E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
patients ≥ 66 years.with a confirmed diagnosis of
o AML (not APL) (see appendix A) or
o refractory anemia with excess of blasts (RAEB) with an IPSS score ≥ 1.5
OR
Patients of any age ≥ 18 years with a confirmed diagnosis of
o AML with very poor risk AML
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E.1.1.1 | Medical condition in easily understood language |
Leukemia, cancer of bone marrow |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 15.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000886 |
E.1.2 | Term | Acute myeloid leukemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 15.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10037803 |
E.1.2 | Term | RAEB |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 15.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10000880 |
E.1.2 | Term | Acute myeloid leukaemia |
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 |
For part A of the study (if applicable):
1. To assess the safety and tolerability of tosedostat added to standard induction chemotherapy for AML (frequency and severity of toxicities and the durations of neutropenia and thrombocytopenia) and select the feasible dose level for part B
2. To assess in a randomized comparison the effect of tosedostat on the CR rate.
For part B:
1. To assess the safety and tolerability of tosedostat added to standard induction chemotherapy for AML (frequency and severity of toxicities and the durations of neutropenia and thrombocytopenia) as regards the selected dose level of tosedostat
2. To assess in a randomized comparison the effect of tosedostat on the CR rate.
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E.2.2 | Secondary objectives of the trial |
For part B:
1. To determine the efficacy profile (event free survival and disease free survival and overall survival) associated with the two therapy regimens.
2. To measure MRD by immunophenotyping in relation to clinical response parameters.
3. To identify potential biomarkers predictive of response, event free survival and disease free survival by exploratory proteomic and genomic analysis (microarray, gene mutations)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Patients eligible for standard chemotherapy.
- Patients ≥ 66 years.with a cytopathologically confirmed diagnosis according WHO classification of
o AML (not APL) (see appendix A) or
o refractory anemia with excess of blasts (RAEB) with an IPSS score ≥ 1.5
OR
- Patients of any age ≥ 18 years with cytopathologically confirmed diagnosis according WHO classification of
o AML with very poor risk AML
- Subjects with secondary AML progressing from antecedent (at least 4 months
duration) myelodysplasia are also eligible.
- SGOT (AST) and SGPT (ALT) <= 1.5 x the upper limit of the normal range (ULN) at the laboratory where the analyses were performed.
- Total serum bilirubin level <= 1.5 x the ULN at the laboratory where the analysis was
performed.
- Serum creatinine concentration <= 1.5 x the ULN at the laboratory where the
analysis was performed.
- WHO performance status ≤ 2
- Written informed consent.
- Female patients of childbearing potential must have a negative serum pregnancy
test within 2 weeks prior to enrollment.
- Male and female patients must use an effective contraceptive method during the
study and for a minimum of 6 months after study treatment.(see protocol appendix J for more information and specific requirements)
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E.4 | Principal exclusion criteria |
-Acute promyelocytic leukemia
- Patients previously treated for AML (any antileukemic therapy including
investigational agents), a short treatment period (< 2 weeks) with Hydroxyurea is
allowed
- Past or current history (within the last 2 years prior to randomization) of
malignancies except for the indication under this study and curatively treated:
- Basal and squamous cell carcinoma of the skin
- in situ carcinoma of the cervix
- Blast crisis of chronic myeloid leukemia
- Clinically significant (i.e. active) cardiovascular disease, for example cerebrovascular
accidents (≤ 6 months prior to randomization), myocardial infarction (≤ 6 months
prior to randomization), unstable angina, New York Heart Association (NYHA) grade
II or greater congestive heart failure,
- Patients with a history of non-compliance to medical regimens or who are
considered unreliable with respect to compliance
- Patients with any serious concomitant medical condition which could, in the opinion
of the investigator, compromise participation in the study.
- Patients who have senile dementia, mental impairment or any other psychiatric
disorder that prohibits the patient from understanding and giving informed consent.
- Pregnant or lactating patients.
- Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.
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E.5 End points |
E.5.1 | Primary end point(s) |
- Incidence of DLT (part A)
- The effect of tosedostat on the CR rate (part B of study)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The final analysis of the primary endpoints will be done one year after last patient is registered in the tosedostat arm. |
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E.5.2 | Secondary end point(s) |
1. To determine the efficacy profile (event free survival (EFS) disease free survival (DFS) and overall survival (OS)) associated with the two therapy regimens.
2. To measure MRD by immunophenotyping in relation to clinical response parameters.
3. To identify potential biomarkers predictive of response, EFS, DFS and OS by exploratory genomic analysis (microarray, gene mutations) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The final analysis of the secondary endpoints will be done one year after last patient is registered in the tosedostat arm. |
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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 | No |
E.6.7 | Pharmacodynamic | No |
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 | Yes |
E.8.1.1 | Randomised | Yes |
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 | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 16 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
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 | No |
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 |
Belgium |
Netherlands |
Norway |
Switzerland |
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E.8.7 | Trial has a data monitoring committee | No |
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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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 | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |