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

Myelofibrosis Clinical Trial

Official 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02370706
• Other study ID #: CPIM447X2104C
• Secondary ID: 2014-003801-14
• Status: Completed
• Phase: Phase 1
• Start date: May 21, 2015
• Est. completion date: November 9, 2020

Study information

• Verified date: February 2022
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: November 9, 2020
• Est. primary completion date: November 9, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Myelofibrosis
• Primary Myelofibrosis

Intervention

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

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	VIC	Melbourne
Canada	Novartis Investigative Site	Toronto	Ontario
France	Novartis Investigative Site	Villejuif Cedex
Germany	Novartis Investigative Site	Mainz
Germany	Novartis Investigative Site	Ulm
Italy	Novartis Investigative Site	Firenze	FI
Netherlands	Novartis Investigative Site	Rotterdam
Singapore	Novartis Investigative Site	Singapore
United Kingdom	Novartis Investigative Site	London

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

Australia,  Canada,  France,  Germany,  Italy,  Netherlands,  Singapore,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of dose limiting toxicities during the first cycle of study treatment	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).	Cycle 1 (28 days)
Secondary	Number of participants with adverse events/serious adverse events	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.	Approximately 27 months (end of study)
Secondary	Proportion of patients achieving = 35% reduction in spleen volume by magnetic resonance imaging (MRI) at Week 24	To assess preliminary anti-myelofibrosis activity of PIM447 plus ruxolitinib, LEE011 plus ruxolitinib, and the triple combination PIM447 plus ruxolitinib and LEE011.	24 weeks
Secondary	Changes in ratio of mutant to wild type JAK2 alleles (i.e. allele burden)	To assess preliminary anti-myelofibrosis activity of PIM447 plus ruxolitinib, LEE011 plus ruxolitinib, and the triple combination PIM447 plus ruxolitinib and LEE011.	Approximately 27 months (end of study)
Secondary	Change in platelets, neutrophils, and hemoglobin	To assess preliminary anti-myelofibrosis activity of PIM447 plus ruxolitinib, LEE011 plus ruxolitinib, and the triple combination PIM447 plus ruxolitinib and LEE011.	Approximately 27 months (end of study)
Secondary	Change in bone marrow fibrosis and histomorphology	To assess preliminary anti-myelofibrosis activity of PIM447 plus ruxolitinib, LEE011 plus ruxolitinib, and the triple combination PIM447 plus ruxolitinib and LEE011.	Approximately 27 months (end of study)
Secondary	Determine single and multiple dose pharmacokinetics (PK) profiles	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	Approximately 12 months
Secondary	Change in spleen volume as measured by MRI from baseline	To assess preliminary anti-myelofibrosis activity of PIM447 plus ruxolitinib, LEE011 plus ruxolitinib, and the triple combination PIM447 plus ruxolitinib and LEE011.	Approximately 27 months (end of study)

External Links

•   Results for CPIM447X2104C can be found on the Novartis Clinical Trial Results Website.