Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Platform Study of Novel Ruxolitinib Combinations in Myelofibrosis Patients (ADORE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04097821
Recruitment Status : Recruiting
First Posted : September 20, 2019
Last Update Posted : February 2, 2021
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE September 17, 2019
First Posted Date  ICMJE September 20, 2019
Last Update Posted Date February 2, 2021
Actual Study Start Date  ICMJE September 26, 2019
Estimated Primary Completion Date January 16, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 27, 2020)
  • Incidence of dose limiting toxicities within the first 2 cycles [ Time Frame: Baseline to the end of Cycle 2 (6 or 8 weeks) ]
    Incidence and severity of dose limiting toxicities within the first 2 cycles (6 or 8 weeks) in Part 1 of the study
  • Response rate at the end of cycle 6 or cycle 8 [ Time Frame: Baseline to the end of Cycle 6 or 8 (24 weeks) ]
    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
Original Primary Outcome Measures  ICMJE
 (submitted: September 19, 2019)
  • Incidence of dose limiting toxicities within the first 2 cycles [ Time Frame: Baseline to the end of Cycle 2 (8 weeks) ]
    Incidence and severity of dose limiting toxicities within the first 2 cycles (8 weeks) in Part 1 of the study
  • Response rate at the end of cycle 6 [ Time Frame: Baseline to the end of Cycle 6 (24 weeks) ]
    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
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 14, 2021)
  • Proportion of subjects achieving an improvement in hemoglobin level of ≥ 1.5 g/dL from baseline [ Time Frame: Baseline to the end of Cycle 6 or 8 (24 weeks), and end of Cycle 12 or 16 (48 weeks) ]
    Proportion 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.
  • Proportion of subjects achieving an improvement in hemoglobin level of at least >= 2.0 g/dL from baseline [ Time Frame: Baseline to the end of Cycle 6 or 8 (24 weeks), and end of Cycle 12 or 16 (48 weeks) ]
    Proportion 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.
  • Change in spleen length from baseline [ Time Frame: 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) ]
    Change in spleen length measured in centimeters by manual palpation summarized at each time point using descriptive statistics in Part 2 and Part 3 of the study
  • Change in spleen volume from baseline [ Time Frame: 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) ]
    Change in spleen volume measured by magnetic resonance imaging (MRI) or computed tomography (CT) summarized at each time point using descriptive statistics, in Part 2 and Part 3 of the study
  • Change in symptoms of MFSAF v4.0 from baseline [ Time Frame: 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) ]
    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.
  • Change in symptoms of EORTC QLQ-C30 from baseline [ Time Frame: 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) ]
    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.
  • Progression free survival, per progressive splenomegaly, accelerated phase, deteriorating cytopenia, leukemic transformation or death from any cause [ Time Frame: 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 ]
    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%.
  • Proportion of subjects achieving an impovement in bone marrow fibrosis of ≥ 1 grade from baseline [ Time Frame: 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) ]
    Proportion 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.
  • Area under the Plasma Concentration versus Time Curve (AUC) [ Time Frame: 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 ]
    AUC for each investigational drug in Part 1, Part 2 and Part 3 of the study
  • Maximum (peak) observed plasma drug concentration (Cmax) [ Time Frame: 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 ]
    Cmax for each investigational drug in Part 1, Part 2 and Part 3 of the study
  • Time to reach maximum (peak) plasma, blood, serum or other body fulid drug concentration after single dose administration (Tmax) [ Time Frame: 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 ]
    Tmax for each investigational drug in Part 1, Part 2 and Part 3 of the study
  • Concentration versus time profile [ Time Frame: 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 ]
    Concentration versus time profile for each investigational drug in Part 1, Part 2 and Part 3 of the study
  • Presence and/or concentration of anti-drug antibody [ Time Frame: 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 ]
    The presence and titer of anti-drug antibodies for crizanlizumab, sabatolimab and NIS793 in Part 1, Part 2 and Part 3 of the study
Original Secondary Outcome Measures  ICMJE
 (submitted: September 19, 2019)
  • Proportion of subjects achieving an improvement in hemoglobin level of ≥ 1.5 g/dL from baseline [ Time Frame: Baseline to the end of Cycle 6 (24 weeks), and end of Cycle 12 (48 weeks) ]
    Proportion 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.
  • Proportion of subjects achieving an improvement in hemoglobin level of at least >= 2.0 g/dL from baseline [ Time Frame: Baseline to the end of Cycle 6 (24 weeks), and end of Cycle 12 (48 weeks) ]
    Proportion 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.
