E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
PMF or PPV- MF, or PET- MF |
|
E.1.1.1 | Medical condition in easily understood language |
Myelofibrosis (a type of blood cancer) |
|
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.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Part 1:
To characterize the safety, tolerability, and recommended phase 2 dose (RP2D) of each
combination partner used with ruxolitinib
Parts 2 & 3:
To evaluate the preliminary efficacy of each novel ruxolitinib combination treatment arm |
|
E.2.2 | Secondary objectives of the trial |
Part 1,2&3
•characterize PK profile of rux administered in combo w. HDM201,SEG101&MBG453
•emergence of anti-SEG101 or anti-MBG453 antibodies following one or more IV infusions
•evaluate long-term safety and tolerability of rux combo treatments in each arm based on frequency,duration&severity of AE,abnormalities in vital signs & lab test values
Part 2&3
•assess proportion of subjects in each arm who achieve Hb improvement of ≥ 2.0 or ≥ 1.5 g/dL from baseline (BL) to end of C6 &end of C12
•evaluate changes in symptoms of MF in each arm using MFSAF v4.0 and EORTC QLQ-C3 PROs from BL
•evaluate changes in spleen size in each arm measured by change in spleen length&spleen volume from BL
•evaluate effect of each rux combo treatment in delaying progression of MF & estimate time to PFS event
•evaluate effect on bone marrow fibrosis in each arm by determining proportion of subjects achieving improvement in bone marrow fibrosis of ≥ 1 gr from BL to end of C6 & subsequent 6 cycles
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Subjects have diagnosis of primary myelofibrosis (PMF) according to the 2016 World Health Organization (WHO) criteria, or diagnosis of post-essential thrombocythemia (ET) (PET-MF) or post-polycythemia vera (PV) myelofibrosis (PPV-MF) according to the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) 2007 criteria
• Palpable spleen of at least 5 cm from the left costal margin (LCM) to the point of greatest splenic protrusion or enlarged spleen volume of at least 450 cm3 per MRI or CT scan at baseline (a MRI/CT scan up to 8 weeks prior to first dose of study treatment can be accepted).
• Have been treated with ruxolitinib for at least 24 weeks prior to first dose of study treatment
• Are stable (no dose adjustments) on the prescribed ruxolitinib dose (between 5 and 25 mg twice a day (BID)) for ≥ 8 weeks prior to first dose of study treatment.
• Hemoglobin < 10 g/dL
• Part 1: Platelet counts ≥ 75 000/μL
• Part 2 and Part 3: Platelet counts ≥ 50 000/μL
Additional inclusion criteria as per full protocol may apply. |
|
E.4 | Principal exclusion criteria |
• Not able to understand and to comply with study instructions and requirements.
• Received any investigational agent for the treatment of MF (except ruxolitinib) within 30 days of first dose of study treatment or within 5 half-lives of the study treatment, whichever is greater
• Peripheral blood blasts count of > 10%.
• Received a monoclonal antibody (Ab) or immunoglobulin-based agent within 1 year of screening, or has documented severe hypersensitivity reactions/immunogenicity (IG) to a prior biologic
• Splenic irradiation within 6 months prior to the first dose of study drug
• Received blood platelet transfusion within 28 days prior to first dose of study treatment.
• Subjects with known TP53 mutation or deletion of TP53
Additional exclusion criteria as per full protocol may apply. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
• Incidence and severity of dose limiting toxicity (DLTs) within the first 2 treatment cycles in Part 1 of the study
• Response rate (RR) for the composite endpoint (anemia improvement of ≥ 1.5 g/dL and no spleen volume progression and no symptom worsening) at the end of Cycle 6
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
• within the first 2 treatment cycles
• End of cycle 6
|
|
E.5.2 | Secondary end point(s) |
• Proportion of subjects achieving improvement of Hb level of ≥ 1.5 g/dL from baseline
• Proportion of subjects achieving improvement of Hb level of ≥ 2.0 g/dL from baseline
• Change in MFSAF v4.0 and EORTC QLQ-C30 from baseline
• PK parameters (e.g., AUC, Cmax, Tmax) and concentration vs. time profiles of each investigational drug within combination regimens
• Presence and/or concentration of anti-crizanlizumab or anti-MBG453 antibodies
• Change in spleen length (by palpation) from baseline
• Change in spleen volume (by MRI/CT) from baseline
• Estimate of progression free survival (PFS) where events are defined as follows:
• Progressive splenomegaly as assessed by increasing spleen volume (by MRI/CT) of ≥ 25% from baseline. The progression date will be the date of MRI/CT assessment confirming spleen volume increase of ≥ 25% from baseline
• Accelerated phase defined by a circulating peripheral blood blast content of > 10% but < 20% confirmed after 2 weeks. The progression date will be the date of first increase in peripheral blood blast content of > 10%
• Deteriorating cytopenia (dCP) independent from treatment defined for all patients by platelet count < 35 x10^9/L or neutrophil count < 0.75 x 10^9/L that lasts for at least 4 weeks. The progression date will be the date of first decrease of platelets < 35 x10^9/L or neutrophils < 0.75 x 10^9/L confirmed after 4 weeks
• Leukemic transformation defined by a peripheral blood blast content of ≥ 20% associated with an absolute blast count of ≥ 1x10^9/L that lasts for at least 2 weeks or a bone marrow blast count of ≥ 20%. The progression date will be the date of first increase in peripheral blood blast content of ≥ 20% associated with an absolute blast count of ≥ 1x10^9/L OR the date of the bone marrow blast count of ≥ 20%
• Death from any cause
• Proportion of subjects achieving improvement in bone marrow fibrosis of ≥ 1 grade from baseline
• Frequency, duration and severity of adverse events, abnormalities in vital signs and laboratory test values, including ECG data |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
• end of cycle 6 and end of cycle 12
• end of cycle 6 and end of cycle 12
• end of cycle 6
• end of cycle 6 and end of cycle 12
• end of cycle 6 and end of cycle 12
• end of cycle 6 and end of cycle 12.
• first 6 cycles
• first 6 cycles
• end of cycle 6 and end of cycle 12
• end of cycle 6 and end of cycle 12
• end of cycle 6 and end of cycle 12
• end of cycle 6 and end of cycle 12.
• From date of informed consent until end of safety follow up (30 days after last dose of ruxolitinib 30 days after last dose of siremadlin, 90 days after last dose of MBG453, 105 days after last dose of crizanlizumab) |
|
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 | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
quality of life and patient reported outcomes |
|
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
safety, tolerability, and the recommended Phase 2 dose (RP2D) of each combination partner used with |
|
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 | 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 | Yes |
E.8.1.7.1 | Other trial design description |
dose escalation for arm with HDM201 in part 1 |
|
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 | 10 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 31 |
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 |
Belgium |
Canada |
Denmark |
France |
Germany |
Hungary |
Italy |
Lebanon |
Netherlands |
Russian Federation |
Spain |
Sweden |
Switzerland |
Turkey |
United Kingdom |
|
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 | 4 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 14 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 5 |