Acute myeloid leukaemia and myelodysplastic syndrome Cancer
Conditions
Interventions
Current interventions as of 25/02/2021:
Patients with CD33 positive de novo AML are randomised in a 1:1 ratio between DA chemotherapy and one dose of Mylotarg (given at a dose of 3 mg/m² on Day 1 of C
Sponsors
Cardiff University (UK)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Current participant inclusion criteria as of 25/02/2021: 1. One of the forms of CD33 positive (any level), favourable, standard risk or unknown cytogenetics de novo AML as defined by theWHO Classification 2. WHO performance status 0-2 3. Considered suitable for intensive chemotherapy 4. Aged 16 to 60 years with the following caveats: 4.1. If intensive therapy is considered a suitable option those aged >60 years are eligible 4.2. To receive midostaurin: aged =18 years 5. A negative pregnancy test within 2 weeks prior to trial entry in WOCBP to be repeated throughout the trial prior to each course of protocol treatment 6. Sexually active participants must agree to use an adequate and medically accepted method of contraception throughout the study, and for 6 months following treatment (female participants receiving Mylotarg should continue for 7 months following treatment), if they, or their sexual partners, are women of childbearing potential (WOCBP) 7. Written informed consent provided 8. Patients must have Serum Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) =2.5 × upper limit of normal (ULN) and bilirubin =2 × ULN 9. To receive midostaurin: FLT3-TKD or FLT3-ITD mutation detected by the central laboratory in Cardiff Previous 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)
Exclusion criteria
Exclusion criteria: Current participant exclusion criteria as of 25/02/2021: 1. Patients with APL, secondary AML, therapy-related AML, high-risk myelodysplastic syndrome with 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Current primary outcome measure as of 25/02/2021: Overall survival in patient groups of differing risk status by measuring time from randomisation into particular arms of the study until death from any cause Previous primary outcome measure: 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 r | — |
Secondary
| Measure | Time frame |
|---|---|
| Current secondary outcome measures as of 01/03/2021: 1. Achievement of complete remission (CR) after treatment in all patient groups by measuring time from randomisation until time of first CR 2. Duration of CR by measuring time from first CR to first relapse 3. Rate of relapse by treatment group measured using number of events of relapse following CR recorded in participant notes between randomisation and the end of the study 4. Toxicities experienced in each course of treatment in all patient groups measured using number of events of toxicity recorded in participant notes between randomisation and the end of the study 5. Safety and efficacy of Midostaurin in patients with a FLT3 mutation who have received DA chemotherapy combined with Gemtuzumab Ozogamicin (Mylotarg) measured using number of adverse events recorded in participant notes between randomisation and the end of the study and overall survival from randomisation until death from any cause 6. Quality of life in all patient groups measured using the EORTC QLQ-C30 Version 3 questionnaire at baseline, prior to C2 (~6 weeks), 3, 6, 9, and 12 months after randomisation Previous secondary outcome measures as of 25/02/2021: 1. Achievement of complete remission (CR) after treatment in all patient groups by measuring time from randomisation until time of first CR 2. Duration of CR by measuring time from first CR to first relapse 3. Rate of relapse by treatment group measured using number of events of relapse following CR recorded in participant notes between randomisation and the end of the study 4. Toxicities experienced in each course of treatment in all patient groups measured using number of events of toxicity recorded in participant notes between randomisation and the end of the study 5. Safety and efficacy of Midostaurin in patients with a FLT3 mutation who have received DA chemotherapy combined with Gemtuzumab Ozogamicin (Mylotarg) measured using number of adverse events recorded in participant notes bet | — |
Countries
Denmark, England, New Zealand, Northern Ireland, Scotland, United Kingdom, Wales
Outcome results
None listed