Trial to Test the Effects of Adding 1 of 2 New Treatment Agents to Commonly Used Chemotherapy Combinations
- Conditions
- Acute Myeloid LeukaemiaMyelodysplastic Syndrome
- Interventions
- Drug: Arm E CPX-351 (200 V 300)Drug: Arm D Small molecule or NotDrug: Arm A Mylotarg plus DA Versus CPX-351Drug: Arm B Vosaroxin and DecitabineDrug: Arm F DA V IDACDrug: Arm C DA V FLAG-Ida V DAC
- Registration Number
- NCT02272478
- Lead Sponsor
- Cardiff University
- Brief Summary
The AML18 Trial will evaluate several relevant therapeutic questions in Acute Myeloid Leukaemia (AML), as defined by the WHO, and High Risk Myelodysplastic Syndrome. The trial is primarily designed for patients over 60 years considered fit for an intensive chemotherapeutic approach, but younger patients who may not be considered suitable for the concurrent NCRI AML Trial for younger patients may also enter. Patients for whom intensive chemotherapy is not thought suitable may enter the concurrent NCRI trial of less intensive therapy (LI1). Approximately 1600 patients will be recruited.
At entry, a randomisation will compare a standard chemotherapy schedule DA (Daunorubicin/Ara-C) combined with 1 dose of Mylotarg (gemtuzumab ozogamicin, or GO) in course 1 against CPX-351. Patients who have known adverse risk cytogenetics (using Grimwade 2010 classification favourable/intermediate/adverse) at diagnosis may enter a Phase 2 evaluation of the combination of Vosaroxin plus Decitabine. Patients who achieve complete remission (CR) and who are MRD negative by flow cytometry after course one of DA will receive one further course of DA, with a randomisation to receive, either a course of DA or intermediate dose Cytarabine (IDAC) as a third course. Patients who are MRD negative by flow cytometry after course one of CPX-351 will receive up to 2 further course of CPX. Patients who fail to achieve a CR after course 1 of DA or who are MRD positive by flow cytometry or for whom MRD information is not available, are eligible to be randomised to compare DA with DA plus Cladribine (DAC) or FLAG-Ida for up to two courses of therapy. Patients who fail to achieve a CR after course 1 of CPX-351 or who are MRD positive by flow cytometry or for whom MRD information is not available are eligible to be randomised between a second course of standard dose CPX versus a repeat of the course 1 schedule. Patients receiving Vosaroxin and Decitabine are excluded from these post course 1 randomisations .
Following the outcome of course 1, patients who received DA chemotherapy on course 1 will be randomised to receive further chemotherapy with the 2nd generation FLT3 inhibitor AC220. Patients randomised to AC220 will be allocated a maximum of 3 courses (short AC220) or 3 courses plus maintenance for 1 year (long AC220). Patients receiving Vosaroxin and Decitabine are excluded from this randomisation.
Patients will be eligible for a non-intensive allogeneic stem cell transplant if a suitable HLA matched donor is available.
- Detailed Description
AML18 is a trial primarily for older patients with AML and high risk Myelodysplastic Syndrome (MDS). It offers a randomised controlled Phase II/III trial which uses a factorial design for maximum efficiency to evaluate two induction options followed by treatment with small molecule beyond course 1, and dose intensification for patients without evidence of MRD negativity.
There are five randomised comparisons within the trial:
1. At diagnosis:
For patients not known to have adverse risk cytogenetics DA chemotherapy plus a single dose of 3 mg/m2 of Mylotarg versus CPX-351. Patients with abnormal LFTs can enter the randomisation but receive DA alone or CPX-351.
2. For patients who received DA chemotherapy but are not in CR or who are MRD +ve, or for whom MRD is not assessable.
DA versus DAC versus FLAG-Ida
3. All patients at second course who have received DA and have not received Vosaroxin and Decitabine induction AC220 versus no AC220 for a maximum of 3 cycles; then with or without maintenance for 1 year for patients allocated AC220
4. For patients who are in CR or CRi and MRD -ve post course1 and have completed 2 courses of DA DA versus intermediate dose Cytarabine (IDAC)
5. For patients who received CPX-351 chemotherapy but are not in CR or who are MRD +ve, or for whom MRD is not assessable CPX-351 100 units/m2 x 3 doses versus CPX-351 100 units/m2 x 2 doses
The trial will also assess:
* Non-intensive allogeneic stem cell transplant for patients with matched sibling or matched unrelated donors.
* The combination of Vosaroxin and Decitabine for those with known adverse risk cytogenetics at diagnosis
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 1600
Not provided
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 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 not 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- FACTORIAL
- Arm && Interventions
Group Intervention Description Arm E Arm E CPX-351 (200 V 300) Prior to Course 2 for patients receiving CPX in course 1 and MRD positive PC1 Randomisation between CPX-351 100 units/m2 on days 1, and 3 (CPX 200) versus CPX-351 100 units/m2 on days 1, 3 and 5 (CPX 300) Arm D Arm D Small molecule or Not Prior to Course 2 - Patients that received DA plus GO in course 1 and MRD negative PC1 Randomisation to receive AC220 or not Arm A Arm A Mylotarg plus DA Versus CPX-351 Patients not known adverse karyotype Randomise between Daunorubicin 60mg/m2 daily by i.v. infusion on days 1, 3 and 5 (3 doses) Cytosine Arabinoside 100mg/m2 12 hourly by i.v. push on days 1 - 10 inclusive (20 doses) Mylotarg (GO) 3mg/m2 on day 1 of DA chemotherapy Versus CPX-351 100 units/m2 on days 1, 3 and 5 Arm B Arm B Vosaroxin and Decitabine Patients with known adverse karyotype 5 cycles of Vosaroxin and Decitabine therapy Arm C Arm D Small molecule or Not Prior to Course 2 - Patients receving DA plus GO in course 1 and MRD positive PC1 Randomise between Daunorubicin 50mg/2 daily by i.v. infusion on days 1, 3 and 5 (3 doses) Cytosine Arabinoside 100mg/m2 12 hourly by i.v.push on days 1 - 8 inclusive (16 doses) Versus Daunorubicin 50mg/m2 daily by i.v. infusion on days 1, 3 and 5 Cytosine Arabinoside 100mg/m2 12 hourly by i.v. push on days 1 - 8 inclusive Cladribine 5mg/m2 daily on days 1 - 5 inclusive Versus Patients aged 60-69 Fludarabine 30mg/m2 daily on i.v. on days 2 - 6 inclusive Cytosine Arabinoside 1g/m2 daily over 4 hours Fludarabine on days 2 - 6 inclusive Patients aged 70+ Fludarabine 25mg/m2 daily i.v. on days 2 - 5 inclusive Cytosine Arabinoside 1g/m2 daily over 4 hours Fludarabine on days 2 - 5 inclusive Idarubicin 5mg/m2 i.v. daily on days 3, 4 and 5 (3 doses) And Randomisation to receive AC220 or not Arm F Arm F DA V IDAC Prior to Course 3 - Patients that received DA plus GO in course 1 and MRD negative PC1 Randomise between Daunorubicin 50 mg/m2 daily by i.v. infusion on days 1 and 3 (2 doses) Cytosine Arabinoside 100 mg/m2 12-hourly by i.v. push on days 1 - 5 inclusive (10 doses) versus Intermediate dose Cytarabine (IDAC) schedule Cytosine Arabinoside 1g/m2 daily by 4 hour infusion on days 1- 5 inclusive (5 doses) Arm C Arm C DA V FLAG-Ida V DAC Prior to Course 2 - Patients receving DA plus GO in course 1 and MRD positive PC1 Randomise between Daunorubicin 50mg/2 daily by i.v. infusion on days 1, 3 and 5 (3 doses) Cytosine Arabinoside 100mg/m2 12 hourly by i.v.push on days 1 - 8 inclusive (16 doses) Versus Daunorubicin 50mg/m2 daily by i.v. infusion on days 1, 3 and 5 Cytosine Arabinoside 100mg/m2 12 hourly by i.v. push on days 1 - 8 inclusive Cladribine 5mg/m2 daily on days 1 - 5 inclusive Versus Patients aged 60-69 Fludarabine 30mg/m2 daily on i.v. on days 2 - 6 inclusive Cytosine Arabinoside 1g/m2 daily over 4 hours Fludarabine on days 2 - 6 inclusive Patients aged 70+ Fludarabine 25mg/m2 daily i.v. on days 2 - 5 inclusive Cytosine Arabinoside 1g/m2 daily over 4 hours Fludarabine on days 2 - 5 inclusive Idarubicin 5mg/m2 i.v. daily on days 3, 4 and 5 (3 doses) And Randomisation to receive AC220 or not
- Primary Outcome Measures
Name Time Method Overall survival 1 year Complete remission (CR + CRi) achievement and reasons for failure (for induction questions) 1 month Toxicity, both haematological and non-haematological 1 month Supportive care requirements (and other aspects of health economics) 6 months Duration of remission, relapse rates and deaths in first CR 1 month
- Secondary Outcome Measures
Name Time Method The relevance of molecular characteristics and response to treatment 1 month The relevance of the presence of a cytogenetic abnormality in the bone marrow of patients in morphological remission At study end To store diagnostic tissue for future research in the AML Tissue Bank 6 years
Trial Locations
- Locations (87)
Aalborg University Hospital
🇩🇰Aalborg, Denmark
Aarhus University Hospital
🇩🇰Aarhus, Denmark
Herlev and Gentofte Hospital
🇩🇰Copenhagen, Denmark
Rigshospitalet
🇩🇰Copenhagen, Denmark
Odense University Hospital
🇩🇰Odense, Denmark
Roskilde Hospital
🇩🇰Roskilde, Denmark
Aberdeen Royal Infirmary
🇬🇧Aberdeen, United Kingdom
Monklands Hospital
🇬🇧Airdrie, United Kingdom
Ysbyty Gwynedd Hospital
🇬🇧Bangor, United Kingdom
Royal United Hospital Bath
🇬🇧Bath, United Kingdom
Scroll for more (77 remaining)Aalborg University Hospital🇩🇰Aalborg, DenmarkMarianne Severinsen, MDContact