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

Novartis

Status and phase: Terminated; Phase 2; Phase 1

Conditions: Myelofibrosis

Treatments: Drug: NIS793; Drug: Rineterkib; Drug: Crizanlizumab; Drug: Ruxolitinib; Drug: Sabatolimab; Drug: Siremadlin

Study type: Interventional

Funder types: Industry

Identifiers

NCT04097821

CINC424H12201

2019-000373-23 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 45 patients

Sex: All

Ages: 18 to 100 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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45 participants in 8 patient groups

Part 1: Ruxolitinib + Siremadlin 20 mg

Experimental group

Description:

Dose escalation of siremadlin added to existing stable dose of ruxolitinib

Treatment:

Drug: Siremadlin

Drug: Ruxolitinib

Part 1: Ruxolitinib + Siremadlin 30 mg

Experimental group

Description:

Dose escalation of siremadlin added to existing stable dose of ruxolitinib

Treatment:

Drug: Siremadlin

Drug: Ruxolitinib

Part 1: Ruxolitinib + Siremadlin 40 mg

Experimental group

Description:

Dose escalation of siremadlin added to existing stable dose of ruxolitinib

Treatment:

Drug: Siremadlin

Drug: Ruxolitinib

Part 1: Ruxolitinib + Rineterkib 200 mg

Experimental group

Description:

Dose escalation of rineterkib added to existing stable dose of ruxolitinib

Treatment:

Drug: Ruxolitinib

Drug: Rineterkib

Part 1: Ruxolitinib + Crizanlizumab

Experimental group

Description:

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

Treatment:

Drug: Ruxolitinib

Drug: Crizanlizumab

Part 1: Ruxolitinib + Sabatolimab

Experimental group

Description:

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

Treatment:

Drug: Sabatolimab

Drug: Ruxolitinib

Part 1: Ruxolitinib + NIS793

Experimental group

Description:

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

Treatment:

Drug: Ruxolitinib

Drug: NIS793

Part 2: Ruxolitinib

Active Comparator group

Description:

Existing stable dose of ruxolitinib as control for Part 2

Treatment:

Drug: Ruxolitinib