  • Change in spleen length from baseline [ Time Frame: Baseline to day 1 and day 15 of Cycle 1, 2 and 3 (each cycle is 28 days), day 1 of all subsequent cycles, and the end of treatment (approx 12 cycles = 48 weeks) ]
    Change in spleen length measured in centimeters by manual palpation summarized at each time point using descriptive statistics in Part 2 and Part 3 of the study
  • Change in spleen volume from baseline [ Time Frame: Baseline to the end of Cycle 6 (24 weeks), the end of Cycle 12 (48 weeks) and at the end of treatment if not performed in the past 12 weeks (up to 48 weeks) ]
    Change in spleen volume measured by magnetic resonance imaging (MRI) or computed tomography (CT) summarized at each time point using descriptive statistics, in Part 2 and Part 3 of the study
  • Change in symptoms of MFSAF v4.0 from baseline [ Time Frame: Baseline to day 1 of Cycle 1, day 1 of all subsequent cycles of treatment (each cycle is 28 days), as well as the end of treatment visit (approximately 52 weeks) ]
    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.
  • Change in symptoms of EORTC QLQ-C30 from baseline [ Time Frame: Baseline to day 1 of Cycle 1, day 1 of all subsequent cycles of treatment (each cycle is 28 days), as well as the end of treatment visit (approximately 52 weeks) ]
    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.
  • Progression free survival, per progressive splenomegaly, accelerated phase, deteriorating cytopenia, leukemic transformation or death from any cause [ Time Frame: 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 ]
    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%.
  • Proportion of subjects achieving an impovement in bone marrow fibrosis of ≥ 1 grade from baseline [ Time Frame: Baseline to the end of Cycle 6 (24 weeks), the end of Cycle 12 (48 weeks) and at the end of treatment if not performed in the past 12 weeks (up to 48 weeks) ]
    Proportion 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.
  • Area under the Plasma Concentration versus Time Curve (AUC) [ Time Frame: Days 1, 2, 5 and 6 of Cycle 1 and 2 for siremadlin and ruxolitinib, and Cycle 1 and Cycle 3 for crizanlizumab and MBG453 (one cycle is 28 days) ]
    Summary statistics of AUC for each investigational drug in Part 1, Part 2 and Part 3 of the study
  • Maximum (peak) observed plasma drug concentration (Cmax) [ Time Frame: Days 1, 2, 5 and 6 of Cycle 1 and 2 for siremadlin and ruxolitinib, and Cycle 1 and Cycle 3 for crizanlizumab and MBG453 (one cycle is 28 days) ]
    Summary statistics of Cmax for each investigational drug in Part 1, Part 2 and Part 3 of the study
  • Time to reach maximum (peak) plasma, blood, serum or other body fulid drug concentration after single dose administration (Tmax) [ Time Frame: Days 1, 2, 5 and 6 of Cycle 1 and 2 for siremadlin and ruxolitinib, and Cycle 1 and Cycle 3 for crizanlizumab and MBG453 (one cycle is 28 days) ]
    Summary statistics of Tmax for each investigational drug in Part 1, Part 2 and Part 3 of the study
  • Concentration versus time profile [ Time Frame: Days 1, 2, 5 and 6 of Cycle 1 and 2 for siremadlin and ruxolitinib, and Cycle 1 and Cycle 3 for crizanlizumab and MBG453 (one cycle is 28 days) ]
    Concentration versus time profile for each investigational drug in Part 1, Part 2 and Part 3 of the study
  • Presence and/or concentration of anti-drug antibody [ Time Frame: Baseline to 105 days after last study drug adminstration for crizanlizumab or to 90 days after last study drug administration for MBG453 ]
    The presence and titer of anti-drug antibodies will be listed by subject and summarized using descriptive statistics for both crizanlizumab and MBG453.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Platform Study of Novel Ruxolitinib Combinations in Myelofibrosis Patients
Official Title  ICMJE A Randomized, Open-label, Phase I/II Open Platform Study Evaluating Safety and Efficacy of Novel Ruxolitinib Combinations in Myelofibrosis Patients
Brief Summary The purpose of this study is to investigate the safety, pharmacokinetics and preliminary efficacy of combinations treatment of ruxolitinib with 5 novel compounds: siremadlin, crizanlizumab, sabatolimab, LTT462 and NIS793 in myelofibrosis (MF) subjects.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description:
