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

A Randomized, Open-label, Phase I/II Open Platform Study Evaluating Safety and Efficacy of Novel Ruxolitinib Combinations in Myelofibrosis Patients

The purpose of this study was 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.

Study Overview

• Status: Terminated
• Conditions: Myelofibrosis
• Intervention / Treatment: Drug: Ruxolitinib; Drug: Siremadlin; Drug: Sabatolimab; Drug: Rineterkib; Drug: Crizanlizumab; Drug: NIS793

Detailed Description

This open-label, multi-center, Phase Ib/II platform study design consisted of 3 parts. Part 1 was a Phase Ib dose escalation and safety run-in for the 5 novel agents in combination with ruxolitinib to assess safety, tolerability and to confirm a recommended Phase II dose. Dose escalation cohorts were treated with ruxoltinib + siremadlin or ruxolitinib + rineterkib. Safety run-in cohorts were treated with either ruxolitinb + sabatolimab, ruxolitinb + crizanlizumab or ruxolitinib + NIS7913.

Parts 2 and 3 were Phase II selection and expansion, respectively, to assess preliminary efficacy of the combination treatments from Part 1 that were evaluated as safe and tolerable. The number of combination treatment arms opening in Part 2 depended on the results of Part 1. In Part 2, an interim analysis was planned to determine if combination treatment(s) could be expanded in Part 3.

In June 2022, Novartis decided to permanently halt the study enrollment in all ongoing parts (Part 1 and Part 2), and Part 3 (expansion) was not initiated. With Protocol Amendment 8, an extension treatment phase of 12 cycles was added in Part 1 to allow access to the combination treatment for ongoing subjects deriving clinical benefit. In consideration of the enrollment halt, Parts 2 and 3 objectives were not pursued, and Part 1 objectives were updated accordingly.

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Novartis Investigative Site
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Novartis Investigative Site
    • Melbourne, Victoria, Australia, 3004
      • Novartis Investigative Site
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Novartis Investigative Site
• Denmark
  • Copenhagen, Denmark, DK-2100
    • Novartis Investigative Site
• Germany
  • Freiburg, Germany, 79106
    • Novartis Investigative Site
  • Greifswald, Germany, 17475
    • Novartis Investigative Site
  • Jena, Germany, 07740
    • Novartis Investigative Site
  • Baden Wuerttemberg
    • Mannheim, Baden Wuerttemberg, Germany, 68305
      • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, H-1083
    • Novartis Investigative Site
• Italy
  • FI
    • Firenze, FI, Italy, 50134
      • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • Novartis Investigative Site
• Russian Federation
  • Moscow, Russian Federation, 125284
    • Novartis Investigative Site
• Spain
  • Alicante, Spain, 03010
    • Novartis Investigative Site
  • Las Palmas de Gran Canaria, Spain, 35010
    • Novartis Investigative Site
  • Madrid, Spain, 28034
    • Novartis Investigative Site
  • Castilla Y Leon
    • Salamanca, Castilla Y Leon, Spain, 37007
      • Novartis Investigative Site
• Sweden
  • Stockholm, Sweden, 14186
    • Novartis Investigative Site
• Switzerland
  • St Gallen, Switzerland, 9007
    • Novartis Investigative Site
  • Zuerich, Switzerland, 8091
    • Novartis Investigative Site
• Turkey
  • Kocaeli, Turkey, 41380
    • Novartis Investigative Site
• United Kingdom
  • London, United Kingdom, SE1 9RT
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Core treatment phase 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

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 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 Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: Ruxolitinib + Siremadlin 20 mg; Dose escalation of siremadlin added to existing stable dose of ruxolitinib	Drug: Ruxolitinib; 5 mg tablets for oral use; Other Names: INC424, Jakavi; Drug: Siremadlin; 10 mg, 20 mg, or 40 mg capsules for oral use; Other Names: HDM201
Experimental: Part 1: Ruxolitinib + Siremadlin 30 mg; Dose escalation of siremadlin added to existing stable dose of ruxolitinib	Drug: Ruxolitinib; 5 mg tablets for oral use; Other Names: INC424, Jakavi; Drug: Siremadlin; 10 mg, 20 mg, or 40 mg capsules for oral use; Other Names: HDM201
Experimental: Part 1: Ruxolitinib + Siremadlin 40 mg; Dose escalation of siremadlin added to existing stable dose of ruxolitinib	Drug: Ruxolitinib; 5 mg tablets for oral use; Other Names: INC424, Jakavi; Drug: Siremadlin; 10 mg, 20 mg, or 40 mg capsules for oral use; Other Names: HDM201
Experimental: Part 1: Ruxolitinib + Rineterkib 200 mg; Dose escalation of rineterkib added to existing stable dose of ruxolitinib	Drug: Ruxolitinib; 5 mg tablets for oral use; Other Names: INC424, Jakavi; Drug: Rineterkib; 100 mg capsule for oral use; Other Names: LTT462
Experimental: Part 1: Ruxolitinib + Crizanlizumab; Safety run-in of crizanlizumab added to existing stable dose of ruxolitinib	Drug: Ruxolitinib; 5 mg tablets for oral use; Other Names: INC424, Jakavi; Drug: Crizanlizumab; 100 mg/10 mL concentrate for infusion for intravenous use; Other Names: SEG101
Experimental: Part 1: Ruxolitinib + Sabatolimab; Safety run-in of sabatolimab added to existing stable dose of ruxolitinib	Drug: Ruxolitinib; 5 mg tablets for oral use; Other Names: INC424, Jakavi; Drug: Sabatolimab; 100 mg/mL or 400 mg/4 mL concentrate for infusion for intravenous use; Other Names: MBG453
Experimental: Part 1: Ruxolitinib + NIS793; Safety run-in of NIS793 added to existing stable dose of ruxolitinib	Drug: Ruxolitinib; 5 mg tablets for oral use; Other Names: INC424, Jakavi; Drug: NIS793; 700 mg/7 mL concentrate for infusion for intravenous use
Active Comparator: Part 2: Ruxolitinib; Existing stable dose of ruxolitinib as control for Part 2	Drug: Ruxolitinib; 5 mg tablets for oral use; Other Names: INC424, Jakavi

