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Trial record 1 of 1 for:    NCT02370706
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Study of the Safety of PIM447 in Combination With Ruxolitinib (INC424) and LEE011 in Patients With Myelofibrosis

This study is currently recruiting participants.
Verified October 2017 by Novartis ( Novartis Pharmaceuticals )
Sponsor:
ClinicalTrials.gov Identifier:
NCT02370706
First Posted: February 25, 2015
Last Update Posted: October 10, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
  Purpose
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 Intervention Phase
Myelofibrosis Drug: PIM447 Drug: Ruxolitinib Drug: LEE011 Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Health Services Research
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

Resource links provided by NLM:


Further study details as provided by Novartis ( Novartis Pharmaceuticals ):

Primary Outcome Measures:
  • Incidence of dose limiting toxicities during the first cycle of study treatment [ Time Frame: Cycle 1 (28 days) ]
    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).


Secondary Outcome Measures:
  • Number of participants with adverse events/serious adverse events [ Time Frame: Approximately 27 months (end of study) ]
    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.

  • Proportion of patients achieving ≥ 35% reduction in spleen volume by magnetic resonance imaging (MRI) at Week 24 [ Time Frame: 24 weeks ]
    To assess preliminary anti-myelofibrosis activity of PIM447 plus ruxolitinib, LEE011 plus ruxolitinib, and the triple combination PIM447 plus ruxolitinib and LEE011.

  • Changes in ratio of mutant to wild type JAK2 alleles (i.e. allele burden) [ Time Frame: Approximately 27 months (end of study) ]
    To assess preliminary anti-myelofibrosis activity of PIM447 plus ruxolitinib, LEE011 plus ruxolitinib, and the triple combination PIM447 plus ruxolitinib and LEE011.

  • Change in platelets, neutrophils, and hemoglobin [ Time Frame: Approximately 27 months (end of study) ]
    To assess preliminary anti-myelofibrosis activity of PIM447 plus ruxolitinib, LEE011 plus ruxolitinib, and the triple combination PIM447 plus ruxolitinib and LEE011.

  • Change in bone marrow fibrosis and histomorphology [ Time Frame: Approximately 27 months (end of study) ]
    To assess preliminary anti-myelofibrosis activity of PIM447 plus ruxolitinib, LEE011 plus ruxolitinib, and the triple combination PIM447 plus ruxolitinib and LEE011.

  • Determine single and multiple dose pharmacokinetics (PK) profiles [ Time Frame: Approximately 12 months ]
    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

  • Change in spleen volume as measured by MRI from baseline [ Time Frame: Approximately 27 months (end of study) ]
    To assess preliminary anti-myelofibrosis activity of PIM447 plus ruxolitinib, LEE011 plus ruxolitinib, and the triple combination PIM447 plus ruxolitinib and LEE011.


Estimated Enrollment: 92
Actual Study Start Date: May 21, 2015
Estimated Study Completion Date: July 26, 2018
Estimated Primary Completion Date: December 29, 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02370706


Contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682 Novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

Locations
Australia, Melbourne
Novartis Investigative Site Recruiting
VIC, Melbourne, Australia, 3004
Canada, Ontario
Novartis Investigative Site Completed
Toronto, Ontario, Canada, M5G 2M9
Canada, Quebec
Novartis Investigative Site Recruiting
Montreal, Quebec, Canada, H3T 1E2
France
Novartis Investigative Site Recruiting
Paris, France, 75010
Novartis Investigative Site Active, not recruiting
Villejuif Cedex, France, 94805
Germany
Novartis Investigative Site Recruiting
Mainz, Germany, 55131
Novartis Investigative Site Recruiting
Ulm, Germany, 89081
Italy
Novartis Investigative Site Recruiting
Firenze, FI, Italy, 50134
Netherlands
Novartis Investigative Site Active, not recruiting
Rotterdam, Netherlands, 3015 CE
Singapore
Novartis Investigative Site Recruiting
Singapore, Singapore, 119228
Spain
Novartis Investigative Site Recruiting
Barcelona, Catalunya, Spain, 08036
United Kingdom
Novartis Investigative Site Recruiting
London, United Kingdom, SE1 9RT
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02370706     History of Changes
Other Study ID Numbers: CPIM447X2104C
2014-003801-14 ( EudraCT Number )
First Submitted: February 6, 2015
First Posted: February 25, 2015
Last Update Posted: October 10, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
PIM447
LGH447
PIM inhibitor
LEE011
CDK 4/6 inhibitor
ruxolitinib
INC424
Jakavi®
Jakafi®
INCB18424
JAK inhibitor
myelofibrosis
PMF
PPV-MF
PET-MF

Additional relevant MeSH terms:
Primary Myelofibrosis
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases