Combination of Nilotinib (AMN107) and RAD001 in Patients With Acute Myeloid Leukemia

August 7, 2012 updated by: Technical University of Munich

An Open-label Phase I/II (Proof of Concept) Trial of an Combination of Nilotinib (AMN 107) and RAD001 in Patients With Acute Myeloid Leukemia

This is a nonrandomized, open-label study to evaluate the efficacy and safety of combination treatment of Nilotinib and RAD001 in the treatment of c-kit + AML. Patients refractory to standard chemotherapy or not eligible to standard chemotherapy can be included. Patients will be treated with 400 mg Nilotinib bid (total daily dose 800 mg). RAD001 will be added after a treatment duration of 1 week in a dosage of 2,5 mg/day. Treatment duration will be 25 weeks.

Study Overview

Status

Completed

Conditions

Acute Myeloid Leukemia

Intervention / Treatment

Study Type

Interventional

Enrollment (Anticipated)

Phase

Phase 2
Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Germany
- Bavaria
  - Munich, Bavaria, Germany, 81675
    - Medical faculty of the Technical University Munich

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Genders Eligible for Study

All

Description

Inclusion criteria:

Patients with:
- De novo AML or secondary AML from MDS who are not candidates for myelosuppressive chemotherapy, or
- De novo AML or secondary AML from MDS who have relapsed disease or are refractory to standard therapy
Patients at least 18 years or older
Patients with WHO performance status of 0 to 2 with a life expectancy under treatment of at least 3 months
Patients must have recovered from prior cytotoxic chemotherapy; treatment with Hydroxyurea or Ara-C is allowed until 24 hours to first administration of study drug.
Patients must have a serum creatinine of <= 1.5 x ULN, SGOT/SGPT <= 3 x ULN and total bilirubin <= 2.0 x ULN
Female patients of childbearing potential must have negative pregnancy test within 7 days before initiation of study drug dosing. Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential.
Written informed consent obtained according to local guidelines

Exclusion criteria:

Patients with AML FAB M3.
Patients with an expected doubling of the peripheral blast within one week.
Patients who had prior allogeneic, syngeneic, or autologous bone marrow transplant or stem cell transplant less than 2 months previously.
Impaired cardiac function, including any one of the following:
- LVEF < 45% or below the institutional lower limit of the normal range (whichever is higher) as determined by MUGA scan or echocardiogram
- Complete left bundle branch block
- Use of a cardiac pacemaker
- ST depression of > 1mm in 2 or more leads and/or T wave inversions in 2 or more contiguous leads
- Congenital long QT syndrome dose levels of 400 to 1200 mg QD. Many of the common adverse events reported in the imatinib Phase II leukemia (STI0106, STI0110) studies were also reported in the nilotinib Phase I study, although a notably lower frequency of peripheral edema was identified in the nilotinib study.
- History of or presence of significant ventricular or atrial tachyarrhythmias
- Clinically significant resting bradycardia (< 50 beats per minute)
- QTc > 450 msec on screening ECG (using the QTcF formula)
- QT prolonging concomitant medication
- Right bundle branch block plus left anterior hemiblock, bifascicular block
- Myocardial infarction within 12 months prior to starting Nilotinib
- Unstable angina diagnosed or treated during the past 12 months
- Other clinically significant heart disease (e.g., congestive heart failure, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)
Female patients who are pregnant or breast feeding, or adults of childbearing age not employing an effective method of birth control.
Concurrent severe and/or uncontrolled medical or psychiatric condition which may interfere with the completion of the study.
Patients who had more than 2 prior regimens for their current relapsed or current primary refractory disease
Patients with uncontrolled active infection.
Patient with any pulmonary infiltrate on the baseline chest X-ray known to be new in the previous 4 weeks. Prior treatment with any investigational drug within the preceding 4 weeks
Chronic treatment with systemic steroids or another immunosuppressive agent
Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases
Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin.
Other concurrent severe and/or uncontrolled medical disease which could compromise participation in the study (i.e., uncontrolled diabetes, uncontrolled hypertension, severe infection, severe malnutrition, unstable angina, or congestive heart failure - New York Heart Association Class III or IV, ventricular arrhythmias active ischemic heart disease, myocardial infarction within six months, chronic liver or renal disease, active upper GI tract ulceration)
A known history of HIV seropositivity
Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)
Patients with an active, bleeding diathesis or on oral anti-vitamin K medication (except low dose coumarin)
Hypokalemia
Women who are pregnant or breast feeding, or women able to conceive and unwilling to practice an highly effective method of birth control.
Patients who have received prior treatment with an mTor inhibitor.
History of noncompliance to medical regimens
Patients unwilling to or unable to comply with the protocol

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To determine the rate of hematological response in adult patients with c-kit + AML. state the primary objective of the study Time Frame: four years	four years

Secondary Outcome Measures

Outcome Measure	Time Frame
To determine the duration of hematological response. To evaluate overall survival. To evaluate the safety profile of a combination treatment of Nilotinib and RAD001. • To evaluate improvement of symptomatic parameters. • To assess mTor, cKit a Time Frame: four years	four years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Technical University of Munich

Investigators

Principal Investigator: Justus Prof. Duyster, MD, Medical faculty of the Technical University Munich

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 2007

Primary Completion (Actual)

June 1, 2012

Study Registration Dates

First Submitted

September 29, 2008

First Submitted That Met QC Criteria