E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary Myelofibrosis (PMF), Post-Polycythemia Vera MF (post-PV MF), Or Post-Essential Thrombocythemia MF (post-ET MF) |
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E.1.1.1 | Medical condition in easily understood language |
Myelofibrosis - a disorder of the bone marrow, in which the marrow is replaced by scar (fibrous) tissue. |
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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 | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10074689 |
E.1.2 | Term | Post polycythemia vera myelofibrosis |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10074690 |
E.1.2 | Term | Post essential thrombocythemia myelofibrosis |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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) |
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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 the effect size of three different doses of PRM-151 on reduction in bone marrow fibrosis by ≥ 1 grade in intermediate-1, intermediate-2, and high risk subjects with PMF, post-PV MF, or post ET-MF who are anemic or thrombocytopenic and who are ineligible for, intolerant of, or have had an inadequate response to ruxolitinib. |
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E.2.2 | Secondary objectives of the trial |
To determine if there is a difference in efficacy between the three doses of PRM-151 used in the study
To evaluate the safety and tolerability of three different doses of PRM-151
To assess the duration of effect of three doses of PRM-151 on reduction in bone marrow fibrosis
To assess the effect and duration of effect of three doses of PRM-151 on disease related anemia, thrombocytopenia, and constitutional symptoms
To assess IWG-MRT response (Complete Response, Partial Response, Clinical Improvement), stable and progressive disease in subjects treated with three doses of PRM-151 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subjects must be ≥18 years of age at the time of signing the Informed Consent Form (ICF);
2. Subjects must voluntarily sign an ICF;
3. Subjects must have a pathologically confirmed diagnosis of PMF as per the WHO diagnostic criteria or post ET/PV MF;
4. At least Grade 2 marrow fibrosis according to the WHO Grading of Bone Marrow Fibrosis;
5. Intermediate-1, intermediate -2, or high risk disease according to the IWG-MRT Dynamic International Prognostic Scoring System;
6. A bone marrow biopsy must be performed within four weeks prior to Cycle 1 Day 1 treatment to establish the baseline fibrosis score;
7. Subjects must not be candidates for ruxolitinib based on EITHER: a. Platelet count < 50 x 10^9/L, OR b. Hgb < 100 g/L, have received ≥ 2 units PRBC in the 12 weeks prior to study entry, and be intolerant of or had inadequate response to ruxolitinib;
8. Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
9. Life expectancy of at least twelve months;
10. At least four weeks must have elapsed between the last dose of any MF-directed drug treatments for myelofibrosis (including investigational therapies) and study enrollment;
11. Recovery to ≤ Grade 1 or baseline of any toxicities due to prior systemic treatments, excluding alopecia;
12. Women of child bearing potential (WCBP), defined as a sexually mature woman not surgically sterilized or not post-menopausal for at least 24 consecutive months if < 55 years or 12 months if > 55 years, must have a negative serum pregnancy test within four weeks prior to the first dose of study drug and must agree to use highly effective methods of birth control throughout the study. Highly effective methods of contraception include combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation by oral, intravaginal, or transdermal administration; progestogen-only hormonal contraception associated with inhibition of ovulation by oral, injectable, or implantable administration; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; partner vasectomy, and total abstinence (only if total abstinence is the preferred method and usual lifestyle of the subject). Adequate contraceptive use should be continued until 28 days after the final dose of the study drug.
13. Ability to adhere to the study visit schedule and all protocol requirements;
14. Must have an adequate organ function as demonstrated by the following:
o ALT (SGPT) and/or AST (SGOT) < 3 x upper limit of normal (ULN), or < 4 x ULN (if upon judgment of the treating physician, it is believed to be due to extramedullary hematopoiesis [EMH] related to MF);
o Direct bilirubin < 1.5 x ULN; or < 2 x ULN (if upon judgment of the treating physician, it is believed to be due to EMH related to MF);
o Serum creatinine < 2.5x ULN. |
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E.4 | Principal exclusion criteria |
1. White blood cell count > 25 x 10^9/L or > 10% peripheral blood blasts;
2. Other invasive malignancies within the last 3 years, except non-melanoma skin cancer and localized cured prostate and cervical cancer;
3. History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within the last 6 months;
4. Presence of active serious infection;
5. Any serious, unstable medical or psychiatric condition that would prevent, (as judged by the Investigator) the subject from signing the informed consent form or any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study;
6. Known history of human immunodeficiency virus (HIV), or known active hepatitis A, B, or C infection;
7. Organ transplant recipients other than bone marrow transplant;
8. Women who are pregnant or lactating. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Bone marrow response rate, defined as the percent of subjects with a reduction in bone marrow fibrosis score by at least one grade according to WHO criteria at any time during the study as determined by a central adjudication panel of expert hematopathologists, blinded to subject, treatment, and time of biopsy |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At any time during the study |
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E.5.2 | Secondary end point(s) |
Comparison of primary and secondary efficacy parameters between doses
Incidence of adverse events (AEs), serious adverse events (SAEs), and changes in laboratory test results
Bone marrow improvement:
Bone marrow response rate at weeks 12, 24, and 36
Duration of bone marrow response
Hemoglobin improvement
Platelet improvement
Hematologic improvement
Symptom improvement:
Percent of subjects with 25% and 50% reduction in MPN-SAF Total Symptom Score from baseline at Week 36
Mean change from baseline in EORTC QLQ-C30 at 36 weeks
Duration of all improvement parameters listed above
Percent of subjects with complete response, partial response, clinical improvement, stable disease, and progressive disease according to IWG-MRT criteria |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At the end of Cycle 9 of the study patient. |
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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 | No |
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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
Randomization into 10 mg/kg PRM-151 or 3 mg/kg PRM-151 or 0.3 mg/kg PRM-151, |
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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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
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 |
Canada |
Israel |
United States |
France |
Germany |
Italy |
Netherlands |
United Kingdom |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |