Clinical trial NCT04097821: Platform Study of Novel Ruxolitinib Combinations in Myelofibrosis Patients
Official title: A Randomized, Open-label, Phase I/II Open Platform Study Evaluating Safety and Efficacy of Novel Ruxolitinib Combinations in Myelofibrosis Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Myelofibrosis
Keywords: myelofibrosis
ruxolitinib
INC424
siremadlin
HDM201
crizanlizumab
SEG101
sabatolimab
MBG453
rineterkib
LTT462
NIS793
platform study
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2019-09-20
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This open-label, multi-center, phase Ib/II platform study design consists of 3 parts. Part 1 is 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 are phase II selection and expansion respectively, to assess preliminary efficacy of the combination treatments from Part 1 that are evaluated as safe and tolerable.

The number of combination treatment arms opening in part 2 will depend on the results of Part 1. In Part 2, interim analysis was planned to determine if combination treatment (s) can be expanded in Part 3
Primary purpose: TREATMENT

Brief summary: The purpose of this study is 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 consists of 3 parts. Part 1 is 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. Dose escalation cohorts are treated with ruxoltinib + siremadlin or ruxolitinib + rineterkib. Safety run in cohorts are treated with either ruxolitinb + sabatolimab, ruxolitinb + crizanlizumab or ruxolitinib + NIS793 Parts 2 and 3 are phase II selection and expansion respectively, to assess preliminary efficacy of the combination treatments from Part 1 that are evaluated as safe and tolerable. The number of combination treatment arms opening in part 2 will depend on the results of Part 1. In Part 2, an interim analysis was planned to determine if combination treatment (s) can 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) will not be initiated. With protocol amendment 8, an extension treatment phase of 12 cycles is 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 will not be pursued and Part 1 objectives are updated accordingly.

Eligibility 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.

Other protocol-defined Inclusion/Exclusion criteria may apply.

Primary outcomes:
measure: Incidence of dose limiting toxicities within the first 2 cycles
timeFrame: Baseline to the end of Cycle 2 (6 or 8 weeks)
measure: Response rate at the end of cycle 6 or cycle 8
timeFrame: Baseline to the end of Cycle 6 or 8 (24 weeks)
Secondary outcomes:
measure: Percentage of subjects achieving an improvement in hemoglobin level of ≥ 1.5 g/dL from baseline
timeFrame: Baseline to the end of Cycle 6 or 8 (24 weeks), and end of Cycle 12 or 16 (48 weeks)
measure: Percentage of subjects achieving an improvement in hemoglobin level of at least >= 2.0 g/dL from baseline
timeFrame: Baseline to the end of Cycle 6 or 8 (24 weeks), and end of Cycle 12 or 16 (48 weeks)
measure: Change in spleen length from baseline
timeFrame: Baseline to day 1 and day 15 of Cycle 1, 2 and 3, day 1 of all subsequent cycles, and the end of 12 or 16 cycles (48 weeks)
measure: Change in spleen volume from baseline
timeFrame: Baseline to the end of Cycle 6 or 8 (24 weeks), the end of Cycle 12 or 16 (48 weeks) and at the end of treatment if not performed in the past 12 weeks (up to 48 weeks)
measure: Change in symptoms of MFSAF v4.0 from baseline
timeFrame: Baseline to day 1 of Cycle 1, day 1 of all subsequent cycles of treatment (each cycle is 28 days except for arms containing NIS793, which are 21 days), as well as the end of treatment visit (approximately 52 weeks)
measure: Change in symptoms of EORTC QLQ-C30 from baseline
timeFrame: Baseline to day 1 of Cycle 1, day 1 of all subsequent cycles of treatment (each cycle is 28 days except for arms containing NIS793, which are 21 days), as well as the end of treatment visit (approximately 52 weeks)
measure: Changes in symptoms in MFSAF v4.0 (Part 1) from baseline
timeFrame: Baseline to end of Cycle 3 or 4 (week 16), and end of Cycle 6 or 8 (week 24weeks), or end Cycle 12 or 16 (48 weeks)
measure: Progression free survival, per progressive splenomegaly, accelerated phase, deteriorating cytopenia, leukemic transformation or death from any cause
timeFrame: Baseline to disease progression, which is up to 24 weeks for Part 1 or through study completion, an average of 1 year, for Part 2 and Part 3
measure: Percentage of subjects achieving an improvement in bone marrow fibrosis of ≥ 1 grade from baseline
timeFrame: Baseline to the end of Cycle 6 or 8 (24 weeks), the end of Cycle 12 or 16 (48 weeks) and at the end of treatment if not performed in the past 12 weeks (up to 48 weeks)
measure: Area under the Plasma Concentration versus Time Curve (AUC)
timeFrame: Days 1 and 5 of Cycle 1 and 2 for siremadlin and ruxolitinib, and Cycle 1 and Cycle 3 for crizanlizumab, sabatolimab and NIS793, and Days 1 and 15 of Cycle 1 for LTT462
measure: Maximum (peak) observed plasma drug concentration (Cmax)
timeFrame: Days 1 and 5 of Cycle 1 and 2 for siremadlin and ruxolitinib, and Cycle 1 and Cycle 3 for crizanlizumab, sabatolimab and NIS793, and Days 1 and 15 of Cycle 1 for LTT462
measure: Time to reach maximum (peak) plasma, blood, serum or other body fluid drug concentration after single dose administration (Tmax)
timeFrame: Days 1 and 5 of Cycle 1 and 2 for siremadlin and ruxolitinib, and Cycle 1 and Cycle 3 for crizanlizumab, sabatolimab and NIS793, and Days 1 and 15 of Cycle 1 for LTT462
measure: Concentration versus time profile
timeFrame: Days 1 and 5 of Cycle 1 and 2 for siremadlin and ruxolitinib, and Cycle 1 and Cycle 3 for crizanlizumab, sabatolimab and NIS793, and Days 1 and 15 of Cycle 1 for LTT462
measure: Presence and/or concentration of anti-drug antibody
timeFrame: Baseline to 105 days after last study drug administration for crizanlizumab, to 150 days after last study drug administration for sabatolimab, or to 90 days after last study drug administration for NIS793
Other outcomes:
Locations:
city: Adelaide
country: Australia
facility: Novartis Investigative Site
state: South Australia
city: Melbourne
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Melbourne
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Copenhagen
country: Denmark
facility: Novartis Investigative Site
city: Mannheim
country: Germany
facility: Novartis Investigative Site
state: Baden Wuerttemberg
city: Freiburg
country: Germany
facility: Novartis Investigative Site
city: Greifswald
country: Germany
facility: Novartis Investigative Site
city: Jena
country: Germany
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Firenze
country: Italy
facility: Novartis Investigative Site
state: FI
city: Groningen
country: Netherlands
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Salamanca
country: Spain
facility: Novartis Investigative Site
state: Castilla Y Leon
city: Alicante
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Las Palmas de Gran Canaria
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Stockholm
country: Sweden
facility: Novartis Investigative Site
city: St Gallen
country: Switzerland
facility: Novartis Investigative Site
city: Zuerich
country: Switzerland
facility: Novartis Investigative Site
city: Kocaeli
country: Turkey
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: