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
In consideration of the enrollment halt, a number of preplanned study objectives will not be pursued. All Parts 2 and 3 objectives will not be pursued. Part 1 exploratory objectives will be pursued only if sufficient data is available. |
|
E.2.2 | Secondary objectives of the trial |
Part 1,2&3 •characterize PK profile of rux administered in combo w.HDM201,SEG101,MBG453, LTT462,NIS793 •emergence of anti-SEG101,anti-MBG453,antiNIS793 antibodies following one or more IV infusions •evaluate long-term safety and tolerability of rux combo treatments in each arm (Part 1 core and extension, Parts 2&3) •evaluate changes in symptoms of MF in each arm using MFSAF v4.0 and EORTC QLQ-C3 PROs from BLevaluate changes in Symptoms of MF in each Treatment arm using MFSAF v4.0 (Part 1) •evaluate changes in spleen size in each arm (Part 1 Core and extension, Parts 2&3) Part2&3 In consideration of the enrollment halt, a number of preplanned study objectives will not be pursued. All Parts 2 and 3 objectives will not be pursued. Part 1 exploratory objectives will be pursued only if sufficient data is available. |
|
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 12 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 ≥ 4 weeks prior to first dose of study treatment. • Hemoglobin < 11 g/dL (≤ 6.8 mmol/L) • Part 1: Platelet counts ≥ 75 000/μL • Part 2 and Part 3: Platelet counts ≥ 50 000/μL
Key inclusion criteria for the extension treatment phase are listed below, please refer to the protocol for the full list of inclusion criteria: • Signed informed consent form prior to participation • On going in the core treatment phase • Demonstrated clinical benefit in the core treatment phase per investigator's assessment.
|
|
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%. • Had history of documented severe hypersensitivity reactions/immunogenicity to a prior biologic product in any treatment arm OR received a monoclonal antibody (Ab) or immunoglobulin-based agent - for treatment arms with NIS793, crizanlizumab or sabatolimab within 1 year of screening - for treatment arms with rineterkib or siremadlin arms within <=4 weeks of screening or <=5 half-lives whichever is shorter for rineterkib or siremadlin arms - for Part 2 and Part 3, the longest window will apply based on the compounds opened for randomization • 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. NOTE: PRBC transfusions are permitted • Subjects with known TP53 mutation or deletion of TP53 • Use of systemic steroid therapy and other immunosuppressive drugs within 14 days prior to first dose of study treatment (> 10 mg/day prednisone or equivalent). Topical, inhaled, nasal, and ophthalmic steroids are allowed. Replacement therapy, steroids given in the context XML File Identifier: vqTUMZ8xU4hhiohIfZSDKEGkXnI= Page 28/45 of a transfusion are allowed and not considered a form of systemic treatment. • Occurrence of any clinically significant bleeding events within 6 months prior to first dose of study treatment. • For patients treated with rineterkib in Part 1 and for all patients in Part 2 and Part 3 (if an rineterkib arm is included in the randomization for Part 2 or Part 3): Pre-existing retinal vein occlusion (RVO) or current risk factors (apart from the underlying MF) for RVO. Key exclusion criteria for the extension treatment phase are listed below, please refer to the protocol for the full list of exclusion criteria: • Patient meeting the list of discontinuation criteria • Evidence of treatment failure • Enrollment in another interventional study • Non-compliance of the subject or consent withdrawal • Unresolved toxicities for which treatment has been interrupted in the core treatment phase • Subject has local access to alternative myelofibrosis treatment as assessed suitable in the opinion of the investigator. |
|
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 8 for all arms containing NIS793 or Cycle 6 for all other arms
|
|
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) |
• 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, anti-sabatolimab or anti-NIS793 antibodies • Change in spleen length (by palpation) from baseline • Change in spleen volume (by MRI/CT) from baseline including proportions of subjects who achieved (i) at least 35% spleen volume reduction and (ii) at least 25% spleen volume reduction at the end of Cycle 8 (NIS793 arms) or Cycle 6 (all other arms) from baseline and, at the end of Cycle 16 (NIS793 arms) or Cycle 12 (all other arms) from baseline respectively. • 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 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 | 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 |
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, extension treatment phase 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 | 14 |
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 | 38 |
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 |
Switzerland |
Australia |
Canada |
China |
Israel |
Japan |
Korea, Republic of |
Lebanon |
Russian Federation |
Saudi Arabia |
United Kingdom |
United States |
Austria |
Belgium |
Denmark |
France |
Germany |
Hungary |
Italy |
Netherlands |
Romania |
Spain |
Sweden |
Türkiye |
|
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 | 5 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 26 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
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 | 0 |