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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT04097821
Registration number
NCT04097821
Ethics application status
Date submitted
17/09/2019
Date registered
20/09/2019
Date last updated
3/05/2024
Titles & IDs
Public title
Platform Study of Novel Ruxolitinib Combinations in Myelofibrosis Patients
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Scientific title
A Randomized, Open-label, Phase I/II Open Platform Study Evaluating Safety and Efficacy of Novel Ruxolitinib Combinations in Myelofibrosis Patients
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Secondary ID [1]
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2019-000373-23
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Secondary ID [2]
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CINC424H12201
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Universal Trial Number (UTN)
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Trial acronym
ADORE
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Myelofibrosis
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Condition category
Condition code
Musculoskeletal
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Other muscular and skeletal disorders
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Human Genetics and Inherited Disorders
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Other human genetics and inherited disorders
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Cancer
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Leukaemia - Chronic leukaemia
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Ruxolitinib
Treatment: Drugs - Siremadlin
Treatment: Drugs - Crizanlizumab
Treatment: Drugs - Sabatolimab
Treatment: Drugs - Rineterkib
Treatment: Drugs - NIS793
Experimental: Part 1 Arm 1: Ruxolitinib + Siremadlin - Dose escalation of siremadlin added to existing stable dose of ruxolitinib
Experimental: Part 1 Arm 2: Ruxolitinib + Crizanlizumab - Safety run-in of crizanlizumab added to existing stable dose of ruxolitinib
Experimental: Part 1 Arm 3: Ruxolitinib + Sabatolimab - Safety run-in of Sabatolimab added to existing stable dose of ruxolitinib
Experimental: Part 2 Arm 1: Ruxolitinib + Siremadlin - Siremadlin added to existing stable dose of ruxolitinib
Experimental: Part 2 Arm 2: Ruxolitinib + Crizanlizumab - Crizanlizumab added to existing stable dose of ruxolitinib
Experimental: Part 2 Arm 3: Ruxolitinib + Sabatolimab - Sabatolimab added to existing stable dose of ruxolitinib
Active Comparator: Part 2 Arm 6: Ruxolitinib monotherapy - Existing stable dose of ruxolitinib as control for Part 2
Experimental: Part 3 Arm 1: Ruxolitinib + Compound X - Compound from Part 2 (to be confirmed) added to existing stable dose of ruxolitinib
Experimental: Part 3 Arm 2: Ruxolitinib cessation - Compound from Part 2 added to existing stable dose of ruxolitinib for 3 cycles followed by compound monotherapy
Active Comparator: Part 3 Arm 3: Ruxolitinib monotherapy - Existing stable dose of ruxolitinib as control for Part 3
Experimental: Part 1 Arm 4: Ruxolitinib + Rineterkib - Dose escalation of Rineterkib added to existing stable dose of ruxolitinib
Experimental: Part 1 Arm 5: Ruxolitinib + NIS793 - Safety run-in of NIS793 added to existing stable dose of ruxolitinib
Experimental: Part 2 Arm 4: Ruxolitinib + Rineterkib - Rineterkib added to existing stable dose of ruxolitinib
Experimental: Part 2 Arm 5: Ruxolitinib + NIS793 - NIS793 added to existing stable dose of ruxolitinib
Treatment: Drugs: Ruxolitinib
5 mg tablets for oral use
Treatment: Drugs: Siremadlin
10 mg, 20 mg, or 40 mg capsules for oral use
Treatment: Drugs: Crizanlizumab
100 mg/mL concentrate for infusion for intravenous use
Treatment: Drugs: Sabatolimab
100 mg/mL or 400 mg/4 mL concentrate for infusion for intravenous use
Treatment: Drugs: Rineterkib
100 mg capsule for oral use
Treatment: Drugs: NIS793
700 mg/7 mL concentrate for intravenous use
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Incidence of dose limiting toxicities within the first 2 cycles
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Assessment method [1]
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Incidence and severity of dose limiting toxicities within the first 2 cycles (6 or 8 weeks) in Part 1 of the study
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Timepoint [1]
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Baseline to the end of Cycle 2 (6 or 8 weeks)
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Primary outcome [2]
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Response rate at the end of cycle 6 or cycle 8
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Assessment method [2]
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Composite of anemia improvement (hemoglobin level) and no spleen volume progression and no symptom worsening in Part 2 and Part 3 of the study. For a subject to be considered a responder, all three components of the composite have to be fulfilled
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Timepoint [2]
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Baseline to the end of Cycle 6 or 8 (24 weeks)
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Secondary outcome [1]
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Percentage of subjects achieving an improvement in hemoglobin level of = 1.5 g/dL from baseline
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Assessment method [1]
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Percentage of subjects achieving an improvement in hemoglobin level of at least >= 1.5 g/dL from baseline at each time point in Part 2 and Part 3 of the study.
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Timepoint [1]
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Baseline to the end of Cycle 6 or 8 (24 weeks), and end of Cycle 12 or 16 (48 weeks)
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Secondary outcome [2]
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Percentage of subjects achieving an improvement in hemoglobin level of at least >= 2.0 g/dL from baseline
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Assessment method [2]
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Percentage of subjects achieving an improvement in hemoglobin level of at least >= 2.0 g/dL from baseline at each time point in Part 2 and Part 3 of the study.
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Timepoint [2]
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Baseline to the end of Cycle 6 or 8 (24 weeks), and end of Cycle 12 or 16 (48 weeks)
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Secondary outcome [3]
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Change in spleen length from baseline
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Assessment method [3]
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Change in spleen length measured in centimeters by manual palpation summarized at each time point using descriptive statistics in Part 1 (core and extension), Part 2 and Part 3 of the study
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Timepoint [3]
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Baseline to day 1 and day 15 of Cycle 1, 2 and 3, day 1 of all subsequent cycles, and the end of 12 or 16 cycles (48 weeks)
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Secondary outcome [4]
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Change in spleen volume from baseline
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Assessment method [4]
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Change in spleen volume measured by magnetic resonance imaging (MRI) or computed tomography (CT) from baseline summarized at each time point using descriptive statistics, 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 6 (or 8 for NIS793 arm) (24 weeks) from baseline and, at the end of Cycle 12 (or 16 in NIS793 arm) (48 weeks) from baseline respectively in Part 1 (core and extension) Part 2 and Part 3 of the study
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Timepoint [4]
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Baseline to the end of Cycle 6 or 8 (24 weeks), the end of Cycle 12 or 16 (48 weeks) and at the end of treatment if not performed in the past 12 weeks (up to 48 weeks)
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Secondary outcome [5]
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Change in symptoms of MFSAF v4.0 from baseline
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Assessment method [5]
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Change in total symptom scores (TSS) assessed by the Myelofibrosis (MF Symptom Assessment Form version 4.0 (MFSAF v4.0) at each time point in Part 2 and Part 3 of the study. The MFSAF v4.0 questionnaire focuses on the 7 core symptoms of MF: fatigue, night sweats, pruritus, abdominal discomfort, pain under the ribs on the left side, early satiety and bone pain. Subjects record symptom severity at it worst for each of the 7 symptoms on an 11-point numeric rating scale, from 0 (absent) to 10 (worst imaginable). The Total Symptom Score (TSS) is the sum of all the scores for all 7 symptoms.
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Timepoint [5]
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Baseline to day 1 of Cycle 1, day 1 of all subsequent cycles of treatment (each cycle is 28 days except for arms containing NIS793, which are 21 days), as well as the end of treatment visit (approximately 52 weeks)
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Secondary outcome [6]
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Change in symptoms of EORTC QLQ-C30 from baseline
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Assessment method [6]
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Change in symptom scores assessed by European Organization for Research and Treatment of Cancer 30-item core quality of life questionnaire (EORTC QLQ C-30) at each time point in Part 2 and Part 3 of the study. The EORTC QLQ-C30 includes 5 functional scales (physical, emotional, social, role, cognitive), eight symptom scales (fatigue, pain, nausea/vomiting, constipation, diarrhea, insomnia, dyspnea, and appetite loss), as well as global health/quality-of-life and financial impact. Subjects respond according to the past week recall period, with the exception of the first 5 questions that represent physical functioning and capture the subject's current status. Raw scores are linearly converted to a 0-100 scale. For functional and global health status/QoL higher scores indicate better QoL and level of functioning; for symptom scales, higher scores indicate greater level of symptoms or difficulties.