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence and Severity of Dose Limiting Toxicities Within the First 2 Cycles in Part 1	Incidence and severity of dose limiting toxicities within the first 2 cycles (6 or 8 weeks) in Part 1 of the study. DLTs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) criteria Version 5.0. Grade 0 was assigned for all non-missing values not graded as 1 or higher. Higher grade indicated more severity. Grade 5 was not used.	Baseline to the end of Cycle 2 (6 or 8 weeks)
Response Rate at the End of Cycle 6 or Cycle 8 in Part 1	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 had to be fulfilled.	Baseline to the end of Cycle 6 or 8 (24 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Subjects Achieving an Improvement in Hemoglobin Level of ≥ 1.5 g/dL From Baseline in Part 1		Week 24, Week 48
Percentage of Subjects Achieving an Improvement in Hemoglobin Level of at Least >= 2.0 g/dL From Baseline in Part 1		Week 24, Week 48
Change in Spleen Length From Baseline in Part 1	Change in spleen length measured in centimeters by manual palpation.	Baseline, Week 24, Week 48
Percentage of Subjects With >=35% Reduction in Spleen Volume From Baseline in Part 1	Change in spleen volume measured by magnetic resonance imaging (MRI) or computed tomography (CT) from baseline.	Week 24, Week 48
Percentage of Subjects With >=25% Reduction in Spleen Volume From Baseline in Part 1	Change in spleen volume measured by magnetic resonance imaging (MRI) or computed tomography (CT) from baseline.	Week 24, Week 48
Percentage of Subjects in Part 1 With >=50% Reduction From Baseline in Myelofibrosis Symptom Assessment Form, Version 4.0 (MFSAF v4.0)	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.	Week 12, Week 24, Week 48
Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) for Siremadlin, Rineterkib, Crizanlizumab, Sabatolimab, and NIS793 in Part 1		Days 1 and 5 of Cycles 1 and 2 for siremadlin and Cycles 1 and 3 for crizanlizumab, sabatolimab, and NIS793; Days 1 and 15 of Cycle 1 for rineterkib
Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) for Ruxolitinib in Part 1		Days 1 and 5 of Cycles 1 and 2; Day 15 of Cycle 1
Maximum (Peak) Observed Plasma Drug Concentration (Cmax) for Siremadlin, Rineterkib, Crizanlizumab, Sabatolimab, and NIS793 in Part 1		Days 1 and 5 of Cycles 1 and 2 for siremadlin and Cycles 1 and 3 for crizanlizumab, sabatolimab, and NIS793; Days 1 and 15 of Cycle 1 for rineterkib
Maximum (Peak) Observed Plasma Drug Concentration (Cmax) for Ruxolitinib in Part 1		Days 1 and 5 of Cycles 1 and 2; Day 15 of Cycle 1
Time to Reach Maximum (Peak) Plasma, Blood, Serum or Other Body Fluid Drug Concentration After Single Dose Administration (Tmax) for Siremadlin, Rineterkib, Crizanlizumab, Sabatolimab, and NIS793 in Part 1		Days 1 and 5 of Cycles 1 and 2 for siremadlin and Cycles 1 and 3 for crizanlizumab, sabatolimab, and NIS793; Days 1 and 15 of Cycle 1 for rineterkib
Time to Reach Maximum (Peak) Plasma, Blood, Serum or Other Body Fluid Drug Concentration After Single Dose Administration (Tmax) for Ruxolitinib in Part 1		Days 1 and 5 of Cycles 1 and 2; Day 15 of Cycle 1
Concentration Versus Time Profile for Siremadlin in Part 1		Day 1 of Cycles 1 and 2; Day 6 of Cycle 1; Days 2 and 5 of Cycles 1, 2, 3, 4, 5, and 6. Each cycle was 28 days.
Concentration Versus Time Profile for Rineterkib in Part 1		Days 1, 2, 15, and 16 of Cycle 1; Day 1 of Cycles 2, 3, 4, 5, and 6. Each cycle was 28 days.
Concentration Versus Time Profile for Crizanlizumab in Part 1	EOI = end of infusion	Days 1, 2, 8, and 15 of Cycles 1, 2, and 3; Day 1 of Cycles 4, 5, 6, and 9. Each cycle was 28 days.
Concentration Versus Time Profile for Sabatolimab in Part 1	EOI = end of infusion	Days 1, 2, 8, and 15 of Cycles 1, 2, and 3; Day 1 of Cycles 4 and 5. Each cycle was 28 days.
Concentration Versus Time Profile for NIS793 in Part 1	EOI = end of infusion	Days 1, 2, 4, 8, 11, and 15 of Cycles 1, 2, and 3; Day 1 of Cycles 4 and 5. Each cycle was 28 days.
Concentration Versus Time Profile for Ruxolitinib in Part 1		Days 1, 2, 5, 6, and 15 of Cycles 1 and 2; Day 16 of Cycle 1; Days 1, 2, and 15 of Cycle 3; Days 1 and 5 of Cycles 4, 5, and 6. Each cycle was 28 days.

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): September 26, 2019
• Primary Completion (Actual): May 3, 2023
• Study Completion (Actual): August 28, 2024

Study Registration Dates

• First Submitted: September 17, 2019
• First Submitted That Met QC Criteria: September 19, 2019
• First Posted (Actual): September 20, 2019

Study Record Updates

• Last Update Posted (Actual): August 7, 2025
• Last Update Submitted That Met QC Criteria: July 21, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: crizanlizumab; SEG101; HDM201; MBG453; INC424; myelofibrosis; ruxolitinib; sabatolimab; siremadlin; NIS793; platform study; LTT462; rineterkib
• Additional Relevant MeSH Terms: Hematologic Diseases; Bone Marrow Diseases; Myeloproliferative Disorders; Primary Myelofibrosis
• Other Study ID Numbers: CINC424H12201; 2019-000373-23 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No