| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis, or Post Essential Thrombocythemia Myelofibrosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| A blood disorder that causes fibre in bone marrow due to producing too many mature blood cells too quickly. |
|
| 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 | 10028537 |
| E.1.2 | Term | 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 | 10028538 |
| E.1.2 | Term | Myelofibrosis with myelometaplasia |
| 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 | 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) |
|
| 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) |
|
| 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.1.2 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.1.3 | 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 MMB versus DAN assessed by improvement in Myelofibrosis Symptom Assessment Form v4.0 (MFSAF) total symptom score (TSS) in subjects with PMF, post-PV myelofibrosis (MF), or post-ET MF who were previously treated with approved JAK inhibitor therapy |
|
| E.2.2 | Secondary objectives of the trial |
• To compare the effect of MMB versus DAN on transfusion independent (TI) status at Week 24
• To compare the splenic response rate (SRR) for subjects treated with MMB versus DAN
• To compare change from baseline in Myelofibrosis Symptom Assessment Form v4.0 (MFSAF) total symptom score (TSS) for subjects treated with MMB versus DAN
• To compare RBC transfusion requirements in subjects treated with MMB versus DAN
• To assess the duration of MFSAF TSS response
• To assess duration of TI status at Week 24
• To compare the benefit of MMB versus DAN on anemia response and transfusion requirements
• To characterize the safety of MMB
• To compare the overall survival (OS) and leukemia-free survival (LFS) of subjects treated with MMB versus DAN
• To compare patient-reported fatigue and physical function for MMB versus DAN
• To compare patient-reported health status and health-related QoL for MMB versus DAN
• To assess association of MMB exposure (pharmacokinetics [PK]) with outcome |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age ≥ 18 years
2. Confirmed diagnosis of PMF in accordance with the World Health Organization (WHO) 2016 criteria, or Post-PV/ET MF in accordance with the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria
3. Symptomatic, defined as a MFSAF TSS of ≥ 10 units assessed by a single MFSAF v4.0 assessment during Screening prior to day BL1t
4. Anemic, defined as any of the following:
− For any subject; having received a transfusion within 28 days prior to the first day of Baseline assessments (BL1), with pre-transfusion Hgb < 10 g/dL (if a subject receives a transfusion after Day BL1, but prior to
Randomization, this pre-transfusion hemoglobin will be used for
eligibility), or
− For subjects without ongoing JAK inhibitor therapy at Screening; Hgb < 10 g/dL during the Baseline Period (Days BL1 to Day BL7), or
− For subjects receiving ongoing JAK inhibitor therapy at Screening; Hgb < 10 g/dL during Screening, prior to the last day of Baseline assessments (Day BL7)
5. Previously treated, with an approved JAK inhibitor for PMF or Post-PV/ET MF for ≥ 90 days, or ≥ 28 days if JAK inhibitor therapy is complicated by RBC transfusion requirement of ≥ 4 units in 8 weeks, or Grade 3/4 AEs of thrombocytopenia, anemia, or hematoma
− Subjects who discontinued JAK inhibitor therapy prior to Screening require no additional non-treatment interval
− For subjects with ongoing JAK inhibitor therapy at Screening, JAK inhibitor therapy must be tapered over a period of at least 1 week. Subjects receiving a low dose of JAK inhibitor, eg, 5 mg QD of RUX, may
have a reduced taper period, or no taper, with the sponsor's approval. A non-treatment interval begins ≥ 7 days prior to Day BL1 (the first of 7 consecutive days of baseline MFSAF assessments)
6. Baseline splenomegaly, defined as having a palpable spleen at ≥ 5 cm, below the LCM, or with volume ≥ 450 cm3 on imaging (ultrasound, MRI or CT are acceptable), assessed during Screening at any point prior to Randomization
7. High risk, intermediate-2, or intermediate-1 risk as defined by DIPSS, or DIPSS-plus
8. No allogeneic stem cell transplant planned
9. Acceptable laboratory assessments:
- ANC ≥ 0.75 x 10(9)/L
- PLT ≥ 25 x 10(9)/L (without requirement for platelet transfusion)
- Peripheral blast count < 10%
- AST/SGOT and ALT/SGPT ≤ 3 x ULN
- Calculated creatinine clearance ≥ 30 mL/min (According to Cockcroft-Gault calculation provided in Section 4.1)
- Direct bilirubin ≤ 2.0 x ULN
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
11. Life expectancy > 24 weeks
12. Able to understand and willing to sign the ICF
13. Willing and able to complete PRO assessments using an ePRO device according to protocol
14. WOCBP, men with partners of childbearing potential, and subjects with pregnant or lactating partners must agree to follow the contraceptive requirements of the clinical trial protocol, effective from the first administration of MMB, throughout the trial and for 6 months after the last dose of MMB. |
|
| E.4 | Principal exclusion criteria |
1. Use of the following treatments within the time periods noted (criteria a-i), restricted therapies are further described in protocol section 5.3.3.
a. MMB at any time
b. Approved JAK inhibitor therapy (eg, fedratinib or ruxolitinib) within 1 week prior to Day BL1 (refer to inclusion criterion #5)
c. Active anti-MF therapy as defined in Section 5.3.3 within 1 week prior to Day BL1.
