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

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ClinicalTrials.gov Identifier: NCT04097821
Recruitment Status : Recruiting
First Posted : September 20, 2019
Last Update Posted : October 4, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
The purpose of this study is to investigate the safety, pharmacokinetics and preliminary efficacy of combinations treatment of ruxolitinib with 3 novel compounds: siremadlin, crizanlizumab and MBG453 in myelofibrosis (MF) subjects.

Condition or disease Intervention/treatment Phase
Myelofibrosis Drug: Ruxolitinib Drug: Siremadlin Drug: Crizanlizumab Drug: MBG453 Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 130 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description: Open label
Primary Purpose: Treatment
Official Title: A Randomized, Open-label, Phase I/II Open Platform Study Evaluating Safety and Efficacy of Novel Ruxolitinib Combinations in Myelofibrosis Patients
Actual Study Start Date : September 26, 2019
Estimated Primary Completion Date : July 14, 2022
Estimated Study Completion Date : March 15, 2024


Arm Intervention/treatment
Experimental: Part 1 Arm 1: Ruxolitinib + Siremadlin
Dose escalation of siremadlin added to existing stable dose of ruxolitinib
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

Experimental: Part 1 Arm 2: Ruxolitinib + Crizanlizumab
Safety run-in of crizanlizumab added to existing stable dose of ruxolitinib
Drug: Ruxolitinib
5 mg tablets for oral use
Other Name: INC424, Jakavi

Drug: Crizanlizumab
100 mg/mL concentrate for infusion for intravenous use
Other Name: SEG101

Experimental: Part 1 Arm 3: Ruxolitinib + MBG453
Safety run-in of MBG453 added to existing stable dose of ruxolitinib
Drug: Ruxolitinib
5 mg tablets for oral use
Other Name: INC424, Jakavi

Drug: MBG453
100 mg/mL concentrate for infusion for intravenous use

Experimental: Part 2 Arm 1: Ruxolitinib + Siremadlin
Siremadlin added to existing stable dose of ruxolitinib
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

Experimental: Part 2 Arm 2: Ruxolitinib + Crizanlizumab
Crizanlizumab added to existing stable dose of ruxolitinib
Drug: Ruxolitinib
5 mg tablets for oral use
Other Name: INC424, Jakavi

Drug: Crizanlizumab
100 mg/mL concentrate for infusion for intravenous use
Other Name: SEG101

Experimental: Part 2 Arm 3: Ruxolitinib + MBG453
MBG453 added to existing stable dose of ruxolitinib
Drug: Ruxolitinib
5 mg tablets for oral use
Other Name: INC424, Jakavi

Drug: MBG453
100 mg/mL concentrate for infusion for intravenous use

Experimental: Part 2 Arm 4: Ruxolitinib monotherapy
Existing stable dose of ruxolitinib as control for Part 2
Drug: Ruxolitinib
5 mg tablets for oral use
Other Name: INC424, Jakavi

Active Comparator: Part 3 Arm 1: Ruxolitinib + Compound X
Compound from Part 2 (to be confirmed) added to existing stable dose of ruxolitinib
Drug: Ruxolitinib
5 mg tablets for oral use
Other Name: INC424, Jakavi

Active Comparator: Part 3 Arm 2: Ruxolitinib cessation
Compound from Part 2 added to existing stable dose of ruxolitinib for 3 cycles followed by compound monotherapy
Drug: Ruxolitinib
5 mg tablets for oral use
Other Name: INC424, Jakavi

Active Comparator: Part 3 Arm 3: Ruxolitinib monotherapy
Existing stable dose of ruxolitinib as control for Part 3
Drug: Ruxolitinib
5 mg tablets for oral use
Other Name: INC424, Jakavi




Primary Outcome Measures :
  1. 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

  2. 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


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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

  4. 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

  5. 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.

  6. 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.

  7. 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%.


  8. 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.

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04097821


Contacts
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Contact: Novartis Pharmaceuticals +41613241111 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals

Locations
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Australia, Victoria
Novartis Investigative Site Recruiting
Melbourne, Victoria, Australia, 3004
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT04097821     History of Changes
Other Study ID Numbers: CINC424H12201
2019-000373-23 ( EudraCT Number )
First Posted: September 20, 2019    Key Record Dates
Last Update Posted: October 4, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
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

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
myelofibrosis
ruxolitinib
INC424
siremadlin
HDM201
crizanlizumab
SEG101
MBG453
platform study
Additional relevant MeSH terms:
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Primary Myelofibrosis
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases