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A trial for older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome
ISRCTN ISRCTN31682779
DOI 10.1186/ISRCTN31682779
ClinicalTrials.gov identifier
EudraCT number 2013-002730-21
Public title A trial for older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome
Scientific title AML18 - A trial for older patients with Acute Myeloid Leukaemia and high risk myelodysplastic syndrome
Acronym AML18
Serial number at source SPON1227-13
Study hypothesis The trial hopes to address several therapeutic questions, including:
1. Does a fractionated schedule of two doses of Gemtuzumab ozogamicin (GO) 3mg/m2 [capped at a maximum of 5mg per dose for patients with body surface area (BSA) above 1.67 m2] improve upon the current standard of care of 3mg/m2 on day 1 of course 1?
2. Does the addition of the HSP90 inhibitor Ganetespib starting at course 2 improve outcomes?
3. Does the addition of either a short or long (maintenance) course of AC220 starting at course 2 improve outcomes?
4. Is minimal residual disease (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?
5. To compare a total of two versus three courses of treatment in patients who are in complete remission (CR) or complete remission with incomplete blood count recovery (CRi) and MRD -ve after induction course 1.
6. To assess the value of Reduced Intensity Allogeneic Stem Cell Transplantation as consolidation for patients with a matched sibling or matched unrelated donor.
Lay summary Lay summary under review with external organisation
Ethics approval Ethical approval will be obtained from Research Ethics Committee for Wales
Study design Randomised controlled trial
Countries of recruitment United Kingdom
Disease/condition/study domain Acute Myeloid Leukaemia and High Risk Myelodysplastic Syndrome
Participants - inclusion criteria 1. They have one of the forms of acute myeloid leukaemia, except Acute Promyelocytic Leukaemia as defined by the WHO Classification, this can be any type of de novo or secondary acute myeloid leukaemia (AML), or high risk myelodysplastic syndrome, defined as greater than 10% marrow blasts (RAEB-2).
2. They should normally be over the age of 60, but patients under this age are eligible if they are not considered eligible for the MRC AML17 trial.
3. They have given written informed consent.
4. Serum creatinine less than or equal to 1.5 x ULN (upper limit of normal)
5. Patients eligible for the Mylotarg randomisation must have Serum Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) less than or equal to 2.5 x ULN and bilirubin less than or equal to 2.x ULN
6. In order to be eligible to receive cladrabine, serum creatinine must be within the local ULN to enter that randomisation. Patients for whom this is not the case can be randomised between the remaining options.
7. 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). Similarly women must agree to adequate contraceptive measures. In both males and females these measures must be in place for at least 30 days after the last administration of ganetespib.
8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
Participants - exclusion criteria Patients are not eligible for the AML18 trial if:
1. 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].
2. They are in blast transformation of chronic myeloid leukaemia (CML).
3. They have a concurrent active malignancy excluding basal cell carcinoma.
4. They are pregnant or lactating.
5. They have Acute Promyelocytic Leukaemia.
6. Patients with AST or ALT more than 2.5 times the local upper limit of normal, or bilirubin more than twice upper limit of normal, are not eligible for the Mylotarg randomisations.
7. In addition patients are not eligible for the AC220 or Ganetespib randomisation if they have uncontrolled or significant cardiovascular disease, including :
7.1. A myocardial infarction within 12 months
7.2. Uncontrolled angina within 6 months
7.3. 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 greater than 45% (or institutional lower limit of normal value)
7.4. Diagnosed or suspected congenital long QT syndrome. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes [TdP]); any history of arrhythmia will be discussed with the Sponsor's Medical Monitor prior to patient's entry into the study
7.5. Prolonged QTcF interval on pre-entry ECG (greater than 450 ms) - this will be the average of three readings within a 2 hour period
7.5. Any history of second or third degree heart block (may be eligible if the patient currently has a pacemaker)
7.6. Heart rate < 50/minute on pre-entry ECG
7.7. Uncontrolled hypertension
7.8. Obligate need for a cardiac pacemaker
7.9. Complete left bundle branch block
7.10. Atrial fibrillation
Anticipated start date 31/10/2013
Anticipated end date 31/10/2019
Status of trial Ongoing
Patient information material Not available in web format, please use the contact details below to request a patient information sheet
Target number of participants 1600
Interventions The AML18 trial will evaluate several therapeutic questions in Acute Myleoid Leukaemia (AML). The trial will recruit 1600 patients primarily over the age of 60 who are considered fit for an intensive approach to treatment.

A randomisation will compare standard chemotherapy schedule Daunorubicin/Ara-C(DA) combined with 1 or 2 doses of Mylotarg in course 1, patients who fail to achieve CR or are MRD positive after course 1 will be randomised to compare DA with DA plus Cladribine or Flag-Ida for up to 2 courses of therapy.

Patients who achieve CR after course 1 will be randomised to 1 or 2 further courses of DA. At course 2, patients will also be randomised to receive AC220 versus no AC220 with or without maintenance, or Ganetespib versus no Ganetespib for a maximum of 3 cycles.
Primary outcome measure(s) 1. Overall survival (at end of treatment)
2. Complete remission (CR + CRi) achievement and reasons for failure (for induction questions) (after course 1)
3. Duration of remission, relapse rates and deaths in first CR (after course 1)
4. Toxicity, both haematological and non-haematological (after each course)
5. Supportive care requirements (and other aspects of health economics) (after each course)
Secondary outcome measure(s) 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.
Sources of funding Cancer Research UK (UK) - Clinical Trials Awards and Advisory Committee (CTAAC); C17415/A13371
Trial website
Publications
Contact name Prof  Nigel  Russell
  Address Department of Haematology
Nottingham University Hospital
Centre for Clinical Haematology
Hucknall Road
  City/town Nottingham
  Zip/Postcode NG5 1PB
  Country United Kingdom
Sponsor Cardiff University (UK)
  Address Research, Innovation and Enterprise Services
30-36 Newport Road
  City/town Cardiff
  Zip/Postcode CF24 0DE
  Country United Kingdom
Date applied 04/09/2013
Last edited 20/03/2014
Date ISRCTN assigned 14/11/2013
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