CML in chronic phase, accelerated phase or blast crisis, relapsed/refractory Ph+ ALL, systemic mastocytosis, or hypereosinophilic syndrome MedDRA version: 14.0 Level: LLT Classification code 10009700 Term: CML System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
Novartis Pharma AG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: •Patients must have the following laboratory values: Potassium = LLN (lower limit of normal) or correctable with supplements Total calcium (corrected for serum albumin) = LLN or correctable with supplements Magnesium = LLN or correctable with supplements Phosphorus = LLN or correctable with supplements ALT and AST = 2.5 x ULN or = 5.0 x ULN if considered due to tumor Alkaline phosphatase = 2.5 x ULN Serum bilirubin = 1.5 x ULN Serum creatinine = 1.5 x ULN or 24-hour creatinine clearance ? 50 ml/min Phase I •Patients with a cytopathologically confirmed diagnosis of Ph+ ALL who are either relapsed after or refractory to standard therapy, or patients with CML in BC, or CML patients in CP or AP who are resistant to Gleevec®. Patients with Ph+ ALL who have minimal residual disease following stem cell transplantation may only be enrolled during the dose escalation portion of the study. Phase II- CML 1. Imatinib resistant or intolerant Ph+ CML in blast crisis defined as at least 30% blasts in peripheral blood or bone marrow or extramedullary disease other than liver or spleen 2. Imatinib resistant or intolerant Ph+ CML patients in accelerated phase defined as never in blast crisis before starting treatment, with one or more of the following criteria present within 4 weeks prior to beginning treatment: • =15% but 15 mast cells in aggregates) in bone marrow biopsies and/or in sections of other extracutaneous organ(s). Minor Criteria: see protocol section 3.3.2.1.2 Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: •Cytopathologically confirmed CNS infiltration NB: in absence of suspicion of CNS involvement, lumbar puncture is not required •Impaired cardiac function, including any one of the following •LVEF 1mm in 2 or more leads and/or T wave inversions in 2 or more contiguous leads •Congenital long QT syndrome •History of or presence of significant ventricular or atrial tachyarrhythmias •Clinically significant resting bradycardia ( 480 msec (> 450 msec in Phase II) screening ECG (using the QTcF formula) •Right bundle branch block plus left anterior hemiblock, bifascicular block •Myocardial infarction within 3 months prior to starting AMN107 •Angina pectoris (unstable angina pectoris diagnosed or treated during the last 12 months in Phase II) •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) •Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of AMN107 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) •Use of therapeutic warfarin. •Acute or chronic liver or renal disease considered unrelated to tumor •Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes, active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol •Treatment with any hematopoietic colony-stimulating growth factors (e.g., G-CSF, GM-CSF) = 1 week prior to starting study drug. Erythropoietin is allowed. •Patients who are currently receiving treatment with any of the medications listed in Post-text supplement 4 and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug. The medications listed in Post-text supplement 4 have the potential to prolong the QT interval. •Patients who have received chemotherapy = 1 week (6 weeks for nitrosurea or mitomycin-C) or who are within 5 half-lives of their last dose chemotherapy dose prior to starting study drug or who have not recovered from side effects of such therapy. •Patients who have received Gleevec® = 1 week or who have not recovered from side effects of such therapy. •Patients who have received immunotherapy =1 week prior to starting study drug or who have not recovered from side effects of such therapy •Patients who have received any investigational drug = 4 weeks or investigational cytotoxic agent within 1 week (or who are within 5 half-lives of a previous investigational cytotoxic agent) prior to starting study drug or who have not recovered from side effects of such therapy •Patients who have received wide field radiotherapy = 4 weeks or limited field radiation for palliation < 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy •Patients who have undergone major surgery = 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy •Patients who are pregnant or breast feeding, or adults of reproductive potential not employing an effective method of birth control. (Women of childbearing potential must have a negative serum pregnancy test within
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase I •Determine the MTD and DLT of AMN107 as a single agent when administered as an oral once-daily dose or twice daily dose to adult patients with Gleevec-resistant CML in chronic phase, accelerated phase or blast crisis, or relapsed/refractory Ph+ ALL. •To characterize the PK profile in plasma and, where samples are available, in tumor cells and normal hematopoietic cells Phase II •To evaluate the efficacy and safety of AMN107 in patients with imatinib-resistant or intolerant CML-BC, imatinib-resistant or intolerant CML-AP and imatinib-resistant or intolerant CML-CP •To evaluate safety and preliminary anticancer activity of AMN107 in relapsed/refractory patients with Ph+ ALL and in patients with HEL/CEL and SM;Secondary Objective: Phase I •To characterize the safety and tolerability of AMN107 •To characterize the pharmacodynamic profile of AMN107 by assessing the following changes: - the mutational status of Abl - the Bcr-Abl, Stat 5,Stat 1,Crk-L, c-kit,PDGFR,AKT phosphorylation status - Crk-L analysis •For the other secondary objectives see protocol section 2.2.1 Phase II •To evaluate the population pharmacokinetics of AMN107 CML 1.To assess changes in Bcr-Abl transcript and Crk-L protein in malignant cells taken from the bone marrow and/or blood, and mutational analysis of Bcr-Abl 2.To examine whether individual genetic variation in genes relating to drug metabolism, CML and the drug pathway confer differential response to AMN107. 3.To identify gene expression patterns in tumor cells that are associated with treatment response to AMN107 or that correlate with the severity or progression of CML. For secondary objectives in ALL, HES/CEL and SM see protocol sections 2.2.2.2 and 2.2.3;Primary end point(s): Phase I: 1. Safety parameters, particulary dose limiting toxicity (DLT) during Cycle 1 2. Pharmacokinetic parameters (Tmax, Cmax, AUC0-24hours) Phase II Response rates as follows: Arm 1(Ph+ ALL) Hematological Response (Complete response | — |
Countries
Denmark, Finland, Italy, Spain, Sweden, United Kingdom
Outcome results
None listed