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

NCT02078609 | Completed Phase 1 FDA Drug

• 2 other identifiers: CLGH447X21022013-003756-20
• Study Type: interventional
• Target: 70
• Locations: 7 countries
• Sites: 9

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.

Conditions

AML and High Risk MDS

Keywords

AML,; MDS,; PIM,; LGH447,; acute myelod leukemia,; myelodysplastic syndrome,; midostaurin,; PKC412

Outcome Measures

Primary Outcomes (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

  Frequency and characteristics of dose limiting toxicities

  28 days post study treatment

Secondary Outcomes (5)

• 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

  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

  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

  screening, days 1 and 29 up to 1.5 years

• Anti-tumor activity in AML or high risk MDS associated wtih LGH447

  Day 29 up to 1.5 years

• Anti-tumor activity in AML or high risk MDS associated wtih LGH447 in combination with midostaurin

  Day 29 up to 1.5 years

Study Arms (2)

LGH447 monotherapy arm

EXPERIMENTAL

LGH447 monotherapy in patients with AML or MDS

Drug: LGH447

LGH447 + midostaurin combination arm

EXPERIMENTAL

LGH447 + midostaurin in patients with AML

Drug: LGH447 + midostaurin

Interventions

LGH447 DRUG

LGH447 in patients with AML or MDS

LGH447 monotherapy arm

LGH447 + midostaurin DRUG

LGH447 + midostaurin in patients with AML

LGH447 + midostaurin combination arm

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (9)

Novartis Investigative Site

Ann Arbor, Michigan, 48109, United States

Location

Novartis Investigative Site

Prahran, Victoria, 3181, Australia

Location

Novartis Investigative Site

Marseille, 13273, France

Location

Novartis Investigative Site

Ulm, 89081, Germany

Location

Novartis Investigative Site

Milan, MI, 20132, Italy

Location

Novartis Investigative Site

Milan, MI, 20162, Italy

Location

Novartis Investigative Site

Roma, RM, 00133, Italy

Location

Novartis Investigative Site

Shinagawa Ku, Tokyo, 141 8625, Japan

Location

Novartis Investigative Site

Amsterdam, 1081 HV, Netherlands

Location

Related Links

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

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Interventions

LGH-447; midostaurin

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 31, 2014
• First Posted: March 5, 2014
• Study Start: March 20, 2014
• Primary Completion: April 18, 2019
• Study Completion: April 18, 2019
• Last Updated: December 17, 2020

Record last verified: 2020-01

Data Sharing

• IPD Sharing: Will not share

Locations

JP (1); NL (1); FR (1); DE (1); IT (3); AU (1); US (1)