| 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 between baseline and Week 24 as measured by MRI (preferred) or CT scans. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are as follows:
1. To compare the efficacy of pacritinib with P/C therapy, as assessed by the proportion of patients achieving a ≥50% reduction in TSS between baseline and Week 24
2. 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
3. To compare the OS of patients treated with pacritinib versus those treated with P/C
4. 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)
2.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 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.If the patient has received prior JAK2 inhibitor treatment, this treatment must meet at least one ofthe following criteria:
a.Prior treatment with any JAK2 inhibitor, irrespective of dose, with a duration of 90 days orless. The 90-day period starts on the date of first administration of JAK2 inhibitor therapy andcontinues for 90 calendar days, regardless of whether therapy is administered continuously orintermittently during that interval.
b.Prior treatment with ruxolitinib, at no more than 10 mg total daily dose on any day, with aduration of 180 days or less. The 180-day period starts on the date of first ruxolitinibadministration and continues for 180 calendar days, regardless of whether therapy isadministered continuously or intermittently. The patient may not have received >10 mg ofruxolitinib on any day during that interval.
The 90- or 180-day period may overlap with the Screening period but may not extend into the washout period (14 days prior to treatment Day 1).
7.Age ≥18 years
8.Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
9.Peripheral blast count of <10% throughout the Screening period and prior to randomization
10.Absolute neutrophil count of ≥500/μL
11.Left ventricular cardiac ejection fraction of ≥50% by echocardiogram or multigated acquisition 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), direct bilirubin ≤4 × ULN, andcreatinine ≤2.5 mg/dL
13.Adequate coagulation defined by prothrombin time (PT)/international normalized ratio (INR) andPTT ≤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 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. Treatment with an experimental therapy within 28 days prior to treatment Day 1
9. Systemic treatment with a strong CYP3A4 inhibitor or a strong 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 NCI 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-VEGF) agents, and daily use of 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., heart failure, 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 GI 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, other than curatively treated basal cell or squamous cell skin or corneal cancer; curatively treated carcinoma in situ of the cervix; 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; curatively treated non-metastatic prostate cancer with negative PSA; or in situ breast carcinoma after complete surgical resection
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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint 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 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary analysis of spleen volume reduction will occur using data from the first 168 patients after they have been followed for 24 weeks. |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoint of Total Symptom Score (TSS) response rate is defined as the percentage of patients with at least 50% reduction in TSS from baseline at Week 24. The TSS endpoint score will be calculated as the sum of scores for six items from the MPN SAF TSS 2.0 instrument: satiety, abdominal discomfort, night sweats, itching, bone pain, and pain under ribs on the left side.
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.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 49 |
| 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 |
| Belarus |
| Canada |
| Czech Republic |
| France |
| Georgia |
| Germany |
| Hungary |
| Israel |
| Italy |
| Korea, Republic of |
| Poland |
| Russian Federation |
| Serbia |
| Spain |
| Ukraine |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 23 |
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