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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/NCT02370706
Registration number
NCT02370706
Ethics application status
Date submitted
6/02/2015
Date registered
25/02/2015
Titles & IDs
Public title
Study of the Safety of PIM447 in Combination With Ruxolitinib (INC424) and LEE011 in Patients With Myelofibrosis
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Scientific title
A Phase Ib, Multi-center, Open-label, Dose-escalation Study of PIM447 in Combination With Ruxolitinib (INC424) and LEE011 Administered Orally in Patients With Myelofibrosis
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Secondary ID [1]
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2014-003801-14
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Secondary ID [2]
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CPIM447X2104C
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Myelofibrosis
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Condition category
Condition code
Musculoskeletal
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Other muscular and skeletal disorders
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Human Genetics and Inherited Disorders
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Other human genetics and inherited disorders
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Cancer
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0
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Leukaemia - Chronic leukaemia
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - PIM447
Treatment: Drugs - Ruxolitinib
Treatment: Drugs - LEE011
Experimental: Dose Escalation Arm 1 -
Experimental: Dose Escalation Arm 2 -
Experimental: Dose Escalation Arm 3 -
Experimental: Dose Expansion Arm 1 -
Experimental: Dose Expansion Arm 2 -
Experimental: Dose Expansion Arm 3 -
Treatment: Drugs: PIM447
pan-pim inhibitor
Treatment: Drugs: Ruxolitinib
JAK1/JAK2 inhibitor
Treatment: Drugs: LEE011
CDK4/6 inhibitor
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Incidence of dose limiting toxicities during the first cycle of study treatment
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Assessment method [1]
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To estimate the maximum tolerated dose and/or recommended dose for expansion for each of the following three treatment arms in patients with myelofibrosis (MF): PIM447 plus ruxolitinib (doublet), LEE011 plus ruxolitinib (doublet), PIM447 plus ruxolitinib and LEE 011 (triple combination).
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Timepoint [1]
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Cycle 1 (28 days)
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Secondary outcome [1]
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Number of participants with adverse events/serious adverse events
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Assessment method [1]
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Frequency and severity of adverse events (AEs), serious AEs (SAEs), changes in laboratory values, and electrocardiograms (ECGs), as a measure of safety and tolerability. Assessments consisted of recording all adverse events (AEs) and serious adverse events (SAEs), the regular monitoring of hematology, blood chemistry, urinalysis, and coagulation parameters, as well as electrocardiograms.
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Timepoint [1]
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Approximately 27 months (end of study)
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Secondary outcome [2]
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Proportion of patients achieving = 35% reduction in spleen volume by magnetic resonance imaging (MRI) at Week 24
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Assessment method [2]
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To assess preliminary anti-myelofibrosis activity of PIM447 plus ruxolitinib, LEE011 plus ruxolitinib, and the triple combination PIM447 plus ruxolitinib and LEE011.
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Timepoint [2]
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24 weeks
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Secondary outcome [3]
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Changes in ratio of mutant to wild type JAK2 alleles (i.e. allele burden)
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Assessment method [3]
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To assess preliminary anti-myelofibrosis activity of PIM447 plus ruxolitinib, LEE011 plus ruxolitinib, and the triple combination PIM447 plus ruxolitinib and LEE011.
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Timepoint [3]
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Approximately 27 months (end of study)
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Secondary outcome [4]
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Change in platelets, neutrophils, and hemoglobin
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Assessment method [4]
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To assess preliminary anti-myelofibrosis activity of PIM447 plus ruxolitinib, LEE011 plus ruxolitinib, and the triple combination PIM447 plus ruxolitinib and LEE011.
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Timepoint [4]
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Approximately 27 months (end of study)
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Secondary outcome [5]
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Change in bone marrow fibrosis and histomorphology
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Assessment method [5]
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To assess preliminary anti-myelofibrosis activity of PIM447 plus ruxolitinib, LEE011 plus ruxolitinib, and the triple combination PIM447 plus ruxolitinib and LEE011.
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Timepoint [5]
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Approximately 27 months (end of study)
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Secondary outcome [6]
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Determine single and multiple dose pharmacokinetics (PK) profiles
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Assessment method [6]
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Plasma concentration-time profiles of PIM447, ruxolitinib, and LEE011. PK parameters, including but not limited to Cmax, AUCinf, AUClast, AUCtau, T½, Tmax, accumulation ratio (Racc), CL/F, and Vz/F
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Timepoint [6]
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Approximately 12 months
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Secondary outcome [7]
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Change in spleen volume as measured by MRI from baseline
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Assessment method [7]
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To assess preliminary anti-myelofibrosis activity of PIM447 plus ruxolitinib, LEE011 plus ruxolitinib, and the triple combination PIM447 plus ruxolitinib and LEE011.
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Timepoint [7]
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Approximately 27 months (end of study)
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Eligibility
Key inclusion criteria
* Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
* Patient must be diagnosed with JAK2V617F-positive primary or secondary MF.
* Dose-escalation and Expansion parts: Patients with a < 35% reduction in spleen volume by MRI/CT or < 50% reduction in spleen size by physical exam, with or without corresponding symptomatic improvement, after at least 6 months of treatment with single agent ruxolitinib at an optimal dose level in line with the label recommendations. Expansion parts only: Ruxolitinib-naive patients and patients who have been previously treated with single agent ruxolitinib and are relapsed and/or refractory.
* Patients must have splenomegaly measuring at least 5 cm by MRI at baseline.
* Have adequate bone marrow function:
* Platelets = 100,000 mm3 without the assistance of growth factors or platelet transfusions
* Absolute Neutrophil Count (ANC) = 1500/mm3 without growth factor support within 7 days prior to testing
* Hemoglobin = 9 g/dL.
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
* Systemic antineoplastic therapy (including unconjugated therapeutic antibodies, toxin immunoconjugates, and alpha-interferon) or any experimental therapy within 14 days or 5 half-lives, whichever is shorter, before the first dose of study treatment
* Major surgery within 2 weeks before the first dose of either study drug.
* Patients who have had splenic irradiation within 2 weeks prior to Screening or prior splenectomy.
* Patients with AML, MDS, or peripheral blasts = 10 %
* Prior autologous or allogeneic stem cell transplant at any time.
* Patients who are currently receiving treatment with a prohibited medication that cannot be discontinued at least one week prior to the start of treatment:
* substrates of CYP3A4/5, CYP2B6 or CYP2D6 that have a narrow therapeutic window
* strong inhibitors of CYP3A4/5 or CYP2D6
* potent inducers of CYP3A4/5 or CYP2D6
* Serum total bilirubin > 1.5 x upper limit of normal (ULN) except in patients with Gilbert's syndrome who are excluded if the total bilirubin is > 3.0 x ULN or direct bilirubin > 1.5 x ULN, or aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) or ALT (SGPT) > 3 x ULN, except in patients with MF involvement of the liver who are excluded if AST or ALT > 5 x ULN.
* Serum creatinine > 1.5 x ULN or calculated creatinine clearance < 60 ml/min according to Cockcroft-Gault equation
* Electrolyte abnormalities CTCAE grade = 2 (e.g. serum potassium, magnesium and calcium) unless they can be repleted during screening and are deemed not clinically significant by the Investigator.
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Study design
Purpose of the study
Other
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Allocation to intervention
NA
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 1
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
21/05/2015
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
9/11/2020
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Sample size
Target
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Accrual to date
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Final
15
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Recruitment in Australia
Recruitment state(s)
Melbourn
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Recruitment hospital [1]
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Novartis Investigative Site - VIC
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Recruitment postcode(s) [1]
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3004 - VIC
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Recruitment outside Australia
Country [1]
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Canada
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State/province [1]
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Ontario
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Country [2]
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France
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State/province [2]
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Villejuif Cedex
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Country [3]
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Germany
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State/province [3]
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Mainz
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Country [4]
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Germany
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State/province [4]
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Ulm
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Country [5]
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Italy
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State/province [5]
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FI
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Country [6]
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Netherlands
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State/province [6]
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Rotterdam
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Country [7]
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Singapore
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State/province [7]
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Singapore
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Country [8]
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United Kingdom
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State/province [8]
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London
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Funding & Sponsors
Primary sponsor type
Commercial sector/industry
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Name
Novartis Pharmaceuticals
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
This is a phase Ib study with the primary purpose is to estimate the MTD and/or RDE for the triple combination of PIM447, formerly LGH447, plus ruxolitinib and LEE011 as well as for the doublets, PIM447 plus ruxolitinib, and LEE011 plus ruxolitinib, in patients with myelofibrosis (MF). Each regimen will be assessed for safety, tolerability, pharmacokinetics (PK) and pharmacodynamic effects, and preliminary anti-myelofibrosis activity, including changes in spleen volume, JAK2V617F allele burden, and hematologic response.
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Trial website
https://clinicaltrials.gov/study/NCT02370706
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Novartis Pharmaceuticals
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Address
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Novartis Pharmaceuticals
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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No/undecided IPD sharing reason/comment
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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/NCT02370706