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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04097821




Registration number
NCT04097821
Ethics application status
Date submitted
17/09/2019
Date registered
20/09/2019

Titles & IDs
Public title
Platform Study of Novel Ruxolitinib Combinations in Myelofibrosis Patients
Scientific title
A Randomized, Open-label, Phase I/II Open Platform Study Evaluating Safety and Efficacy of Novel Ruxolitinib Combinations in Myelofibrosis Patients
Secondary ID [1] 0 0
2019-000373-23
Secondary ID [2] 0 0
CINC424H12201
Universal Trial Number (UTN)
Trial acronym
ADORE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Myelofibrosis 0 0
Condition category
Condition code
Musculoskeletal 0 0 0 0
Other muscular and skeletal disorders
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Ruxolitinib
Treatment: Drugs - Siremadlin
Treatment: Drugs - Crizanlizumab
Treatment: Drugs - Sabatolimab
Treatment: Drugs - Rineterkib
Treatment: Drugs - NIS793

Experimental: Part 1 Arm 1: Ruxolitinib + Siremadlin - Dose escalation of siremadlin added to existing stable dose of ruxolitinib

Experimental: Part 1 Arm 2: Ruxolitinib + Crizanlizumab - Safety run-in of crizanlizumab added to existing stable dose of ruxolitinib

Experimental: Part 1 Arm 3: Ruxolitinib + Sabatolimab - Safety run-in of Sabatolimab added to existing stable dose of ruxolitinib

Experimental: Part 2 Arm 1: Ruxolitinib + Siremadlin - Siremadlin added to existing stable dose of ruxolitinib

Experimental: Part 2 Arm 2: Ruxolitinib + Crizanlizumab - Crizanlizumab added to existing stable dose of ruxolitinib

Experimental: Part 2 Arm 3: Ruxolitinib + Sabatolimab - Sabatolimab added to existing stable dose of ruxolitinib

Active comparator: Part 2 Arm 6: Ruxolitinib monotherapy - Existing stable dose of ruxolitinib as control for Part 2

Experimental: Part 3 Arm 1: Ruxolitinib + Compound X - Compound from Part 2 (to be confirmed) added to existing stable dose of ruxolitinib

Experimental: Part 3 Arm 2: Ruxolitinib cessation - Compound from Part 2 added to existing stable dose of ruxolitinib for 3 cycles followed by compound monotherapy

Active comparator: Part 3 Arm 3: Ruxolitinib monotherapy - Existing stable dose of ruxolitinib as control for Part 3

Experimental: Part 1 Arm 4: Ruxolitinib + Rineterkib - Dose escalation of Rineterkib added to existing stable dose of ruxolitinib

Experimental: Part 1 Arm 5: Ruxolitinib + NIS793 - Safety run-in of NIS793 added to existing stable dose of ruxolitinib

Experimental: Part 2 Arm 4: Ruxolitinib + Rineterkib - Rineterkib added to existing stable dose of ruxolitinib

Experimental: Part 2 Arm 5: Ruxolitinib + NIS793 - NIS793 added to existing stable dose of ruxolitinib


Treatment: Drugs: Ruxolitinib
5 mg tablets for oral use

Treatment: Drugs: Siremadlin
10 mg, 20 mg, or 40 mg capsules for oral use

Treatment: Drugs: Crizanlizumab
100 mg/mL concentrate for infusion for intravenous use

Treatment: Drugs: Sabatolimab
100 mg/mL or 400 mg/4 mL concentrate for infusion for intravenous use

Treatment: Drugs: Rineterkib
100 mg capsule for oral use

Treatment: Drugs: NIS793
700 mg/7 mL concentrate for intravenous use
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Incidence of dose limiting toxicities within the first 2 cycles
Timepoint [1] 0 0
Baseline to the end of Cycle 2 (6 or 8 weeks)
Primary outcome [2] 0 0
Response rate at the end of cycle 6 or cycle 8
Timepoint [2] 0 0
Baseline to the end of Cycle 6 or 8 (24 weeks)
Secondary outcome [1] 0 0
Percentage of subjects achieving an improvement in hemoglobin level of = 1.5 g/dL from baseline
Timepoint [1] 0 0
Baseline to the end of Cycle 6 or 8 (24 weeks), and end of Cycle 12 or 16 (48 weeks)
Secondary outcome [2] 0 0
Percentage of subjects achieving an improvement in hemoglobin level of at least >= 2.0 g/dL from baseline
Timepoint [2] 0 0
Baseline to the end of Cycle 6 or 8 (24 weeks), and end of Cycle 12 or 16 (48 weeks)
Secondary outcome [3] 0 0
Change in spleen length from baseline
Timepoint [3] 0 0
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)
Secondary outcome [4] 0 0
Change in spleen volume from baseline
Timepoint [4] 0 0
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)
Secondary outcome [5] 0 0
Change in symptoms of MFSAF v4.0 from baseline
Timepoint [5] 0 0
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)
Secondary outcome [6] 0 0
Change in symptoms of EORTC QLQ-C30 from baseline
Timepoint [6] 0 0
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)
Secondary outcome [7] 0 0
Changes in symptoms in MFSAF v4.0 (Part 1) from baseline
Timepoint [7] 0 0
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)
Secondary outcome [8] 0 0
Progression free survival, per progressive splenomegaly, accelerated phase, deteriorating cytopenia, leukemic transformation or death from any cause
Timepoint [8] 0 0
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
Secondary outcome [9] 0 0
Percentage of subjects achieving an improvement in bone marrow fibrosis of = 1 grade from baseline
Timepoint [9] 0 0
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)
Secondary outcome [10] 0 0
Area under the Plasma Concentration versus Time Curve (AUC)
Timepoint [10] 0 0
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
Secondary outcome [11] 0 0
Maximum (peak) observed plasma drug concentration (Cmax)
Timepoint [11] 0 0
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
Secondary outcome [12] 0 0
Time to reach maximum (peak) plasma, blood, serum or other body fluid drug concentration after single dose administration (Tmax)
Timepoint [12] 0 0
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
Secondary outcome [13] 0 0
Concentration versus time profile
Timepoint [13] 0 0
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
Secondary outcome [14] 0 0
Presence and/or concentration of anti-drug antibody
Timepoint [14] 0 0
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

Eligibility
Key inclusion criteria
Core treatment phase

* 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
Minimum age
18 Years
Maximum age
100 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

* 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
26/09/2019
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
28/08/2024
Sample size
Target
Accrual to date
Final
45
Recruitment in Australia
Recruitment state(s)
SA,VIC
Recruitment hospital [1] 0 0
Novartis Investigative Site - Adelaide
Recruitment hospital [2] 0 0
Novartis Investigative Site - Melbourne
Recruitment postcode(s) [1] 0 0
5000 - Adelaide
Recruitment postcode(s) [2] 0 0
3000 - Melbourne
Recruitment postcode(s) [3] 0 0
3004 - Melbourne
Recruitment outside Australia
Country [1] 0 0
Canada
State/province [1] 0 0
Ontario
Country [2] 0 0
Denmark
State/province [2] 0 0
Copenhagen
Country [3] 0 0
Germany
State/province [3] 0 0
Baden Wuerttemberg
Country [4] 0 0
Germany
State/province [4] 0 0
Freiburg
Country [5] 0 0
Germany
State/province [5] 0 0
Greifswald
Country [6] 0 0
Germany
State/province [6] 0 0
Jena
Country [7] 0 0
Hungary
State/province [7] 0 0
Budapest
Country [8] 0 0
Italy
State/province [8] 0 0
FI
Country [9] 0 0
Netherlands
State/province [9] 0 0
Groningen
Country [10] 0 0
Russian Federation
State/province [10] 0 0
Moscow
Country [11] 0 0
Spain
State/province [11] 0 0
Castilla Y Leon
Country [12] 0 0
Spain
State/province [12] 0 0
Comunidad Valenciana
Country [13] 0 0
Spain
State/province [13] 0 0
Las Palmas de Gran Canaria
Country [14] 0 0
Spain
State/province [14] 0 0
Madrid
Country [15] 0 0
Sweden
State/province [15] 0 0
Stockholm
Country [16] 0 0
Switzerland
State/province [16] 0 0
St Gallen
Country [17] 0 0
Switzerland
State/province [17] 0 0
Zuerich
Country [18] 0 0
Turkey
State/province [18] 0 0
Kocaeli
Country [19] 0 0
United Kingdom
State/province [19] 0 0
London

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Novartis Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.
When will data be available (start and end dates)?
Available to whom?
Available for what types of analyses?
How or where can data be obtained?
IPD available at link: https://www.clinicalstudydatarequest.com


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT04097821