E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
secondary acute myeloid leukemia |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000886 |
E.1.2 | Term | Acute myeloid leukemia |
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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 |
The rate of confirmed complete remission with or without hematopoietic recovery [complete remission (CR) and complete remission with incomplete hematopoietic recovery (CRi); this includes complete cytogenetic remission (CRc) and complete remission with persistent morphologic dysplasia (CRd)]. Confirmed CR or CRi is defined as documentation of CR or CRi at least 30 days after initial determination of CR or CRi following remission induction therapy, or immediately prior to postremission therapy if such therapy occurs within 30 days from the initial determination of CR or CRi. |
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E.2.2 | Secondary objectives of the trial |
- Rate of initial complete remission with or without hematopoietic recovery; - Rate of CR + CRi within different clinical subsets; - Rate of response overall and within different clinical subsets; - Rate of response for each individual response category overall and within different clinical subsets; - Median duration of remission; - Median duration of disease free survival (DFS); - Proportion of patients remaining in remission at 6 months, at 12 months, and at 18 months; - Median duration of overall survival (OS) for all patients, for all patients in remission and for each individual response category; - Correlation of clinical responses, duration of responses, DFS and OS with cytogenetic abnormalities; - Correlation of clinical responses, duration of responses, DFS and OS with expression and function of Pgp; - Correlation of PK exposure of amonafide and N-acetyl amonafide with both safety and efficacy assessments. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
a.) Diagnosis of AML according to WHO diagnostic criteria (at least 20% blasts in the peripheral blood or bone marrow), with FAB classification other than M3 (Acute Promyelocytic Leukemia), documented by bone marrow aspiration and biopsy performed within 14 days prior to administration of 1st dose of remission induction chemotherapy;
b.) Either a. Known and documented exposure to specific leukemogenic therapy of a specified nature for a non-myeloid condition. OR b. Documented diagnosis of MDS or chronic myelomonocytic leukemia (CMML) according to WHO criteria for at least 3 months prior to study entry, with prior bone marrow aspirate, biopsy and peripheral blood smear documenting MDS available to be submitted for subsequent central pathology review.
c.) Age 18 years or older;
d.) Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2;
e.) Fertile sexually active patients (men and women) must use an effective method of contraception which must be continued throughout the study.
f.) Women of childbearing potential must have a negative serum pregnancy test. A woman of childbearing potential is defined as one who is biologically capable of becoming pregnant. This includes women who are using contraceptives or whose sexual partners are either sterile or using contraceptives;
g.) Left Ventricular Ejection Fraction (LVEF) ≥ 50%, as determined by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO) within 14 days prior to administration of 1st dose of remission induction chemotherapy;
h.) Adequate renal function as evidenced by the following laboratory test, obtained within 14 days prior to administration of 1st dose of remission induction chemotherapy: •Serum creatinine ≤ 1.5 x ULN;
i.) Adequate hepatic function as evidenced by the following laboratory tests, obtained within 14 days prior to administration of 1st dose of remission induction chemotherapy (unless attributed to hepatic involvement with AML): •Total serum bilirubin ≤ 1.5 x ULN; •Serum AST and ALT ≤ 1.5 x ULN;
j.) Ability of the patient to participate fully in all aspects of this clinical trial;
k.) Written Informed Consent and HIPAA authorization (USA sites only) must be obtained and documented. |
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E.4 | Principal exclusion criteria |
a.) Histologic diagnosis of FAB M3 Acute Promyelocytic Leukemia;
b.) Clinically active CNS leukemia;
c.) Prior induction therapy for AML;
d.) Known HIV positive;
e.) Known active hepatitis B or C, or any other active liver disease;
f.) Patients with parenchymal abnormality on screening chest x-ray must have no evidence of pulmonary infection on chest tomography (CT) prior to starting remission induction therapy.
g.) Any major surgery or radiation therapy within 4 weeks prior to study entry;
h.) Prior cytotoxic chemotherapy for MDS within 4 weeks prior to study entry (patients with rapidly rising blast count may be enrolled within 4 weeks of prior cytotoxic chemotherapy with waiver from the Medical Monitor);
i.) Persistent chronic non-hematologic toxicity (other than alopecia) greater than grade 1 from prior therapy for MDS;
j.) Serious concomitant illnesses (for example, pulmonary infiltrate, unstable angina or myocardial infarction or stroke within 3 months prior to study entry, congestive heart failure AHA class 2 or greater, uncontrolled hypertension, uncontrolled diabetes, actively bleeding gastric ulcer, etc.), which in the investigator’s opinion would not make the patient a good candidate for the trial;
k.) Pregnant or breast feeding;
l.) History of clinically significant allergic reactions attributed to compounds of similar chemical or biological composition to amonafide, cytarabine or daunorubicin;
m.) Prior enrollment in this trial;
n.) Any other known condition (e.g., familial, sociological, or geographical) or behavior (including substance dependence or abuse, psychological or psychiatric illness), which in the investigator’s opinion would make the patient a poor candidate for the trial.
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E.5 End points |
E.5.1 | Primary end point(s) |
The rate of confirmed CR + CRi (which includes CRc and CRd) will be determined by assessing the proportion of patients who achieved confirmed CR or CRi among all evaluable patients. Peripheral blood hematopoietic recovery in accord with a CR may occur up to several months after resolution of leukemia, i.e., < 5% blasts in the bone marrow. |
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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 | 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 | Information not present in EudraCT |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | 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) | Yes |
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.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 71 |
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 | Yes |
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 | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |