| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| CML in chronic phase, accelerated phase or blast crisis, relapsed/refractory Ph+ ALL, systemic mastocytosis, or hypereosinophilic syndrome |
|
| MedDRA Classification |
| 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 |
|
| 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 phosphorylation status
- Stat 5 analysis/Stat 1 analysis
- 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 |
|
| 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
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 <30% blasts in blood or bone marrow
• ≥30% blasts plus promyelocytes in peripheral blood or bone marrow (providing that <30% blasts present in bone marrow)
• peripheral basophils ≥20%
• thrombocytopenia <100 X 109 /L unrelated to therapy
3. Imatinib resistant or intolerant Ph+ CML in chronic phase defined as never in blast crisis or accelerated phase before starting treatment and the presence of the following criteria:
• < 15% blasts in peripheral blood and bone marrow
• < 30% blasts plus promyelocytes in peripheral blood and bone marrow
• < 20% basophils in the peripheral blood
• ≥ 100 x 109 /L (≥ 100,000 /mm3) platelets
• No evidence of extramedullary leukemic involvement, with the exception of liver or spleen
Phase II: Relapsed or refractory Ph+ ALL
•Patients with Ph+ ALL who have minimal residual disease (MRD) are eligible only if there is indication of evolving relapse defined as a ≥ 2 log increase of Bcr-Abl transcript level (as reported by local laboratories), as compared to the minimum level achieved with prior therapy in peripheral blood
•Patients with Ph+ALL whose disease exhibits features of biphenotypic acute leukemia are eligible
Phase II: Hypereosinophilic syndrome/chronic eosinophilic leukemia
• eosinophilia greater than 1500/mm3 for at least 6 months
• exclusion of other causes of eosinophilia including clonal or abnormal T-cell populations, exclusion of reactive eosinophilia, and malignancies or T-cell disorders associated with eosinophilia
• signs and symptoms of organ involvement
Phase II: Systemic mastocytosis who have a clinical indication for treatment and meet at least one major and one minor or three minor criteria (
Major criterion: Multifocal dense infiltrates of mast cells (>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
|
|
| 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 on 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
•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 48 hrs prior to administration of AMN107). Post menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Male and female patients must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug
•Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory)
•Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention.
•Patients unwilling or unable to comply with the protocol
|
|
| 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 |
|
| 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 | Information not present in EudraCT |
| 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 |
|
| 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
|
| Last visit of last subject |
|
| 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 |
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