A Safety and Efficacy Study of LGH447 in Patients With Acute Myeloid Leukemia (AML) or High Risk Myelodysplastic Syndrome (MDS)

A Phase I, Multicenter, Open-label Study of Oral LGH447 in Patients With Acute Myeloid Leukemia or High Risk Myelodysplastic Syndrome

This study will assess the safety and preliminary efficacy of escalating doses of LGH447 monotherapy in AML and MDS and LGH447 in combination with midostaurin in AML.

Study Overview

• Status: Completed
• Conditions: AML and High Risk MDS
• Intervention / Treatment: Drug: LGH447; Drug: LGH447 + midostaurin

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Prahran, Victoria, Australia, 3181
      • Novartis Investigative Site
• France
  • Marseille, France, 13273
    • Novartis Investigative Site
• Germany
  • Ulm, Germany, 89081
    • Novartis Investigative Site
• Italy
  • MI
    • Milano, MI, Italy, 20162
      • Novartis Investigative Site
    • Milano, MI, Italy, 20132
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00133
      • Novartis Investigative Site
• Japan
  • Tokyo
    • Shinagawa ku, Tokyo, Japan, 141 8625
      • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • Novartis Investigative Site
• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • 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

-Male or female patients ≥18 years of age who present with one of the following:

LGH447 monotherapy arm

• Refractory/Relapsed AML following no more than 2 prior therapies, or in previously untreated AML patients who are not candidates for standard therapy.
• High and very high risk MDS according to the revised International Prognostic Scoring System (rIPSS) who have failed prior therapies, such as azacitidine and decitabine
• Patients with rIPSS score of > 4.5

LGH447 and midostaurin combination arm

• Refractory/Relapsed AML following no more than 2 prior therapies, or in previously untreated AML patients who are not candidates for standard therapy. AML patients may have either FLT3 wild type or FLT3-ITD/TKD mutant disease, and FLT3 mutation status needs to be defined at study entry.

  • For AML patients, peripheral blast counts < 50,000 blasts/mm3
  • For MDS patients;
• Platelet count > 25,000/mm3
• Neutrophils > 500/mm3

• Blood transfusions are allowed to maintain clinically adequate hemoglobin and hematocrit levels

  • Patients with active central nervous system (CNS) disease are eligible to participate and may be treated concurrently with intrathecal (or intra Ommaya) chemotherapy
  • Patients who are maintained on prophylactic antibiotics are eligible to participate as long as agents comply with the list of approved concomitant medications
  • Performance status ≤ 2
  • Meet other lab criteria

Exclusion Criteria

• Systemic antineoplastic therapy (including unconjugated therapeutic antibodies and toxin immunoconjugates) or any experimental therapy within 7 days or 5 half-lives, whichever is longer, before the first dose of LGH447 monotherapy or LGH447 in combination with midostaurin
• Radiotherapy with a wide field of radiation within 28 days or radiotherapy with a limited field of radiation for palliation within 7 days of the first dose of LGH447 monotherapy or LGH447 in combination with midostaurin
• Patients who received CNS irradiation for meningeal leukemia, except if radiotherapy occurred > 3 months previously
• Major surgery within 4 weeks before the first dose of LGH447 monotherapy or LGH447 in combination with midostaurin
• Ongoing therapy with corticosteroids greater than 10 mg of prednisone or its equivalent per day. Inhaled and topical steroids are permitted
• Patients who are currently receiving hydroxyurea to control peripheral blood leukemic blasts and cannot be discontinued for at least 48 hours prior to obtaining PD biomarkers at screening/baseline and during the study
• Patients who are currently receiving treatment with prohibited medication and that cannot be discontinued at least one week prior to the start of treatment with LGH447 monotherapy or LGH447 in combination with midostaurin
• Active infection requiring systemic therapy or other severe infection, including pneumonia, within 2 weeks before the first dose of LGH447 monotherapy or LGH447 in combination with midostaurin
• Known human immunodeficiency virus (HIV) positive
• Corrected QT interval (QTc) of > 450 milliseconds (ms) in males and > 470 milliseconds (ms) in females on baseline electrocardiogram (ECG) (using corrected QT interval using Fridericia [QTcF] or local standards).
• Uncontrolled cardiovascular condition, including ongoing cardiac arrhythmias, congestive heart failure, angina, or myocardial infarction within the past 6 months
• Pregnant or nursing

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LGH447 monotherapy arm; LGH447 monotherapy in patients with AML or MDS	Drug: LGH447; LGH447 in patients with AML or MDS
Experimental: LGH447 + midostaurin combination arm; LGH447 + midostaurin in patients with AML	Drug: LGH447 + midostaurin; LGH447 + midostaurin in patients with AML

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence rate of dose limiting toxicities (DLTs) of LGH447 monotherapy arm in patients with AML or MDS and of LGH447 + midostaurin in patients with AML	Frequency and characteristics of dose limiting toxicities	28 days post study treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with the type, frequency, and severity of adverse events (AEs) as a measure of safety and tolerability of the LGH447 monotherapy arm in patients with AML or MDS and of the LGH447 + midostaurin treatment arm in patients with AML	Includes changes in hematology and blood chemistry values, assessments of physical examinations, vital signs, and electrocardiograms (ECGs)	weekly to bi-weekly up to 1.5 years
PK parameters of the LGH447 monotherapy arm in patients with AML or MDS and of the LGH447 + midostaurin treatment arm in patients with AML	LGH447 and midostaurin plasma concentrations and basic PK parameters	days 1, 2, 15, 16, 29, 30, 44, 57, and approximately monthly through Cycle 3
Changes between pre- and post-treatment levels of pS6RP and p4EBP1 in bone marrow aspirates and p4EBP1 in peripheral blood of the LGH447 monotherapy arm in patients with AML or MDS and of the LGH447 + midostaurin treatment arm in patients with AML	Assess pharmacodynamic effects of LGH447	screening, days 1 and 29 up to 1.5 years
Anti-tumor activity in AML or high risk MDS associated wtih LGH447	To assess any preliminary anti-tumor activity in AML or high risk MDS associated with LGH447	Day 29 up to 1.5 years
Anti-tumor activity in AML or high risk MDS associated wtih LGH447 in combination with midostaurin	To assess any preliminary anti-tumor activity in AML or high risk MDS associated with LGH447 in combination with midostaurin	Day 29 up to 1.5 years

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• Results for CLGH447X2102 can be found on the Novartis Clinical Trial Results Website

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2014
• Primary Completion (Actual): April 18, 2019
• Study Completion (Actual): April 18, 2019

Study Registration Dates

• First Submitted: January 31, 2014
• First Submitted That Met QC Criteria: March 3, 2014
• First Posted (Estimate): March 5, 2014

Study Record Updates

• Last Update Posted (Actual): December 17, 2020
• Last Update Submitted That Met QC Criteria: December 16, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: AML,; MDS,; PIM,; LGH447,; acute myelod leukemia,; myelodysplastic syndrome,; midostaurin,; PKC412
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Leukemia, Myeloid; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid, Acute; Preleukemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Midostaurin
• Other Study ID Numbers: CLGH447X2102; 2013-003756-20 (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: Yes
• Studies a U.S. FDA-regulated device product: No