Platform Study of Novel Ruxolitinib Combinations in Myelofibrosis Patients

NCT04097821 | Terminated Phase 1 Results DMC

• 2 other identifiers: CINC424H122012019-000373-23
• Study Type: interventional
• Target: 45
• Locations: 13 countries
• Sites: 22

Brief Summary

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.

Conditions

Myelofibrosis

Keywords

myelofibrosis; ruxolitinib; INC424; siremadlin; HDM201; crizanlizumab; SEG101; sabatolimab; MBG453; rineterkib; LTT462; NIS793; platform study

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (18)

• 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

  Baseline, Week 24, Week 48

• Percentage of Subjects With >=35% Reduction in Spleen Volume From Baseline in Part 1

  Week 24, Week 48

• Percentage of Subjects With >=25% Reduction in Spleen Volume From Baseline in Part 1

  Week 24, Week 48

Study Arms (8)

Part 1: Ruxolitinib + Siremadlin 20 mg

EXPERIMENTAL

Dose escalation of siremadlin added to existing stable dose of ruxolitinib

Drug: Ruxolitinib; Drug: Siremadlin

Part 1: Ruxolitinib + Siremadlin 30 mg

EXPERIMENTAL

Dose escalation of siremadlin added to existing stable dose of ruxolitinib

Drug: Ruxolitinib; Drug: Siremadlin

Part 1: Ruxolitinib + Siremadlin 40 mg

EXPERIMENTAL

Dose escalation of siremadlin added to existing stable dose of ruxolitinib

Drug: Ruxolitinib; Drug: Siremadlin

Part 1: Ruxolitinib + Rineterkib 200 mg

EXPERIMENTAL

Dose escalation of rineterkib added to existing stable dose of ruxolitinib

Drug: Ruxolitinib; Drug: Rineterkib

Part 1: Ruxolitinib + Crizanlizumab

EXPERIMENTAL

Safety run-in of crizanlizumab added to existing stable dose of ruxolitinib

Drug: Ruxolitinib; Drug: Crizanlizumab

Part 1: Ruxolitinib + Sabatolimab

EXPERIMENTAL

Safety run-in of sabatolimab added to existing stable dose of ruxolitinib

Drug: Ruxolitinib; Drug: Sabatolimab

Part 1: Ruxolitinib + NIS793

EXPERIMENTAL

Safety run-in of NIS793 added to existing stable dose of ruxolitinib

Drug: Ruxolitinib; Drug: NIS793

Part 2: Ruxolitinib

ACTIVE COMPARATOR

Existing stable dose of ruxolitinib as control for Part 2

Drug: Ruxolitinib

Interventions

Ruxolitinib DRUG

5 mg tablets for oral use

Also known as: INC424, Jakavi

Part 1: Ruxolitinib + Crizanlizumab; Part 1: Ruxolitinib + NIS793; Part 1: Ruxolitinib + Rineterkib 200 mg; Part 1: Ruxolitinib + Sabatolimab; Part 1: Ruxolitinib + Siremadlin 20 mg; Part 1: Ruxolitinib + Siremadlin 30 mg; Part 1: Ruxolitinib + Siremadlin 40 mg; Part 2: Ruxolitinib

Siremadlin DRUG

10 mg, 20 mg, or 40 mg capsules for oral use

Also known as: HDM201

Part 1: Ruxolitinib + Siremadlin 20 mg; Part 1: Ruxolitinib + Siremadlin 30 mg; Part 1: Ruxolitinib + Siremadlin 40 mg

Crizanlizumab DRUG

100 mg/10 mL concentrate for infusion for intravenous use

Also known as: SEG101

Part 1: Ruxolitinib + Crizanlizumab

Sabatolimab DRUG

100 mg/mL or 400 mg/4 mL concentrate for infusion for intravenous use

Also known as: MBG453

Part 1: Ruxolitinib + Sabatolimab

Rineterkib DRUG

100 mg capsule for oral use

Also known as: LTT462

Part 1: Ruxolitinib + Rineterkib 200 mg

NIS793 DRUG

700 mg/7 mL concentrate for infusion for intravenous use

Part 1: Ruxolitinib + NIS793

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (22)

Novartis Investigative Site

Adelaide, South Australia, 5000, Australia

Location

Novartis Investigative Site

Melbourne, Victoria, 3000, Australia

Location

Novartis Investigative Site

Melbourne, Victoria, 3004, Australia

Location

Novartis Investigative Site

Toronto, Ontario, M5G 2M9, Canada

Location

Novartis Investigative Site

Copenhagen, DK-2100, Denmark

Location

Novartis Investigative Site

Mannheim, Baden-Wurttemberg, 68305, Germany

Location

Novartis Investigative Site

Freiburg im Breisgau, 79106, Germany

Location

Novartis Investigative Site

Greifswald, 17475, Germany

Location

Novartis Investigative Site

Jena, 07740, Germany

Location

Novartis Investigative Site

Budapest, H-1083, Hungary

Location

Novartis Investigative Site

Florence, FI, 50134, Italy

Location

Novartis Investigative Site

Amsterdam, 1081 HV, Netherlands

Location

Novartis Investigative Site

Moscow, 125284, Russia

Location

Novartis Investigative Site

Salamanca, Castille and León, 37007, Spain

Location

Novartis Investigative Site

Alicante, 03010, Spain

Location

Novartis Investigative Site

Las Palmas de Gran Canaria, 35010, Spain

Location

Novartis Investigative Site

Madrid, 28034, Spain

Location

Novartis Investigative Site

Stockholm, 14186, Sweden

Location

Novartis Investigative Site

Sankt Gallen, 9007, Switzerland

Location

Novartis Investigative Site

Zurich, 8091, Switzerland

Location

Novartis Investigative Site

Kocaeli, 41380, Turkey (Türkiye)

Location

Novartis Investigative Site

London, SE1 9RT, United Kingdom

Location

Related Publications (1)

• Ross DM, Heidel FH, Perkins AC, Reiter A, Crodel C, Riley C, Gomez-Casares MT, Takacs I, Becker H, Lehmann T, Vinogradova O, Burbury K, Vannucchi AM, Gupta V, Wondergem M, Kiladjian JJ, Cleary G, Zhang A, Kota J, Prahallad A, Wroclawska M, Lu M, Harrison CN. ADORE: an open platform study of ruxolitinib in combination with other novel therapies in patients with myelofibrosis. Blood Adv. 2025 Aug 26;9(16):4195-4205. doi: 10.1182/bloodadvances.2025015860.

  PMID: 40334082 DERIVED

MeSH Terms

Conditions

Primary Myelofibrosis

Interventions

ruxolitinib; siremadlin; crizanlizumab; sabatolimab; NIS-793

Condition Hierarchy (Ancestors)

Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@Novartis.com

+ 1 862 778 8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: Open label
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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 recommended Phase II dose. 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, interim analysis was planned to determine if combination treatment(s) could be expanded in Part 3.

Study Record Dates

• First Submitted: September 17, 2019
• First Posted: September 20, 2019
• Study Start: September 26, 2019
• Primary Completion: May 3, 2023
• Study Completion: August 28, 2024
• Last Updated: August 7, 2025
• Results First Posted: August 7, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will share

Locations

HU (1); NL (1); ES (4); DK (1); RU (1); IT (1); SE (1); CH (2); GB (1); AU (3); CA (1); TU (1); DE (4)