Study of the Safety of PIM447 in Combination With Ruxolitinib (INC424) and LEE011 in Patients With Myelofibrosis

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

ClinicalTrials.gov Identifier: NCT02370706

Novartis Reference Number: CPIM447X2104C

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All compounds are either investigational or being studied for (a) new use(s). Efficacy and safety have not been established. There is no guarantee that they will become commercially available for the use(s) under investigation. 

Study Description

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.

Condition 
Myelofibrosis
Phase 
Phase 1
Overall status 
Active, not recruiting
Enrollment count 
15 participants
Start date 
May 21, 2015
Completion date 
Oct 14, 2020
Gender 
All
Age(s)
18 Years and older (Adult, Older Adult)

Interventions

Drug
PIM447
pan-pim inhibitor
Drug
Ruxolitinib
JAK1/JAK2 inhibitor
Drug
LEE011
CDK4/6 inhibitor

Eligibility Criteria

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.

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 Locations

Australia
Novartis Investigative Site
-
VIC, 3004
Melbourne
Australia
Canada
Novartis Investigative Site
-
Toronto, M5G 2M9
Ontario
Canada
France
Novartis Investigative Site
-
Villejuif Cedex, 94800
-
France
Germany
Novartis Investigative Site
-
Mainz, 55131
-
Germany
Novartis Investigative Site
-
Ulm, 89081
-
Germany
Italy
Novartis Investigative Site
-
Firenze, 50134
FI
Italy
Netherlands
Novartis Investigative Site
-
Rotterdam, 3015 GD
-
Netherlands
Singapore
Novartis Investigative Site
-
Singapore, 119228
-
Singapore
United Kingdom
Novartis Investigative Site
-
London, SE1 9RT
-
United Kingdom

Have a question?

Call 1-999-669-6682 or email [email protected]