Platform Study of Novel Ruxolitinib Combinations in Myelofibrosis Patients

NCT ID: NCT04097821

Last Updated: 2025-08-07

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 45 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-09-26
• Study Completion Date: 2024-08-28

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.

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.

Conditions

Myelofibrosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Part 1: Ruxolitinib + Siremadlin 20 mg

Dose escalation of siremadlin added to existing stable dose of ruxolitinib

Group Type: EXPERIMENTAL

Ruxolitinib

Intervention Type: DRUG

5 mg tablets for oral use

Siremadlin

Intervention Type: DRUG

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

Part 1: Ruxolitinib + Siremadlin 30 mg

Dose escalation of siremadlin added to existing stable dose of ruxolitinib

Group Type: EXPERIMENTAL

Ruxolitinib

Intervention Type: DRUG

5 mg tablets for oral use

Siremadlin

Intervention Type: DRUG

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

Part 1: Ruxolitinib + Siremadlin 40 mg

Dose escalation of siremadlin added to existing stable dose of ruxolitinib

Group Type: EXPERIMENTAL

Ruxolitinib

Intervention Type: DRUG

5 mg tablets for oral use

Siremadlin

Intervention Type: DRUG

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

Part 1: Ruxolitinib + Rineterkib 200 mg

Dose escalation of rineterkib added to existing stable dose of ruxolitinib

Group Type: EXPERIMENTAL

Ruxolitinib

Intervention Type: DRUG

5 mg tablets for oral use

Rineterkib

Intervention Type: DRUG

100 mg capsule for oral use

Part 1: Ruxolitinib + Crizanlizumab

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

Group Type: EXPERIMENTAL

Ruxolitinib

Intervention Type: DRUG

5 mg tablets for oral use

Crizanlizumab

Intervention Type: DRUG

100 mg/10 mL concentrate for infusion for intravenous use

Part 1: Ruxolitinib + Sabatolimab

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

Group Type: EXPERIMENTAL

Ruxolitinib

Intervention Type: DRUG

5 mg tablets for oral use

Sabatolimab

Intervention Type: DRUG

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

Part 1: Ruxolitinib + NIS793

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

Group Type: EXPERIMENTAL

Ruxolitinib

Intervention Type: DRUG

5 mg tablets for oral use

NIS793

Intervention Type: DRUG

700 mg/7 mL concentrate for infusion for intravenous use

Part 2: Ruxolitinib

Existing stable dose of ruxolitinib as control for Part 2

Group Type: ACTIVE_COMPARATOR

Ruxolitinib

Intervention Type: DRUG

5 mg tablets for oral use

Interventions

Ruxolitinib

5 mg tablets for oral use

Intervention Type: DRUG

Siremadlin

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

Intervention Type: DRUG

Crizanlizumab

100 mg/10 mL concentrate for infusion for intravenous use

Intervention Type: DRUG

Sabatolimab

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

Intervention Type: DRUG

Rineterkib

100 mg capsule for oral use

Intervention Type: DRUG

NIS793

700 mg/7 mL concentrate for infusion for intravenous use

Intervention Type: DRUG

Other Intervention Names

INC424, Jakavi; HDM201; SEG101; MBG453; LTT462

Eligibility 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 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.

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.

• 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 100 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Novartis Investigative Site

Adelaide, South Australia, Australia

Novartis Investigative Site

Melbourne, Victoria, Australia

Novartis Investigative Site

Melbourne, Victoria, Australia

Novartis Investigative Site

Toronto, Ontario, Canada

Novartis Investigative Site

Copenhagen, , Denmark

Novartis Investigative Site

Mannheim, Baden-Wurttemberg, Germany

Novartis Investigative Site

Freiburg im Breisgau, , Germany

Novartis Investigative Site

Greifswald, , Germany

Novartis Investigative Site

Jena, , Germany

Novartis Investigative Site

Budapest, , Hungary

Novartis Investigative Site

Florence, FI, Italy

Novartis Investigative Site

Amsterdam, , Netherlands

Novartis Investigative Site

Moscow, , Russia

Novartis Investigative Site

Salamanca, Castille and León, Spain

Novartis Investigative Site

Alicante, , Spain

Novartis Investigative Site

Las Palmas de Gran Canaria, , Spain

Novartis Investigative Site

Madrid, , Spain

Novartis Investigative Site

Stockholm, , Sweden

Novartis Investigative Site

Sankt Gallen, , Switzerland

Novartis Investigative Site

Zurich, , Switzerland

Novartis Investigative Site

Kocaeli, , Turkey (Türkiye)

Novartis Investigative Site

London, , United Kingdom

Countries

Australia; Canada; Denmark; Germany; Hungary; Italy; Netherlands; Russia; Spain; Sweden; Switzerland; Turkey (Türkiye); United Kingdom

References

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.

Reference Type: DERIVED

PMID: 40334082 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2019-000373-23

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CINC424H12201

Identifier Type: -

Identifier Source: org_study_id