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Timepoint [6]
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Baseline to day 1 of Cycle 1, day 1 of all subsequent cycles of treatment (each cycle is 28 days except for arms containing NIS793, which are 21 days), as well as the end of treatment visit (approximately 52 weeks)
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Secondary outcome [7]
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Changes in symptoms in MFSAF v4.0 (Part 1) from baseline
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Assessment method [7]
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Change in total symptom scores (TSS) assessed by the Myelofibrosis (MF Symptom Assessment Form version 4.0 (MFSAF v4.0) from baseline including proportion of subjects who achieved at least 50% reduction.
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Timepoint [7]
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Baseline to end of Cycle 3 or 4 (week 16), and end of Cycle 6 or 8 (week 24weeks), or end Cycle 12 or 16 (48 weeks)
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Secondary outcome [8]
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Progression free survival, per progressive splenomegaly, accelerated phase, deteriorating cytopenia, leukemic transformation or death from any cause
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Assessment method [8]
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Progressive splenomegaly is assessed by increasing spleen volume (by MRI/CT) of = 25% from baseline. Accelerated phase: a circulating peripheral blood blast content of > 10% but < 20% confirmed after 2 weeks.
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.
Leukemic transformation, 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%.
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Timepoint [8]
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Baseline to disease progression, which is up to 24 weeks for Part 1 or through study completion, an average of 1 year, for Part 2 and Part 3
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Secondary outcome [9]
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Percentage of subjects achieving an improvement in bone marrow fibrosis of = 1 grade from baseline
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Assessment method [9]
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Percentage of subjects achieving an improvement in bone marrow fibrosis of >= 1 grade at each time point will be summarized in Part 2 and Part 3 of the study.
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Timepoint [9]
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Baseline to the end of Cycle 6 or 8 (24 weeks), the end of Cycle 12 or 16 (48 weeks) and at the end of treatment if not performed in the past 12 weeks (up to 48 weeks)
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Secondary outcome [10]
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Area under the Plasma Concentration versus Time Curve (AUC)
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Assessment method [10]
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AUC for each investigational drug in Part 1, Part 2 and Part 3 of the study
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Timepoint [10]
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Days 1 and 5 of Cycle 1 and 2 for siremadlin and ruxolitinib, and Cycle 1 and Cycle 3 for crizanlizumab, sabatolimab and NIS793, and Days 1 and 15 of Cycle 1 for LTT462
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Secondary outcome [11]
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Maximum (peak) observed plasma drug concentration (Cmax)
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Assessment method [11]
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Cmax for each investigational drug in Part 1, Part 2 and Part 3 of the study
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Timepoint [11]
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Days 1 and 5 of Cycle 1 and 2 for siremadlin and ruxolitinib, and Cycle 1 and Cycle 3 for crizanlizumab, sabatolimab and NIS793, and Days 1 and 15 of Cycle 1 for LTT462
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Secondary outcome [12]
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Time to reach maximum (peak) plasma, blood, serum or other body fluid drug concentration after single dose administration (Tmax)
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Assessment method [12]
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Tmax for each investigational drug in Part 1, Part 2 and Part 3 of the study
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Timepoint [12]
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Days 1 and 5 of Cycle 1 and 2 for siremadlin and ruxolitinib, and Cycle 1 and Cycle 3 for crizanlizumab, sabatolimab and NIS793, and Days 1 and 15 of Cycle 1 for LTT462
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Secondary outcome [13]
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Concentration versus time profile
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Assessment method [13]
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Concentration versus time profile for each investigational drug in Part 1, Part 2 and Part 3 of the study
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Timepoint [13]
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Days 1 and 5 of Cycle 1 and 2 for siremadlin and ruxolitinib, and Cycle 1 and Cycle 3 for crizanlizumab, sabatolimab and NIS793, and Days 1 and 15 of Cycle 1 for LTT462
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Secondary outcome [14]
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Presence and/or concentration of anti-drug antibody
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Assessment method [14]
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The presence and titer of anti-drug antibodies for crizanlizumab, sabatolimab and NIS793 in Part 1, Part 2 and Part 3 of the study
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Timepoint [14]
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Baseline to 105 days after last study drug administration for crizanlizumab, to 150 days after last study drug administration for sabatolimab, or to 90 days after last study drug administration for NIS793
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Eligibility
Key inclusion criteria
Core treatment phase
- 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
Extension treatment phase inclusion criteria:
- Signed consent for the extension treatment phase
- ongoing in the core treatment phase
- demonstrates clinical benefit of treatment in core treatment phase per investigator's
assessment.
