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 Pharma AG
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 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 =65 years) yes F.1.3.1 Number of subjects for this age range 63
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%. • 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 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.
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 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.;Secondary Objective: 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.;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 ;Timepoint(s) of evaluation of this end point: • within the first 2 treatment cycles • 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, 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 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 sig | — |
Countries
Australia, Austria, Belgium, Canada, China, Denmark, France, Germany, Hungary, Israel, Italy, Japan, Korea, Republic of, Lebanon, Netherlands, Romania, Russian Federation, Saudi Arabia, Spain, Sweden, Switzerland, Türkiye, United Kingdom, United States
Contacts
Public ContactMedizinischer Infoservice (MCC)
Novartis Pharma GmbH
Outcome results
None listed