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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT02370706




Registration number
NCT02370706
Ethics application status
Date submitted
6/02/2015
Date registered
25/02/2015
Date last updated
9/02/2022

Titles & IDs
Public title
Study of the Safety of PIM447 in Combination With Ruxolitinib (INC424) and LEE011 in Patients With Myelofibrosis
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
Secondary ID [1] 0 0
2014-003801-14
Secondary ID [2] 0 0
CPIM447X2104C
Universal Trial Number (UTN)
Trial acronym
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 - 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
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Incidence of dose limiting toxicities during the first cycle of study treatment
Timepoint [1] 0 0
Cycle 1 (28 days)
Secondary outcome [1] 0 0
Number of participants with adverse events/serious adverse events
Timepoint [1] 0 0
Approximately 27 months (end of study)
Secondary outcome [2] 0 0
Proportion of patients achieving = 35% reduction in spleen volume by magnetic resonance imaging (MRI) at Week 24
Timepoint [2] 0 0
24 weeks
Secondary outcome [3] 0 0
Changes in ratio of mutant to wild type JAK2 alleles (i.e. allele burden)
Timepoint [3] 0 0
Approximately 27 months (end of study)
Secondary outcome [4] 0 0
Change in platelets, neutrophils, and hemoglobin
Timepoint [4] 0 0
Approximately 27 months (end of study)
Secondary outcome [5] 0 0
Change in bone marrow fibrosis and histomorphology
Timepoint [5] 0 0
Approximately 27 months (end of study)
Secondary outcome [6] 0 0
Determine single and multiple dose pharmacokinetics (PK) profiles
Timepoint [6] 0 0
Approximately 12 months
Secondary outcome [7] 0 0
Change in spleen volume as measured by MRI from baseline
Timepoint [7] 0 0
Approximately 27 months (end of study)

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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
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.

Study design
Purpose of the study
Health Services Research
Allocation to intervention
N/A
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
21/05/2015
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
9/11/2020
Sample size
Target
Accrual to date
Final
15
Recruitment in Australia
Recruitment state(s)
Melbourn
Recruitment hospital [1] 0 0
Novartis Investigative Site - VIC
Recruitment postcode(s) [1] 0 0
3004 - VIC
Recruitment outside Australia
Country [1] 0 0
Canada
State/province [1] 0 0
Ontario
Country [2] 0 0
France
State/province [2] 0 0
Villejuif Cedex
Country [3] 0 0
Germany
State/province [3] 0 0
Mainz
Country [4] 0 0
Germany
State/province [4] 0 0
Ulm
Country [5] 0 0
Italy
State/province [5] 0 0
FI
Country [6] 0 0
Netherlands
State/province [6] 0 0
Rotterdam
Country [7] 0 0
Singapore
State/province [7] 0 0
Singapore
Country [8] 0 0
United Kingdom
State/province [8] 0 0
London

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

Ethics approval
Ethics application status

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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT02370706
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



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT02370706