Open label
Primary Purpose: Treatment
Condition  ICMJE Myelofibrosis
Intervention  ICMJE
  • Drug: Ruxolitinib
    5 mg tablets for oral use
    Other Name: INC424, Jakavi
  • Drug: Siremadlin
    10 mg, 20 mg, or 40 mg capsules for oral use
    Other Name: HDM201
  • Drug: Crizanlizumab
    100 mg/mL concentrate for infusion for intravenous use
    Other Name: SEG101
  • Drug: Sabatolimab
    100 mg/mL or 400 mg/4 mL concentrate for infusion for intravenous use
    Other Name: MBG453
  • Drug: LTT462
    100 mg capsule for oral use
  • Drug: NIS793
    700 mg/7 mL concentrate for intravenous use
Study Arms  ICMJE
  • Experimental: Part 1 Arm 1: Ruxolitinib + Siremadlin
    Dose escalation of siremadlin added to existing stable dose of ruxolitinib
    Interventions:
    • Drug: Ruxolitinib
    • Drug: Siremadlin
  • Experimental: Part 1 Arm 2: Ruxolitinib + Crizanlizumab
    Safety run-in of crizanlizumab added to existing stable dose of ruxolitinib
    Interventions:
    • Drug: Ruxolitinib
    • Drug: Crizanlizumab
  • Experimental: Part 1 Arm 3: Ruxolitinib + Sabatolimab
    Safety run-in of Sabatolimab added to existing stable dose of ruxolitinib
    Interventions:
    • Drug: Ruxolitinib
    • Drug: Sabatolimab
  • Experimental: Part 2 Arm 1: Ruxolitinib + Siremadlin
    Siremadlin added to existing stable dose of ruxolitinib
    Interventions:
    • Drug: Ruxolitinib
    • Drug: Siremadlin
  • Experimental: Part 2 Arm 2: Ruxolitinib + Crizanlizumab
    Crizanlizumab added to existing stable dose of ruxolitinib
    Interventions:
    • Drug: Ruxolitinib
    • Drug: Crizanlizumab
  • Experimental: Part 2 Arm 3: Ruxolitinib + Sabatolimab
    Sabatolimab added to existing stable dose of ruxolitinib
    Interventions:
    • Drug: Ruxolitinib
    • Drug: Sabatolimab
  • Active Comparator: Part 2 Arm 6: Ruxolitinib monotherapy
    Existing stable dose of ruxolitinib as control for Part 2
    Intervention: Drug: Ruxolitinib
  • Experimental: Part 3 Arm 1: Ruxolitinib + Compound X
    Compound from Part 2 (to be confirmed) added to existing stable dose of ruxolitinib
    Intervention: Drug: 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
    Intervention: Drug: Ruxolitinib
  • Active Comparator: Part 3 Arm 3: Ruxolitinib monotherapy
    Existing stable dose of ruxolitinib as control for Part 3
    Intervention: Drug: Ruxolitinib
  • Experimental: Part 1 Arm 4: Ruxolitinib + LTT462
    Dose escalation of LTT462 added to existing stable dose of ruxolitinib
    Interventions:
    • Drug: Ruxolitinib
    • Drug: LTT462
  • Experimental: Part 1 Arm 5: Ruxolitinib + NIS793
    Safety run-in of NIS793 added to existing stable dose of ruxolitinib
    Interventions:
    • Drug: Ruxolitinib
    • Drug: NIS793
  • Experimental: Part 2 Arm 4: Ruxolitinib + LTT462
    LTT462 added to existing stable dose of ruxolitinib
    Interventions:
    • Drug: Ruxolitinib
    • Drug: LTT462
  • Experimental: Part 2 Arm 5: Ruxolitinib + NIS793
    NIS793 added to existing stable dose of ruxolitinib
    Interventions:
    • Drug: Ruxolitinib
    • Drug: NIS793
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 30, 2021)
243
Original Estimated Enrollment  ICMJE
 (submitted: September 19, 2019)
130
Estimated Study Completion Date  ICMJE June 10, 2025
Estimated Primary Completion Date January 16, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

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.

Other protocol-defined Inclusion/Exclusion criteria may apply.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Novartis Pharmaceuticals +41613241111 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals
Listed Location Countries  ICMJE Australia,   Belgium,   Canada,   Denmark,   Germany,   Hungary,   Italy,   Netherlands,   Spain,   Sweden,   Switzerland,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04097821
Other Study ID Numbers  ICMJE CINC424H12201
2019-000373-23 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.

URL: https://www.clinicalstudydatarequest.com
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP