E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
The scope of this study is the treatment of patient acute myeloid leukaemia. |
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E.1.1.1 | Medical condition in easily understood language |
The scope of this study is the treatment of patient acute myeloid leukaemia. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
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 |
Phase I part: To determine the maximal tolerated dose (MTD) of F14512 administered as a three-hour daily infusion given for 5 consecutive days in combination with cytarabine 1 g/m²/day for 5 consecutive days in patients 60 years old or older with refractory or relapsing AML.
Phase II part: To evaluate the efficacy of F14512 in combination with cytarabine (rate of CR and CRi) in AML patients 60 years old and older in first relapse or with refractory disease.
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E.2.2 | Secondary objectives of the trial |
Phase I part: - To determine the recommended dose (RD) of F14512 in combination with cytarabine to be used in the Phase II part, - To assess the safety of F14512, - To assess the molecular, biologic and clinical effects of F14512 in combination with cytarabine, - To assess the pharmacokinetics of F14512 in combination with cytarabine.
Phase II part: - To extend the evaluation of safety at the RD, - To assess Relapse-Free Survival, Progression-Free Survival, remission duration and Overall Survival, - To assess the molecular, biologic and clinical effects of F14512 in combination with cytarabine, - To assess the pharmacokinetics of F14512 in combination with cytarabine at recommended dose.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients must satisfy all the following inclusion criteria before they are allowed to participate in the study:
- Cytogenetically and molecularly characterized AML according to WHO classification (excluding acute promyelocytic leukemia),
- De novo or secondary AML arising from myelodysplastic syndrome or myeloproliferative syndrome or therapy-related (if the patient is cancer-free for at least 3 years excluding non-melanoma skin cancer) who meets the following criteria:
Phase I part: -Refractory AML after failure of one induction chemotherapy regimen or who had recurrence of disease < 3 months after CR, -Relapsed AML: recurrence of disease superior or equal to 3 months after CR,
Phase II part: - Refractory AML after failure of one induction chemotherapy regimen or who had recurrence of disease < 3 months after CR. - First relapse after a first CR or CRi lasting at least 3 months but less than 24 months
- 60 years of age or older, - WHO performance status inferior or equal to 2, - Adequate liver function tests defined as total bilirubin inferior or equal Upper Limit of Normal (ULN), AST and ALT inferior or equal 3 x ULN, - Adequate renal function defined as serum creatinine inferior or equal 1.5 x ULN, - Left Ventricular Ejection Fraction (LVEF) superior or equal 45% measured by radionuclide angiography (MUGA scan) or bidimensional echography, - No prior therapy for AML for 2 weeks before study entry and patients must have recovered from any treatment-related toxicities. Prior therapy with etoposide for prior solid tumour or AML is allowed. In case of rapidly progressive disease, the use of hydroxyurea in order to control the peripheral blood cell count is allowed; in this case, hydroxyurea should be discontinued at least 48 hours before the start of study treatment, - Fertile men must be using an effective method of birth control throughout the study period and for up to 3 months after the last dose of study treatment if their partners are women of childbearing potential, - The patient must have access to social insurance, - Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be assessed with the patient before registration in the trial, - The patient must give written (personally signed and dated) informed consent before completing any study-related procedure which means assessment or evaluation that would not form part of the normal medical care of the patient.
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E.4 | Principal exclusion criteria |
If any of the following apply, the patient must not enter the study: - Patient candidate for allograft at study entry, - Acute promyelocytic leukaemia, - Clinical symptoms suggesting active central nervous system leukaemia, - Peripheral blast count superior or equal to 30.000/mm3, - Severe complication of leukaemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, disseminated intravascular coagulation, - Current active infection; serious concurrent, uncontrolled medical disorder, - Thrombocytopenia refractory to platelet transfusion, - Prior total body irradiation up to more than 12 Gy, - Known HIV, HTLV1, Hepatitis B or C positivity, - History of another malignancy within the past 3 years except basal cell carcinoma of the skin or carcinoma in situ of the cervix, - Active heart disease including myocardial infarction within the previous 6 months, symptomatic coronary artery disease, arrhythmia not controlled by medication or uncontrolled congestive heart failure [New York Heart Association NYHA class III-IV], - Clinically relevant cardiovascular, hepatic, neurological or other systemic disease making implementation of the protocol difficult, - Concurrent treatment with any other anti-cancer treatment, - Participation in another trial of an investigational agent within 30 days before study entry, - Known hypersensitivity to the study drug or to drugs with similar chemical structures, - Concurrent treatment with inhibitors of ornithine decarboxylase or polyamine analogues, - Chronic treatment with systemic or inhaled steroids. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase I part: To determine the maximal tolerated dose (MTD) of F14512 administered as a three-hour daily infusion given for 5 consecutive days in combination with cytarabine 1 g/m²/day for 5 consecutive days in patients 60 years old or older with refractory or relapsing AML.
Phase II part: To evaluate the efficacy of F14512 in combination with cytarabine (rate of CR and CRi) in AML patients 60 years old and older in first relapse or with refractory disease. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase I part: Dose escalation of F14512 will be stopped once the MTD is reached. Phase II part: Up to a maximum of 5 cycles at investigator's discretion |
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E.5.2 | Secondary end point(s) |
Phase I part: - To determine the recommended dose (RD) of F14512 in combination with cytarabine to be used in the Phase II part, - To assess the safety of F14512, - To assess the molecular, biologic and clinical effects of F14512 in combination with cytarabine, - To assess the pharmacokinetics of F14512 in combination with cytarabine
Phase II part: - To extend the evaluation of safety at the RD, - To assess Relapse-Free Survival, Progression-Free Survival, remission duration and Overall Survival, - To assess the molecular, biologic and clinical effects of F14512 in combination with cytarabine, - To assess the pharmacokinetics of F14512 in combination with cytarabine at recommended dose.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase I part: Dose escalation of F14512 will be stopped once the MTD is reached. Phase II part: Up to a maximum of 5 cycles at investigator's discretion |
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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 | No |
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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Phase I-II study to evaluate the efficacy of the use of F14512 + cytarabine after MTD determination |
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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 | No |
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.8.2.4 | Number of treatment arms in the trial | 1 |
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.8.5.1 | Number of sites anticipated in the EEA | 15 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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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Phase I part: The end of the study is the date of the last visit of the last treated patient, which is scheduled 60 days after last study drug administration.
Phase II part: The end of study is the date of the last disease progression/relapse observed in the treated patients. Any change to this definition during the study, for whatever reason, must be notified as a substantial amendment.
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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 | 1 |
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 | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |