| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute myeloid leukemia and high-risk myelodysplastic syndrome |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10005329 |
| E.1.2 | Term | Blood and lymphatic system disorders |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To compare standard treatment, low-dose Ara-C against the available novel approaches:
•LD Ara-C combined with AC220
•LD Ara-C combined with Tosedostat
•LD Ara-C combined with Selinexor
•LD Ara-C combined with Lenalidomide
•LD Ara-C combined with BCT100
•Drug X
During the course of the Programme other novel therapies (Drug X) are expected to become available, and will be considered for inclusion in this comparison. |
|
| E.2.2 | Secondary objectives of the trial |
Information will be collected from investigators entering a patient regarding the reasons that the patient was not suitable for intensive treatment. In order to understand the process, co-morbidity assessment information will be collected at study entry.
Blood and bone marrow will be required at diagnosis (if available) and at relapse to evaluate the therapeutic relevance of some laboratory markers, in particular to:
•Evaluate the relevance of the presence of a cytogenetic abnormality in the bone marrow of patients in remission.
•Evaluate the relevance of molecular characteristics and response to treatment.
•Store diagnostic tissue for future research in the AML Tissue Bank. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients are eligible for the LI-1 trial if:
•They have one of the forms of acute myeloid leukaemia, except Acute Promyelocytic Leukaemia as defined by the WHO Classification (Appendix A) this can be any type of de novo or secondary AML – or high risk Myelodysplastic Syndrome, defined as greater than 10% marrow blasts (RAEB-2).
Note: patients with prior MDS (>10% blasts, RAEB 2) who have received azacitidine are not eligible for the trial, but patients with <10% who have failed a demethylation agent and developed AML may enter the trial
•They should be over the age of 60
•They have given written informed consent.
•Male patients with partners of childbearing potential must agree to use effective contraception during the study period and a period of 3 months after the last dose of study drug.
For the AC220 (quizartinib) and tosedostat interventions:
•Additional cardiac criteria must be met
•Electrolyte levels of Potassium, Magnesium and Calcium must be within the institutional normal range
|
|
| E.4 | Principal exclusion criteria |
Patients are not eligible for the LI-1 trial if:
•They are less than 60 years of age
•They have previously received cytotoxic chemotherapy for AML. [Hydroxycarbamide, or similar low-dose therapy, to control the white count is not an exclusion criterion].
•They are in blast transformation of chronic myeloid leukaemia (CML).
•They have a concurrent active malignancy under treatment.
•They are pregnant or lactating.
•They have Acute Promyelocytic Leukaemia.
•Known infection with human immunodeficiency virus (HIV)
•Total bilirubin ≥ 1.5 x ULN, unless due to Gilbert’s syndrome
•Aspartate aminotransferase (AST) ≥ 2.5 x ULN and/or alkaline phosphatase ≥2.5 x ULN
•Serum creatinine ≥ 175µmol/L
•History of myocardial infarction (MI), unstable angina, cerebrovascular accident, or transient ischemic attack (CVA/TIA) within 6 months
For AC220 (quizartinib) and tosedostat treatment the following criteria make a patient ineligible for that randomisation:
•A myocardial infarction within 12 months
•Uncontrolled angina within 6 months
•Current or history of congestive heart failure New York Heart Association (NYHA) class 3 or 4, unless an echocardiogram (ECHO) or Multiple Gated Acquisition Scan (MUGA) performed either within 1 month prior to study screening or during screening results in a left ventricular ejection fraction (LVEF) that is ≥ 45% (or institutional lower limit of normal value).
•Diagnosed or suspected congenital long QT syndrome. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, torsades de pointes [TdP]) or any history of arrhythmia will be discussed with the Clinical Coordinator/Safety Physician prior to patient’s entry into the study.
•Prolonged QTcF interval on pre-entry ECG (≥450 ms)
•Any history of second or third degree heart block (may be eligible if the patient currently has a pacemaker
•Heart rate < 50/minute on pre-entry ECG
•Uncontrolled hypertension
•Obligate need for a cardiac pacemaker
•Complete left bundle branch block
•Uncontrolled atrial fibrillation |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary initial outcome measure (during the first 50 patients) is complete remission (CR + CRi). When the option progresses (to 100, then 200), relapse and overall survival are also used as primary outcome measures. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For treatments where the proposed effect is to improve survival by inducing a greater number of remissions, recruitment will proceed until at least 50 patients have been entered, and analysed using CR as endpoint. If the arm appears sufficiently promising, then recruitment will continue until 100 patients are in each arm. At this point, a similar analysis on CR will be undertaken.
Where improvements may occur in the absecne of remission, a minimum of six months follow-up will be sought on each patient. Analyses will be based on overall survival once one quarter and one half of the required number of events has occurred. |
|
| E.5.2 | Secondary end point(s) |
Details of toxicity (both haematological and non-haematological), supportive care requirements, other aspects of health economics) and Quality of Life assessment are gathered in the web-based database using an electronic CRF.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Evaluations will be as requested by the Data Monitoring Committee. |
|
| 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) | 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 | 140 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| Australia |
| Denmark |
| France |
| Italy |
| New Zealand |
|
| 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
|
| One year following last patient last visit. Annual follow up is conducted for life to assess survival. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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