PMF or PPV- MF, or PET- MF MedDRA version: 20.0 Level: PT Classification code 10028537 Term: Myelofibrosis System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
Novartis Farmacéutica, S.A
Eligibility
Sex/Gender
All
Inclusion criteria
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 =65 years) yes F.1.3.1 Number of subjects for this age range 33
Exclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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;Timepoint(s) of evaluation of this end point: • within the first 2 treatment cycles • End of cycle 6;Secondary Objective: 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;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 | — |
Secondary
| Measure | Time frame |
|---|---|
| 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 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 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;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 cyc | — |
Countries
Australia, Austria, Belgium, Canada, Denmark, France, Germany, Hungary, Italy, Lebanon, Netherlands, Romania, Russian Federation, Spain, Sweden, Switzerland, Turkey, United Kingdom
Contacts
Public ContactTrial Monitoring Organization (TMo)
Novartis Farmacéutica, S.A.
Outcome results
None listed