy endpoint of TSS rate is defined as the percentage of
patients with at least 50% reduction in TSS from baseline at Week 24 (as defined by the Myeloproliferative Neoplasm Symptom Assessment Form [MPN SAF TSS 2.0], excluding the “tiredness” component).
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- The secondary endpoint of Patient Global Impression of Change response rate is defined as the percentage of patients who self-assess as “very much improved” or “much improved” at Week 24.
- The secondary endpoint of Overall Survival is defined as the time between randomization and death.
- The tertiary endpoints include time to achievement of at least 35% reduction in spleen volume, best response in SVR by MRI or CT, percentage of patients who achieve at least 25% reduction in spleen volume, achievement of RBC transfusion independence, improvement in hemoglobin level without transfusion, improvement in platelet count, frequency of platelet transfusions, improvement in fatigue as measured by the PROMIS v.1.0 – Fatigue – Short Form 7a, LFS, hematologic improvement, change in hemoglobin A1c, proportion of patients who experience MACE, changes in mutated allelic burden, gene expression, and other biomarkers. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- The secondary endpoint of PGIC will be measured at Week 24.
- The secondary endpoint of OS will be assessed over the period of 2.5 years from randomization
- The tertiary endpoint will be measured assessed over the period of 2.5 years from randomization |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 66 |
| 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 |
| Bosnia and Herzegovina |
| Ukraine |
| Australia |
| Belarus |
| Canada |
| Georgia |
| India |
| Israel |
| Korea, Republic of |
| Russian Federation |
| Serbia |
| United Kingdom |
| United States |
| Bulgaria |
| Czechia |
| France |
| Hungary |
| Italy |
| Poland |
| Romania |
| Spain |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 23 |
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