Supportive care including steroids for non-MF indications may be used as defined in Section 5.3.3
d. Potent cytochrome P450 3A4 (CYP3A4) inducers within 1 week prior to Randomization (refer to Appendix 5)
e. Investigational agent (including investigational JAK inhibitors) within 4 weeks prior to Randomization
f. Erythropoiesis stimulating agent (ESA) within 4 weeks prior to Randomization
g. Danazol within 3 months prior to Randomization
h. Splenic irradiation within 3 months prior to Randomization
i. Current treatment with simvastatin, atorvastatin, lovastatin or rosuvastatin
2. History of prostate cancer, with the exception of localized prostate cancer that has been treated surgically or by radiotherapy with curative intent and presumed cured
3. Prostate specific antigen (PSA) > 4 ng/mL
4. Unsuitable for spleen volume measurements due to prior splenectomy or unwilling or unable to undergo an MRI or CT scan for spleen volume measurement per protocol requirements in Section 8.3
5. Any of the following (criteria a-k):
a. 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 trial)
b. Significant active or chronic bleeding event ≥ Grade 2 per Common Terminology Criteria for Adverse Events (CTCAE) v5.0, within 4 weeks prior to Randomization
c. Unstable angina pectoris within 6 months prior to Randomization
d. Symptomatic congestive heart failure within 6 months prior to Randomization
e. Uncontrolled cardiac arrhythmia within 6 months prior to Randomization
f. QTcF interval > 500 msec, unless attributed to bundle branch block
g. Current progressive thrombosis despite treatment
h. History of porphyria
i. Child-Pugh score ≥ 10
j. Psychiatric illness, social situation, or any other condition that would limit compliance with trial requirements or may interfere with the interpretation of study results, as judged by investigator or sponsor
k. Inability or unwillingness to comply with the protocol restrictions on MF therapy and other medications prior to and during study treatment
6. Subjects with a prior or concurrent malignancy, whose natural history or treatment has a significant potential to interfere with the safety or efficacy assessment of the investigational regimen
7. Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding, or thalassemia
8. Known positive status for HIV
9. Chronic active or acute viral hepatitis A, B, or C infection, or hepatitis B or C carrier (testing required for hepatitis B and C)
10. Unresolved non-hematologic toxicities from prior therapies that are > Grade 1 per CTCAE v5.0
11. Presence of peripheral neuropathy ≥ Grade 2 per CTCAE v5.0
12. Women who are already pregnant or lactating
13. Known intolerance or hypersensitivity to MMB or DAN, their metabolites, or formulation excipients.
14. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption. Note: DAN capsules contain lactose, further details are provided in protocol section 1.6.3. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The MFSAF TSS response rate at Week 24. TSS response rate is defined as the proportion of subjects who achieve a ≥ 50% reduction in TSS over the 28 days immediately prior to the end of Week 24 compared to baseline. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| TSS response at Week 24 is the primary endpoint. The MFSAF TSS response rate at Week 24 is defined as the proportion of subjects who achieve a ≥ 50% reduction compared with the TSS at baseline. |
|
| E.5.2 | Secondary end point(s) |
• Proportion of subjects with TI status at the end of Week 24; defined as not requiring RBC transfusion (except in the case of clinically overt bleeding) for ≥ 12 weeks, with all Hgb levels during the ≥ 12-week
interval of ≥ 8 g/dL (again, except in the case of clinically overt bleeding)
• SRR; defined as the proportion of subjects who have splenic response (reduction in spleen volume of ≥ 35% from baseline) at the end of Week 24
• Mean change from baseline to the end of Week 24 in MFSAF TSS will be analyzed using a mixed model for repeated measures (MMRM), using all available TSS data
• Other secondary endpoints include: measures of anemia benefit and duration of response, mean change from baseline MFSAF TSS, safety assessments, survival analyses, change from baseline in PROs, and plasma concentration of MMB. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The proportion of subjects who have TI status in the terminal 12 weeks of the 24-week Randomized Treatment Period, will be assessed in all subjects. Analysis of TI status will be performed on the ITT analysis set using a CMH test, stratified by baseline MFSAF TSS, baseline spleen length, and baseline RBC units transfused. |
|
| 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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Blood samples will be collected for assessments including mutational analysis via next generation sequencing (NGS) |
|
| 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 | 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 | Yes |
| 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 | 125 |
| 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 |
| Australia |
| Singapore |
| Austria |
| Belgium |
| Bulgaria |
| Canada |
| Czechia |
| Denmark |
| Germany |
| Hungary |
| Israel |
| Italy |
| Korea, Republic of |
| New Zealand |
| Poland |
| Romania |
| Spain |
| Sweden |
| Taiwan |
| United Kingdom |
| United States |
| France |
|
| 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
|
| The end of trial is defined as the date when the last subject has completed the Safety Follow-Up visit or Survival Follow-Up assessment (whichever is later). |
|
| 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 | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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