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

Study Overview
=================
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.

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

Conditions
-----------------
AML and High Risk MDS

Intervention / Treatment
-----------------
* Drug: LGH447
* Drug: LGH447 + midostaurin


Participation Criteria
=================
Eligibility 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LGH447 monotherapy arm<br>LGH447 monotherapy in patients with AML or MDS | Drug: LGH447<br>* LGH447 in patients with AML or MDS<br>|
| Experimental: LGH447 + midostaurin combination arm<br>LGH447 + midostaurin in patients with AML | Drug: LGH447 + midostaurin<br>* LGH447 + midostaurin in patients with AML<br>|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
AML,, MDS,, PIM,, LGH447,, acute myelod leukemia,, myelodysplastic syndrome,, midostaurin,, PKC412