Core treatment phase
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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%.
- has documented severe hypersensitivity reactions/immunogenicity (IG) to a prior
biologic product or Received a monoclonal antibody (Ab) or immunoglobulin-based agent
within 1 year of screening in NIS793, crizanlizumab or sabatolimab arms, or in
rineterkib or siremadlin arms within <=4 weeks of screening or <=5 half-lives
whichever is shorter
- 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.
Extension treatment phase
- meets any of study treatment discontinuation criteria
- current evidence of treatment failure per investigator, following treatment in core
treatment phase
- enrolled in another interventional study
- evidence of non-compliance to study procedures or withdrew consent in core treatment
phase
- currently has unresolved toxicities for which study treatment has been interrupted in
the core treatment phase
- local access to alternative myelofibrosis treatment including those currently under
investigation in clinical trials as assessed suitable in the opinion of the
investigator.
Other protocol-defined Inclusion/Exclusion criteria may apply.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 1/Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Active, not recruiting
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
26/09/2019
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
31/07/2024
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Actual
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Sample size
Target
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Accrual to date
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Final
45
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Recruitment in Australia
Recruitment state(s)
SA,VIC
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Recruitment hospital [1]
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Novartis Investigative Site - Adelaide
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Recruitment hospital [2]
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Novartis Investigative Site - Melbourne
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Recruitment postcode(s) [1]
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5000 - Adelaide
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Recruitment postcode(s) [2]
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3000 - Melbourne
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Recruitment postcode(s) [3]
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3004 - Melbourne
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Recruitment outside Australia
Country [1]
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Canada
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State/province [1]
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Ontario
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Country [2]
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Denmark
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State/province [2]
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Copenhagen
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Country [3]
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Germany
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State/province [3]
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Baden Wuerttemberg
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Country [4]
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Germany
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State/province [4]
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Freiburg
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Country [5]
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Germany
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State/province [5]
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Greifswald
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Country [6]
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Germany
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State/province [6]
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Jena
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Country [7]
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Hungary
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State/province [7]
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HUN
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Country [8]
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Italy
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State/province [8]
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FI
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Country [9]
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Netherlands
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State/province [9]
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Amsterdam
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Country [10]
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Russian Federation
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State/province [10]
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Moscow
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Country [11]
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Spain
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State/province [11]
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Castilla Y Leon
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Country [12]
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Spain
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State/province [12]
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Comunidad Valenciana
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Country [13]
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Spain
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State/province [13]
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Las Palmas de Gran Canaria
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Country [14]
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Spain
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State/province [14]
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Madrid
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Country [15]
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Sweden
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State/province [15]
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Stockholm
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Country [16]
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Switzerland
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State/province [16]
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St. Gallen
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Country [17]
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Switzerland
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State/province [17]
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Zurich
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Country [18]
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Turkey
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State/province [18]
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Kocaeli
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Country [19]
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United Kingdom
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State/province [19]
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London
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Novartis Pharmaceuticals
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
The purpose of this study is to investigate the safety, pharmacokinetics and preliminary
efficacy of combination treatment of ruxolitinib with 5 novel compounds: siremadlin,
crizanlizumab, sabatolimab, rineterkib and NIS793 in myelofibrosis (MF) subjects.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT04097821
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Novartis Pharmaceuticals
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Address
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Novartis Pharmaceuticals
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT04097821
Download to PDF