Platform Study of Novel Ruxolitinib Combinations in Myelofibrosis Patients

Phase 1

Terminated

Conditions: Myelofibrosis

Interventions: Drug: Ruxolitinib
Drug: Siremadlin
Drug: Crizanlizumab
Drug: Rineterkib
Drug: Sabatolimab
Drug: NIS793

Registration Number: NCT04097821

Lead Sponsor: Novartis Pharmaceuticals

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 45

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Part 1: Ruxolitinib + Siremadlin 20 mg	Ruxolitinib	Dose escalation of siremadlin added to existing stable dose of ruxolitinib
Part 1: Ruxolitinib + Siremadlin 20 mg	Siremadlin	Dose escalation of siremadlin added to existing stable dose of ruxolitinib
Part 1: Ruxolitinib + Siremadlin 30 mg	Ruxolitinib	Dose escalation of siremadlin added to existing stable dose of ruxolitinib
Part 1: Ruxolitinib + Siremadlin 30 mg	Siremadlin	Dose escalation of siremadlin added to existing stable dose of ruxolitinib
Part 1: Ruxolitinib + Crizanlizumab	Crizanlizumab	Safety run-in of crizanlizumab added to existing stable dose of ruxolitinib
Part 1: Ruxolitinib + Siremadlin 40 mg	Ruxolitinib	Dose escalation of siremadlin added to existing stable dose of ruxolitinib
Part 1: Ruxolitinib + Siremadlin 40 mg	Siremadlin	Dose escalation of siremadlin added to existing stable dose of ruxolitinib
Part 1: Ruxolitinib + Rineterkib 200 mg	Ruxolitinib	Dose escalation of rineterkib added to existing stable dose of ruxolitinib
Part 1: Ruxolitinib + Sabatolimab	Ruxolitinib	Safety run-in of sabatolimab added to existing stable dose of ruxolitinib
Part 1: Ruxolitinib + Rineterkib 200 mg	Rineterkib	Dose escalation of rineterkib added to existing stable dose of ruxolitinib
Part 1: Ruxolitinib + Crizanlizumab	Ruxolitinib	Safety run-in of crizanlizumab added to existing stable dose of ruxolitinib
Part 1: Ruxolitinib + Sabatolimab	Sabatolimab	Safety run-in of sabatolimab added to existing stable dose of ruxolitinib
Part 1: Ruxolitinib + NIS793	Ruxolitinib	Safety run-in of NIS793 added to existing stable dose of ruxolitinib
Part 1: Ruxolitinib + NIS793	NIS793	Safety run-in of NIS793 added to existing stable dose of ruxolitinib
Part 2: Ruxolitinib	Ruxolitinib	Existing stable dose of ruxolitinib as control for Part 2

Primary Outcome Measures

Name	Time	Method
Incidence and Severity of Dose Limiting Toxicities Within the First 2 Cycles in Part 1	Baseline to the end of Cycle 2 (6 or 8 weeks)	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.
Response Rate at the End of Cycle 6 or Cycle 8 in Part 1	Baseline to the end of Cycle 6 or 8 (24 weeks)	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.

Secondary Outcome Measures

Name	Time	Method
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	Change in spleen length measured in centimeters by manual palpation.
Percentage of Subjects With >=35% Reduction in Spleen Volume From Baseline in Part 1	Week 24, Week 48	Change in spleen volume measured by magnetic resonance imaging (MRI) or computed tomography (CT) from baseline.
Percentage of Subjects With >=25% Reduction in Spleen Volume From Baseline in Part 1	Week 24, Week 48	Change in spleen volume measured by magnetic resonance imaging (MRI) or computed tomography (CT) from baseline.
Percentage of Subjects in Part 1 With >=50% Reduction From Baseline in Myelofibrosis Symptom Assessment Form, Version 4.0 (MFSAF v4.0)	Week 12, Week 24, Week 48	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.
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	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.	EOI = end of infusion
Concentration Versus Time Profile for Sabatolimab in Part 1	Days 1, 2, 8, and 15 of Cycles 1, 2, and 3; Day 1 of Cycles 4 and 5. Each cycle was 28 days.	EOI = end of infusion
Concentration Versus Time Profile for NIS793 in Part 1	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.	EOI = end of infusion
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.