E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
CML in accelerated or chronic phase or blast crisis, relapsed/refractory Ph+ ALL, systemic mastocytosis, or hypereosinophilic syndrome. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10009700 |
E.1.2 | Term | CML |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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
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E.2.2 | Secondary objectives of the trial |
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
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal 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
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E.4 | Principal 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 < 45% 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
•History of or presence of significant ventricular or atrial tachyarrhythmias
•Clinically significant resting bradycardia (< 50 beats per minute)
•QTc > 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.
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E.5 End points |
E.5.1 | 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 + Partial response [CR + PR])
Arm 2 (CML-BC) Complete Hematologic Response and Major (Complete or Partial) Cytogenetic Response
Arm 3 (CML-AP) Complete Hematologic Response and Major (Complete or Partial) Cytogenetic Response
Arm 4 (CML-CP) Major Cytogenetic Response
Arm 5 (HES/CEL) Complete response + Partial response [CR + PR]
Arm 6 (SM) All categories of response better than stable disease, ie, complete remission, incomplete remission, pure clinical response, good partial response and minor response
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The extension protocol will allow patients to continue to receive AMN107 until their end-of-study evaluation visit which is to occur no later than 30-Nov-2011 defined as the LPLV and last dose of study drug in the extension study, or as long as they remain on study, until either death, the development of intolerable toxicity or the investigator feels it is no longer in the patient's best interest to continue therapy, whichever comes first. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |