Condition category
Cancer
Date applied
30/09/2014
Date assigned
08/12/2014
Last edited
27/04/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Contact information

Type

Scientific

Primary contact

Prof Nigel Russell

ORCID ID

Contact details

Nottingham University
Haematology Department
Hucknall Road
Nottingham
NG5 1PB
United Kingdom
-
nigel.russell@nottingham.ac.uk

Additional identifiers

EudraCT number

2014-002195-90

ClinicalTrials.gov number

Protocol/serial number

SPON1334-04

Study information

Scientific title

Adults with Acute Myeloid Leukaemia or High-Risk Myelodysplastic Syndrome (AML19): a randomised, controlled, open label Phase III trial

Acronym

AML19

Study hypothesis

For patients with acute myeloid leukaemia (AML) the aims of the AML19 trial are:
1. To compare four induction chemotherapy schedules (namely DA + Mylotarg (3mg/m2) or DA + Mylotarg (3mg/m2 x2, maximum 5mg per day)versus FLAG-Ida + Mylotarg (3mg/m2) or FLAG-Ida + Mylotarg (3mg/m2 x2, maximum 5mg per day)) in patients who are not known at entry to have adverse cytogenetics
2. For patients receiving FLAG-Ida to compare one or two courses of HDAC consolidation versus no further treatment
3. Patients with FLT3 mutations may enter the AML19 pilot trial
4. To assess the value of Ganetespib in patients who lack a FLT3 mutation and are not high risk
5. In high risk patients, and those known to have adverse cytogenetics at entry, to compare novel treatment, CPX-351 vs FLAG-Ida
6. In high risk patients who have received 2 courses of FLAG-Ida induction, to evaluate in a non randomised fashion the combination of Fludarabine + CPX-351
7. In high risk patients, to evaluate, the value of allogeneic stem cell transplantation (SCT), from sibling or alternative donors
8. To assess the clinical value of minimal residual disease monitoring for patients’ overall survival
For patients with APL the aims of the AML19 trial are:
1. To evaluate the Idarubicin based, AIDA Schedule
2. Endpoints for Patients who have non-APL AML. The main endpoints for each comparison will be:
2.1. Overall survival (OS)
2.2. Complete remission (CR) achievement and reasons for failure (for induction questions)
2.3. Duration of remission, relapse rates and deaths in first CR
2.4. Toxicity, both haematological and non-haematological
2.5. Quality of life for patients in the disease monitoring randomisation
2.6. Supportive care requirements (and other aspects of health economics)

Ethics approval

Wales REC 3, 12/08/2014, ref. 14/WA/1056

Study design

Randomised controlled open-label phase III trial, factorial design

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Patient information sheets are provided through the patients hospital setting

Condition

Acute Myeloid Leukaemia
High-Risk Myelodysplastic Syndrome

Intervention

The AML19 trial looks to build upon previous trials in AML. It is known that the condition can present with one of two subtypes, and this is taken into account in the trial design.

In the majority of patients (those who do not have the APL-subtype), the trial looks to refine the current standard of care (which is a combination of drugs called DA) by asking a number of questions:
1. To compare two drug combinations (Daunorubicin/Ara-C – DA vs Fludarabine/Ara-C/G-CSF/Idarubicin – FLAG-Ida) to see which gives better survival
2. To identify the best way of giving the drug Mylotarg in addition to chemotherapy – either at a single dose of 3mg/m2 or in 2 doses of either 3mg/m2 or 5mg whichever is smaller. (This randomisation will only be available to patients who are suitable to receive Mylotarg).
3. In patients who receive FLAG-Ida, to work out the optimal number of courses of treatment. In particular, how much if any consolidation treatment with Ara-C is required – a randomisation between 0,1 and 2 courses of consolidation
4. To see if inhibiting a protein called HSP-90 with a drug called Ganetespib will improve outcomes
5. For poor risk patients, to see if a new drug called CPX-351 is any better than standard of care, which is FLAG-Ida
6. In patients who fail following 2 courses of FLAG-Ida (and so would not be suitable for further FLAG-Ida treatment) to evaluate a combination of Fludarabine and CPX-351
7. To evaluate whether a stem-cell transplant (e.g a bone marrow transplant) from either a matched sibling or unrelated donor can improve outcomes
8. To see whether monitoring patients bone marrow and blood sequentially can improve outcomes by successfully predicting patients who are likely to relapse, and what effect his has on quality of life.
Additionally patients who are found to have a FLT-3 mutation will be able to access the AML19 Pilot Trial of Ponatinib.

In patients with the APL subtype we will continue to assess the real-world effectiveness of standard of care, which is a combination of drugs called AIDA (ATRA plus Idarubicin), and to allow patients to access residual disease monitoring.

Intervention type

Drug

Phase

Phase III

Drug names

Primary outcome measures

To be assessed at the end of trial.
The AML19 trial looks to build upon previous trials in AML. It is known that the condition can present with one of two subtypes, and this is taken into account in the trial design. In the majority of patients (those who do not have the APL-subtype), the trial looks to refine the current standard of care (which is a combination of drugs called DA) by asking a number of questions:
1. To compare two drug combinations (Daunorubicin/Ara-C – DA vs Fludarabine/Ara-C/G-CSF/Idarubicin – FLAG-Ida) to see which gives better survival
2. To identify the best way of giving the drug Mylotarg in addition to chemotherapy – either at a single dose of 3mg/m2 or in 2 doses of either 3mg/m2 or 5mg whichever is smaller. (This randomisation will only be available to patients who are suitable to receive Mylotarg).
3. In patients who receive FLAG-Ida, to work out the optimal number of courses of treatment. In particular, how much if any consolidation treatment with Ara-C is required – a randomisation between 0,1 and 2 courses of consolidation
4. To see if inhibiting a protein called HSP-90 with a drug called Ganetespib will improve outcomes
5. For poor risk patients, to see if a new drug called CPX-351 is any better than standard of care, which is FLAG-Ida
6. In patients who fail following 2 courses of FLAG-Ida (and so would not be suitable for further FLAG-Ida treatment) to evaluate a combination of Fludarabine and CPX-351
7. To evaluate whether a stem-cell transplant (e.g a bone marrow transplant) from either a matched sibling or unrelated donor can improve outcomes
8. To see whether monitoring patients bone marrow and blood sequentially can improve outcomes by successfully predicting patients who are likely to relapse, and what effect his has on quality of life.
Additionally patients who are found to have a FLT-3 mutation will be able to access the AML19 Pilot Trial of Ponatinib. In patients with the APL subtype we will continue to assess the real-world effectiveness of standard of care, which is a combination of drugs called AIDA (ATRA plus Idarubicin), and to allow patients to access residual disease monitoring.

Secondary outcome measures

To be reviewed at the end of the trial.
In addition to the main clinical questions above, the trial will collect a lot of data on a well characterised group of patients. This will enable the following questions to be addressed:
1. What is the relevance of detecting minimal residual disease using one of two methods (molecular and immunophenotypic)
2. Are there biomarkers or other molecular (laboratory) measurements that correlate with clinical outcome
Consent will be taken to store any excess diagnostic material for future research that will inform future trials.

Overall trial start date

01/01/2015

Overall trial end date

01/01/2021

Reason abandoned

Eligibility

Participant inclusion criteria

AML Patients:
1. They have one of the forms of acute myeloid 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 >10% bone marrow blasts)
2. Patients with acute promyelocytic leukaemia (APL) are eligible and should be entered into the randomisations specifically for APL (see Section 9)
3. They are considered suitable for intensive chemotherapy
4. They should normally be 18 years up to the age of 60, but patients over this age are eligible if = intensive therapy is considered a suitable option
5. The serum creatinine should be ≤ 1.5 × ULN (upper limit of normal)
6. Patients eligible for the Mylotarg randomisation must have Serum Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤2.5 × ULN and bilirubin ≤2.× ULN (Note: Patients who do not comply with the liver inclusion criteria are eligible to enter the trial but will be excluded from the Mylotarg randomisation)
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. This applies to APL and AML patients. In both males and females these measures must be in place for at least 30 days after the last administration of ganetespib
8. They have given written informed consent
APL Patients:
1. They have provided signed written informed consent (PIS 3)
2. They have a morphological diagnosis of APL (if cytogenetic or molecular diagnosis is not confirmed patients will transfer to the non-APL treatments)
3. They should be over 18 years
4. They have WHO performance status 0-2
5. Their serum total bilirubin is < 2.0 mg/dL (≤51 µmol/L)
6. Their serum creatinine is < 3.0 mg/dL (< 260 µmol/L)

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

3000

Participant exclusion criteria

Patients are not eligible for the AML arms of the AML19 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 have received demethylation therapy for AML or high risk MDS defined as marrow blasts >10%. Patients treated for lower risk MDS who progress to AML are eligible
3. They are in blast transformation of chronic myeloid leukaemia (CML)
4. They have a concurrent active malignancy requiring treatment
5. They are pregnant or lactating
6. The physician and patient consider that intensive therapy is not an appropriate treatment option
7. Known infection with Human Immunodeficiency Virus (HIV)
8. 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
For Ganetespib randomisation there are specific cardiac exclusions:
1. A myocardial infarction within 12 months
2. Uncontrolled angina within 6 months
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 ≥ 45% (or institutional lower limit of normal value)
4. 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
5. Prolonged QTcF interval on pre-entry ECG (≥450 ms)
6. Any history of second or third degree heart block (may be eligible if the patient currently has a pacemaker
7. Heart rate < 50/minute on pre-entry ECG
8. Uncontrolled hypertension
9. Obligate need for a cardiac pacemaker
10. Complete left bundle branch block
11. Atrial fibrillation
APL Patients:
1. They are aged < 18
2. They have an active malignancy requiring treatment at time of study entry
3. There is a lack of subsequent diagnostic confirmation of PML-RARA fusion at molecular level
4. Known infection with Human Immunodeficiency Virus (HIV)
5. Significant arrhythmias, ECG abnormalities or neuropathy are apparent
6. Severe uncontrolled pulmonary or cardiac disease is apparent
7. They are pregnant or lactating

Recruitment start date

01/01/2015

Recruitment end date

01/01/2021

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Nottingham University
Nottingham
NG5 1PB
United Kingdom

Sponsor information

Organisation

Cardiff University (UK)

Sponsor details

Research
Innovation & Enterprise Services
7th Floor
30-36 Newport Road
Cardiff
CF10 3XQ
United Kingdom
-
resgov@cardiff.ac.uk

Sponsor type

University/education

Website

Funders

Funder type

Charity

Funder name

Cancer Research UK

Alternative name(s)

CRUK

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

27/04/2016: Plain English summary link added.