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

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ClinicalTrials.gov Identifier: NCT02078609
Recruitment Status : Recruiting
First Posted : March 5, 2014
Last Update Posted : June 19, 2018
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
AML and High Risk MDS Drug: LGH447 Drug: LGH447 + midostaurin Phase 1

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 86 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I, Multicenter, Open-label Study of Oral LGH447 in Patients With Acute Myeloid Leukemia or High Risk Myelodysplastic Syndrome
Actual Study Start Date : March 20, 2014
Estimated Primary Completion Date : September 3, 2019
Estimated Study Completion Date : September 3, 2019


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




Primary Outcome Measures :
  1. 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 [ Time Frame: 28 days post study treatment ]
    Frequency and characteristics of dose limiting toxicities


Secondary Outcome Measures :
  1. 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 [ Time Frame: weekly to bi-weekly up to 1.5 years ]
    Includes changes in hematology and blood chemistry values, assessments of physical examinations, vital signs, and electrocardiograms (ECGs)

  2. PK parameters of the LGH447 monotherapy arm in patients with AML or MDS and of the LGH447 + midostaurin treatment arm in patients with AML [ Time Frame: days 1, 2, 15, 16, 29, 30, 44, 57, and approximately monthly through Cycle 3 ]
    LGH447 and midostaurin plasma concentrations and basic PK parameters

  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 [ Time Frame: screening, days 1 and 29 up to 1.5 years ]
    Assess pharmacodynamic effects of LGH447

  4. Anti-tumor activity in AML or high risk MDS associated wtih LGH447 [ Time Frame: Day 29 up to 1.5 years ]
    To assess any preliminary anti-tumor activity in AML or high risk MDS associated with LGH447

  5. Anti-tumor activity in AML or high risk MDS associated wtih LGH447 in combination with midostaurin [ Time Frame: Day 29 up to 1.5 years ]
    To assess any preliminary anti-tumor activity in AML or high risk MDS associated with LGH447 in combination with midostaurin



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

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): NCT02078609


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

Locations
United States, Michigan
Novartis Investigative Site Recruiting
Ann Arbor, Michigan, United States, +1 48109 0944
Contact: Sabrina Pelton Hargrove    +1 734 936 8538    sgomes@med.umich.edu   
Principal Investigator: Dale Bixby         
United States, Texas
Novartis Investigative Site Recruiting
Houston, Texas, United States, 77030
Australia, Victoria
Novartis Investigative Site Recruiting
Prahran, Victoria, Australia, 3181
France
Novartis Investigative Site Completed
Marseille, France, 13273
Germany
Novartis Investigative Site Completed
Ulm, Germany, 89081
Italy
Novartis Investigative Site Recruiting
Milano, MI, Italy, 20132
Novartis Investigative Site Recruiting
Milano, MI, Italy, 20162
Novartis Investigative Site Recruiting
Roma, RM, Italy, 00133
Japan
Novartis Investigative Site Recruiting
Shinagawa-ku, Tokyo, Japan, 141 8625
Netherlands
Novartis Investigative Site Recruiting
Amsterdam, Netherlands, 1081 HV
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02078609     History of Changes
Other Study ID Numbers: CLGH447X2102
2013-003756-20 ( EudraCT Number )
First Posted: March 5, 2014    Key Record Dates
Last Update Posted: June 19, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
AML,
MDS,
PIM,
LGH447,
acute myelod leukemia,
myelodysplastic syndrome,
midostaurin,
PKC412

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Midostaurin
Staurosporine
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action