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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Completed

CT.gov ID

NCT02078609

Collaborator

(none)

Enrollment

Locations

Arms

60.9

Actual Duration (Months)

7.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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 Design

Study Type:

Interventional

Actual Enrollment :

70 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 :

Mar 20, 2014

Actual Primary Completion Date :

Apr 18, 2019

Actual Study Completion Date :

Apr 18, 2019

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

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 [28 days post study treatment]
Frequency and characteristics of dose limiting toxicities

Secondary Outcome Measures

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]
Includes changes in hematology and blood chemistry values, assessments of physical examinations, vital signs, and electrocardiograms (ECGs)
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]
LGH447 and midostaurin plasma concentrations and basic PK parameters
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]
Assess pharmacodynamic effects of LGH447
Anti-tumor activity in AML or high risk MDS associated wtih LGH447 [Day 29 up to 1.5 years]
To assess any preliminary anti-tumor activity in AML or high risk MDS associated with LGH447
Anti-tumor activity in AML or high risk MDS associated wtih LGH447 in combination with midostaurin [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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Ann Arbor	Michigan	United States	48109
2	Novartis Investigative Site	Prahran	Victoria	Australia	3181
3	Novartis Investigative Site	Marseille		France	13273
4	Novartis Investigative Site	Ulm		Germany	89081
5	Novartis Investigative Site	Milano	MI	Italy	20132
6	Novartis Investigative Site	Milano	MI	Italy	20162
7	Novartis Investigative Site	Roma	RM	Italy	00133
8	Novartis Investigative Site	Shinagawa ku	Tokyo	Japan	141 8625
9	Novartis Investigative Site	Amsterdam		Netherlands	1081 HV