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

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.

Study Overview

• Status: Completed
• Conditions: Myelofibrosis
• Intervention / Treatment: Drug: PIM447; Drug: Ruxolitinib; Drug: LEE011

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Health Services Research
• Allocation: N/A
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Escalation Arm 1	Drug: PIM447; pan-pim inhibitor; Drug: Ruxolitinib; JAK1/JAK2 inhibitor
Experimental: Dose Escalation Arm 2	Drug: Ruxolitinib; JAK1/JAK2 inhibitor; Drug: LEE011; CDK4/6 inhibitor
Experimental: Dose Escalation Arm 3	Drug: PIM447; pan-pim inhibitor; Drug: Ruxolitinib; JAK1/JAK2 inhibitor; Drug: LEE011; CDK4/6 inhibitor
Experimental: Dose Expansion Arm 1	Drug: PIM447; pan-pim inhibitor; Drug: Ruxolitinib; JAK1/JAK2 inhibitor
Experimental: Dose Expansion Arm 2	Drug: Ruxolitinib; JAK1/JAK2 inhibitor; Drug: LEE011; CDK4/6 inhibitor
Experimental: Dose Expansion Arm 3	Drug: PIM447; pan-pim inhibitor; Drug: Ruxolitinib; JAK1/JAK2 inhibitor; Drug: LEE011; CDK4/6 inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)
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
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)
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)
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)
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
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)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): May 21, 2015
• Primary Completion (Actual): November 9, 2020
• Study Completion (Actual): November 9, 2020

Study Registration Dates

• First Submitted: February 6, 2015
• First Submitted That Met QC Criteria: February 18, 2015
• First Posted (Estimate): February 25, 2015

Study Record Updates

• Last Update Posted (Actual): February 9, 2022
• Last Update Submitted That Met QC Criteria: February 7, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: LEE011; INC424; JAK inhibitor; myelofibrosis; PMF; PET-MF; ruxolitinib; CDK 4/6 inhibitor; PIM447; LGH447; PIM inhibitor; Jakavi®; Jakafi®; INCB18424; PPV-MF
• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Primary Myelofibrosis
• Other Study ID Numbers: CPIM447X2104C; 2014-003801-14 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No