| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary Myelofibrosis, Post-polycythemia Vera Myelofibrosis or Post-essential Thrombocythemia Myelofibrosis. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Blood disorder that means the body produces too many mature blood cells too quickly. |
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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 | 18.0 |
| 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 the efficacy of momelotinib (MMB) versus best available therapy (BAT) in anemic or thrombocytopenic subjects with primary myelofibrosis (PMF), or post-polycythemia vera or post-essential thrombocythemia myelofibrosis (Post-PV/EF MF) who were treated with ruxolitinib as measured by splenic response rate at Week 24 (SRR24). |
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| E.2.2 | Secondary objectives of the trial |
- To determine the effect of MMB compared with BAT on the improvement of total symptom score (TSS) on Week 24
- To determine the effect of MMB compared with BAT on rate of red blood cell (RBC) transfusion through Week 24
- To determine the effect of MMB compared with BAT on RBC transfusion independance rate at Week 24
- To determined the effect of MMB compared with BAT on RBC transfusion dependance rate at Week 24 |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
MMB PK/Pharmacodynamic Substudy (optional; additional consent required)
The substudy will target enrollment of approximately 20 study subjects for additional PK and pharmacodynamic blood sampling.
MMB Biomarker substudy (optional; additional consent required)
Additional blood samples will be collected in a biomarker substudy from consenting subjects who also agree to storage of samples for future research. These samples will be used to conduct research related drug-activity such as JAK inhibition and disease persistence. |
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| E.3 | Principal inclusion criteria |
1) Age ≥ 18 years old
2) Palpable splenomegaly at least 5 cm below left costal margin
3) Confirmed diagnosis of PMF in accordance with the World Health Organization (WHO) criteria, or Post-PV/ET MF in accordance with the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria
4) Currently or previously treated with ruxolitinib for PMF or Post-PV/ET MF for at least 28 days and characterized by:
- Requirement for red blood cell (RBC) transfusion while on ruxolitinib treatment, or
- Dose adjustment of ruxolitinib to < 20 mg twice-daily at start of or during ruxolitinib treatment AND at least one of the following while on ruxolitinib treatment:
* ≥ CTCAE Grade 3 thrombocytopenia, OR
* ≥ CTCAE Grade 3 anemia, OR
* ≥ CTCAE Grade 3 hematoma (bleed)
5) High risk OR intermediate-2 risk as defined by Dynamic International Prognostic Scoring System (DIPSS), OR intermediate-1 risk as defined by DIPSS and associated with symptomatic splenomegaly and/or hepatomegaly
6) If receiving myelofibrosis therapy, must be on a stable dose of the same regimen for at least 2 weeks prior to screen date and through the screening period
7) If not receiving therapy for myelofibrosis, must remain off therapy for at least 2 weeks prior to screen date and through the screening period
8) Acceptable laboratory assessment obtained within 14 days prior to randomization
- Absolute neutrophil count (ANC) > 0.75 x 10^9/L in the absence of growth factor in the prior 7 days
- Peripheral blood blast count < 10%
- AST/SGOT and ALT/SGPT ≤ 3 x ULN (≤ 5 x ULN if liver is involved by extramedullary hematopoiesis as judged by the investigator or if related to iron chelator therapy that was started within the prior 60 days)
- Calculated creatinine clearance of ≥ 45 mL/min
- Direct bilirubin ≤ 2.0 x ULN
9) Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
10) Life expectancy > 24 weeks
11) Negative serum pregnancy test for female subjects (unless surgically sterile or greater than 2 years post-menopausal)
12) Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception
13) Females who are nursing must agree to discontinue nursing before the first dose of MMB
14) Able to understand and willing to sign informed consent form (ICF) |
|
| E.4 | Principal exclusion criteria |
1) Prior splenectomy
2) Splenic irradiation within 3 months prior to randomization
3) Use of investigational agent within 28 days prior to randomization
4) Prior treatment with MMB
5) Hematopoietic growth factor (granulocyte growth factor, erythropoiesis stimulating agent, thrombopoietin mimetic) within 28 days prior to Day 1
6) Uncontrolled intercurrent illness including, but not limited to: active uncontrolled infection (subjects receiving outpatient antibacterial and/or antiviral treatments for infection that is under control or as infection prophylaxis may be included in the study); active or chronic bleeding event within 4 weeks prior to randomization; symptomatic congestive heart failure (CHF); unstable angina pectoris; uncontrolled cardiac arrhythmia; or psychiatric illness/social situation that would limit compliance with study requirements as judged by treating physician
7) QTc interval > 450 msec, unless attributed to bundle branch block
8) History of a concurrent or second malignancy except for adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for ≥ 1 year prior to randomization, adequately treat Stage 1 or 2 cancer currently in complete remission, or any other cancer that has been in complete remission for ≥ 5 years
9) Known positive status for human immunodeficiency virus (HIV)
10) Chronic active or acute viral hepatitis A. B or C infection (testing required for hepatitis B and C), or hepatitis B or C carrier
11) Unresolved non-hematologic toxicities from prior therapies that are > CTCAE Grade 1
12) Use of strong CYP3A4 inducers within 1 week prior to randomization
13) Changes to dose of iron chelator therapy within 14 days prior to randomization
14) Presence of peripheral neuropathy ≥ CTCAE Grade 2
15) Unwilling or unable to undergo a MRI or CT Scan
16) Known hypersensitivity to MMB, the metabolites, or formulation excipients |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is SRR24 - defined as the proportion of subjects who achieves a ≥ 35 % reduction in spleen volume at Week 24 from baseline as measure by MRI or CT |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Response rate in total symptom score (TSS) from Baseline to Week 24 - defined as the proportion of subjects who achieves a ≥ 50 % reduction from Baseline in total symptom score to Week 24 as measured by the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPNSAF) TSS diary
- Rate of RBC transfusion - defined as the average number of RBC units per subject-month during the randomized treatment period (through Week 24)
- RBC transfusion independence rate at Week 24 - defined as the proportion of subjects who is transfusion independent at Week 24, where transfusion independence is defined as absence of RBC transfusion and no hemoglobin (Hgb) level below 8 g/dL in the prior 12 weeks
- RBC transfusion dependence rate at Week 24 - defined as the proportion of subjects who is transfusion dependent at Week 24, where transfusion dependence is defined as at least 4 units of RBS transfusions, or a Hgb level below 8 g/dL, in the prior 8 weeks |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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) | 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 | Yes |
| 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 |
|
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| 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 |
| France |
| Germany |
| Israel |
| Italy |
| Spain |
| United Kingdom |
| United States |
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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 | 6 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
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