Clinical trial NCT02370706: Study of the Safety of PIM447 in Combination With Ruxolitinib (INC424) and LEE011 in Patients With Myelofibrosis
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Myelofibrosis
Keywords: PIM447
LGH447
PIM inhibitor
LEE011
CDK 4/6 inhibitor
ruxolitinib
INC424
Jakavi®
Jakafi®
INCB18424
JAK inhibitor
myelofibrosis
PMF
PPV-MF
PET-MF
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2015-02-25
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: PARALLEL
Primary purpose: HEALTH_SERVICES_RESEARCH

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.


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.

Primary outcomes:
measure: Incidence of dose limiting toxicities during the first cycle of study treatment
timeFrame: Cycle 1 (28 days)
Secondary outcomes:
measure: Number of participants with adverse events/serious adverse events
timeFrame: Approximately 27 months (end of study)
measure: Proportion of patients achieving ≥ 35% reduction in spleen volume by magnetic resonance imaging (MRI) at Week 24
timeFrame: 24 weeks
measure: Changes in ratio of mutant to wild type JAK2 alleles (i.e. allele burden)
timeFrame: Approximately 27 months (end of study)
measure: Change in platelets, neutrophils, and hemoglobin
timeFrame: Approximately 27 months (end of study)
measure: Change in bone marrow fibrosis and histomorphology
timeFrame: Approximately 27 months (end of study)
measure: Determine single and multiple dose pharmacokinetics (PK) profiles
timeFrame: Approximately 12 months
measure: Change in spleen volume as measured by MRI from baseline
timeFrame: Approximately 27 months (end of study)
Other outcomes:
Locations:
city: VIC
country: Australia
facility: Novartis Investigative Site
state: Melbourne
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Villejuif Cedex
country: France
facility: Novartis Investigative Site
city: Mainz
country: Germany
facility: Novartis Investigative Site
city: Ulm
country: Germany
facility: Novartis Investigative Site
city: Firenze
country: Italy
facility: Novartis Investigative Site
state: FI
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: