Platform Study of Novel Ruxolitinib Combinations in Myelofibrosis Patients

Phase 2TerminatedNCT04097821

Novartis Pharmaceuticals45 enrolled

Overview

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.

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Myelofibrosis

Interventions

RuxolitinibDRUG

5 mg tablets for oral use

SiremadlinDRUG

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

CrizanlizumabDRUG

100 mg/10 mL concentrate for infusion for intravenous use

Sabatolimab

Eligibility

Sex: ALLMin age: 18 YearsMax age: 100 Years

Medical Language ↔ Plain English

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.

Locations (22)

Novartis Investigative Site

Adelaide, South Australia, Australia

Novartis Investigative Site

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: Baseline to the end of Cycle 6 or 8 (24 weeks)

Secondary Outcomes

Percentage of Subjects Achieving an Improvement in Hemoglobin Level of ≥ 1.5 g/dL From Baseline in Part 1

Time frame: 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

Time frame: Week 24, Week 48

Change in Spleen Length From Baseline in Part 1

Change in spleen length measured in centimeters by manual palpation.

Time frame: 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.

Time frame: Week 24, Week 48

Data from ClinicalTrials.gov

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