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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Completed

CT.gov ID

NCT02370706

Collaborator

(none)

Enrollment

Locations

Arms

65.7

Actual Duration (Months)

1.7

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Myelofibrosis	Drug: PIM447 Drug: Ruxolitinib Drug: LEE011	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

15 participants

Allocation:

N/A

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

Actual Study Start Date :

May 21, 2015

Actual Primary Completion Date :

Nov 9, 2020

Actual Study Completion Date :

Nov 9, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Incidence of dose limiting toxicities during the first cycle of study treatment [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 [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 [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) [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 [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 [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 [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 [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	VIC	Melbourne	Australia	3004
2	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 2M9
3	Novartis Investigative Site	Villejuif Cedex		France	94800
4	Novartis Investigative Site	Mainz		Germany	55131
5	Novartis Investigative Site	Ulm		Germany	89081
6	Novartis Investigative Site	Firenze	FI	Italy	50134
7	Novartis Investigative Site	Rotterdam		Netherlands	3015 GD
8	Novartis Investigative Site	Singapore		Singapore	119228
9	Novartis Investigative Site	London		United Kingdom	SE1 9RT