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

NCT02370706 | Completed Phase 1

• 2 other identifiers: CPIM447X2104C2014-003801-14
• Study Type: interventional
• Target: 15
• Locations: 8 countries
• Sites: 9

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.

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (7)

• Number of participants with adverse events/serious adverse events

  Approximately 27 months (end of study)

• Proportion of patients achieving ≥ 35% reduction in spleen volume by magnetic resonance imaging (MRI) at Week 24

  24 weeks

• Changes in ratio of mutant to wild type JAK2 alleles (i.e. allele burden)

  Approximately 27 months (end of study)

• Change in platelets, neutrophils, and hemoglobin

  Approximately 27 months (end of study)

• Change in bone marrow fibrosis and histomorphology

  Approximately 27 months (end of study)

Study Arms (6)

Dose Escalation Arm 1

EXPERIMENTAL

Drug: PIM447; Drug: Ruxolitinib

Dose Escalation Arm 2

EXPERIMENTAL

Drug: Ruxolitinib; Drug: LEE011

Dose Escalation Arm 3

EXPERIMENTAL

Drug: PIM447; Drug: Ruxolitinib; Drug: LEE011

Dose Expansion Arm 1

EXPERIMENTAL

Drug: PIM447; Drug: Ruxolitinib

Dose Expansion Arm 2

EXPERIMENTAL

Drug: Ruxolitinib; Drug: LEE011

Dose Expansion Arm 3

EXPERIMENTAL

Drug: PIM447; Drug: Ruxolitinib; Drug: LEE011

Interventions

PIM447 DRUG

pan-pim inhibitor

Dose Escalation Arm 1; Dose Escalation Arm 3; Dose Expansion Arm 1; Dose Expansion Arm 3

Ruxolitinib DRUG

JAK1/JAK2 inhibitor

Dose Escalation Arm 1; Dose Escalation Arm 2; Dose Escalation Arm 3; Dose Expansion Arm 1; Dose Expansion Arm 2; Dose Expansion Arm 3

LEE011 DRUG

CDK4/6 inhibitor

Dose Escalation Arm 2; Dose Escalation Arm 3; Dose Expansion Arm 2; Dose Expansion Arm 3

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (9)

Novartis Investigative Site

VIC, Melbourne, 3004, Australia

Location

Novartis Investigative Site

Toronto, Ontario, M5G 2M9, Canada

Location

Novartis Investigative Site

Villejuif, 94800, France

Location

Novartis Investigative Site

Mainz, 55131, Germany

Location

Novartis Investigative Site

Ulm, 89081, Germany

Location

Novartis Investigative Site

Florence, FI, 50134, Italy

Location

Novartis Investigative Site

Rotterdam, 3015 GD, Netherlands

Location

Novartis Investigative Site

Singapore, 119228, Singapore

Location

Novartis Investigative Site

London, SE1 9RT, United Kingdom

Location

Related Links

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

MeSH Terms

Conditions

Primary Myelofibrosis

Interventions

LGH-447; ruxolitinib; ribociclib

Condition Hierarchy (Ancestors)

Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: HEALTH SERVICES RESEARCH
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 6, 2015
• First Posted: February 25, 2015
• Study Start: May 21, 2015
• Primary Completion: November 9, 2020
• Study Completion: November 9, 2020
• Last Updated: February 9, 2022

Record last verified: 2022-02

Data Sharing

• IPD Sharing: Will not share

Locations

DE (2); CA (1); GB (1); FR (1); SG (1); NL (1); AU (1); IT (1)