| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Acute Myeloid Leukaemia
High Risk Myelodysplastic Syndrome |
|
| E.1.1.1 | Medical condition in easily understood language |
| AML and MDS are malignant conditions of the bone marrow. They both result in failure of the bone marrow to manufacture enough blood cells because the marrow contains too many leukaemia cells |
|
| 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 | 20.0 |
| 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 |
This trial will aim to answer the following questions:
1.Does CPX-351 given for 3 courses improve survival compared to the current standard of care of DA plus two doses of GO 3mg/m2 (maximum 5 mg per dose) for older patients with AML without known adverse risk cytogenetics?
2.Does the addition of either a short or long (maintenance) course of AC220 starting at course 2 after DA chemotherapy for patients with a FLT3 mutation in the diagnostic sample improve outcomes?
3.Is MRD status following course 1 of clinical value? In particular, can outcomes be improved by intensifying treatment in patients who show evidence of residual disease following course 1 of treatment?
4.To compare a further course of DA versus intermediate-dose Cytarabine in patients who are in CR or CRi and MRD -ve after induction course 1 and have received a second course of DA induction
5.In patients with known adverse risk cytogenetics (using Grimwade 2010 classification favourable/intermediate/adverse, see table 1 a |
|
| E.2.2 | Secondary objectives of the trial |
Blood and bone marrow will be collected at diagnosis, post course 1, during remission and at relapse to evaluate the therapeutic relevance of morphological, cytogenetic, molecular-genetic and immunophenotypic assessments, with particular respect to:
1)The relevance of the presence of a cytogenetic abnormality in the bone marrow of patients in morphological remission
2)The relevance of molecular characteristics and response to treatment
3)To store diagnostic tissue for future research in the AML Tissue Bank
4)To determine the predictive impact of the LSC17 gene signature on outcome of patients entering the two arms of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients are eligible for the AML18 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). (NB patients with prior MDS (>10% blasts, RAEB2) who have received prior azacitidine are not eligible for the trial, but patients with <10% who have failed a hypomethylating agent and developed AML may enter the trial)
•Patients should normally be over the age of 60, but patients under this age are eligible if they are not considered eligible for the MRC AML19 trial. Please contact the trial team for further information
•Patients entering the Vosaroxin/Decitabine arm must be over the age of 60 and have known adverse risk cytogenetics at entry
•They have given written informed consent
•Serum creatinine ≤ 1.5 × ULN (upper limit of normal)
•Sexually mature males must agree to use an adequate and medically accepted method of contraception throughout the study if their sexual partners are women of child bearing potential (WOCBP). Men should be advised to not father a child while receiving trial treatment. Similarly women must agree to adequate contraceptive measures and avoid becoming pregnant while on protocol treatment. In both males and females these measures must be in place for at least 3 months following completion of Decitabine and at least 6 months after the last administration of Cladribine. The time period following treatment with Decitabine where it is safe to become pregnant is unknown. In the event of pregnancy at any point during the trial, the IMPs should be immediately stopped and the Trial Team should be contacted and pregnancy reporting procedures followed
•ECOG Performance Status of 0-2
Please note for the AC220 intervention: specific electrolyte and cardiac criteria (see page 29) must be met. Only patients with a confirmed FLT3 mutation in the diagnostic sample are eligible for the AC220 randomisation.
|
|
| E.4 | Principal exclusion criteria |
Patients are not eligible for the AML18 trial if:
•They have previously received cytotoxic chemotherapy for AML
[Hydroxycarbamide, or similar low-dose therapy, to control the white count prior to initiation of intensive therapy, is not an exclusion]
•They are in blast transformation of chronic myeloid leukaemia (CML)
•They have a concurrent active malignancy excluding basal cell carcinoma
•They are pregnant or lactating
•They have Acute Promyelocytic Leukaemia
•Known infection with human immunodeficiency virus (HIV)
•Patients with prior cumulative anthracycline exposure (from prior treatment of a non AML cancer) of greater than 300 mg/m2 daunorubicin (or equivalent).
•History of myocardial infarction (MI), unstable angina, cerebrovascular accident, or transient ischemic attack (CVA/TIA) within 3 months before entry
•Patients with known adverse risk cytogenetics are excluded from entering the AML18 trial unless they are registered to receive vosaroxin and decitabine
Specific exclusion criteria for the Mylotarg Arm
•Pre-existing liver impairment with known cirrhosis
•Total bilirubin > 1.5 x the upper limit of normal (ULN)
•Aspartate aminotransferase (AST) > 2.5 x ULN
•Alanine aminotransferase (ALT) > 2.5 x ULN
Specific exclusion criteria for the Vosaroxin/Decitabine Arm
•Total bilirubin > 1.5 x the upper limit of normal (ULN),
•Aspartate aminotransferase (AST) > 2.5 x ULN
•Alanine aminotransferase (ALT) > 2.5 x ULN
•Left ventricular ejection fraction (LVEF) < 40% by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO)]
Specific exclusion criteria for CPX-351 treatment
•Hypersensitivity to cytarabine, daunorubicin or liposomal products
•History of Wilson’s disease or other copper-metabolism disorder
Specific exclusion criteria for Cladribine
•Patient’s serum creatinine must be within the local ULN to enter the randomisation. Patients for whom this is not the case can be randomised between the remaining options.
In addition patients are not eligible for the AC220 randomisation if they have:
Cardiovascular System Exclusion Criteria:
Known serious cardiac illness or medical conditions, including but not limited to:
I.Clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, active myocardial ischemia, or indwelling temporary pacemaker
II.Ventricular tachycardia or a supraventricular tachycardia that requires treatment with a Class Ia antiarrhythmic drug (e.g., quinidine, procainamide, disopyramide) or Class III antiarrhythmic drug (e.g., sotalol, amiodarone, dofetilide). Use of other antiarrhythmic drugs is permitted.
III.Use of medications that have been linked to the occurrence of torsades de pointes (see Appendix B for the list of such medications)
IV.Second- or third-degree atrioventricular (AV) block unless treated with a permanent pacemaker
V.Complete left bundle branch block (LBBB)
VI.History of long QT Syndrome or a family member with this condition
VII.Serum potassium, magnesium, and calcium levels outside the laboratory’s reference range
VIII. QTc >450 ms (average of triplicate ECG recordings); a consistent method of QTc calculation must be used for each patient’s QTc measurements. QTcF (Fridericia’s formula) is preferred. Please see the trial website for QTcF calculator. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary outcome measure will be:
1)Overall survival
2)Complete remission (CR + CRi) achievement and reasons for failure (for induction questions)
3)Duration of remission, relapse rates and deaths in first CR
4)Toxicity, both haematological and non-haematological
5)Supportive care requirements (and other aspects of health economics).
|
|
| E.5.2 | Secondary end point(s) |
Blood and bone marrow will be required at diagnosis, post course 1 during remission and at relapse to evaluate the therapeutic relevance of morphological, cytogenetic, molecular-genetic and immunophenotypic assessments, with particular respect to:
•The relevance of the presence of a cytogenetic abnormality in the bone marrow of patients in morphological remission.
•The relevance of molecular characteristics and response to treatment.
•To store diagnostic tissue for future research in the AML Tissue Bank.
•To determine the predictive impact of the LSC17 gene signature on outcome of patients entering the two arms of the trial
|
|
| 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 9 |
| 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 | 150 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
|
| 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 | 7 |
| 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 | 7 |
| 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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