Welcome to the AML LI1 initiation - Cardiff University
Welcome to the AML18 initiation Version 1.2 July 2014 Welcome Site will require the following personnel to attend training before site is opened: PI Research nurse Pharmacist Information should be cascaded down and onsite training documented in training log Training certificates will be emailed Trial Background
Phase III multi-centre trial Replacement trial for intensive arm of AML16 Building on findings from AML18 Pilot > 60 years of age Standard chemotherapy plus novel treatment 5 treatment arms Not all randomisation options may be available, well keep you informed! Trial Design Objectives Does a fractionated schedule of two doses of Mylotarg
3mg/m2 improve upon the current standard of care for patients with good and intermediate risk cytogenetics? Does the addition of Ganetespib starting at course 2 improve outcomes? Does the addition of either a short or long (maintenance) course of AC220 improve outcomes? Continued Is MRD status following course 1 of clinical value? Does intensification of treatment for MRD+ patients improve outcome ?
To compare a total of two versus three courses of treatment in patients who are in CR or CRi and MRD -ve after induction course 1 To assess the value of Reduced Intensity Allogeneic Stem Cell Transplantation as consolidation for patients with a matched sibling or matched unrelated donor Endpoints Overall survival Complete remission (CR + CRi) achievement and reasons for failure (for induction questions) Duration of remission, relapse rates and deaths in first CR
Toxicity, both haematological and nonhaematological Supportive care requirements (and other aspects of health economics) Randomisation options There are four randomisations in the trial one at entry to the trial (1 or 2 doses of Mylotarg) two following course 1 when MRD status is known For no CR or MRD +ve patients (DA versus DAC versus FLAG-Ida) one is for all patients eligible to enter the small molecule (AC220 or ganetespib) randomisation A fourth randomisation follows course 2 for MRD-ve patients (2 vs 3 courses of chemotherapy) In special circumstances, contact HCTU
Eligibility all patients Inclusion: They have one of the forms of AML, or high risk MDS. Over the age of 60, but patients under this age are eligible if they are not considered eligible for the MRC AML17 trial. They have given written informed consent. Serum creatinine 1.5 ULN (upper limit of normal) Patients eligible for the Mylotarg randomisation must have ALT and AST 2.5 ULN and bilirubin 2. ULN 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. Adequate and medically accepted method of contraception throughout the study. These measures must be in place for at least 30 days after the last administration of ganetespib and 6 months after the last administration of Cladribine. ECOG Performance Status of 0-2
Exclusion: Eligibility all patients Exclusion: 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 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. Cardiovascular System Exclusion Criteria Small Molecule Known serious cardiac illness or medical conditions, including but not limited to: Clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, active myocardial ischemia, or indwelling temporary pacemaker 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. Use of medications that have been linked to the occurrence of torsades de pointes (see Appendix for the list of such medications) Second- or third-degree atrioventricular (AV) block unless treated with a permanent pacemaker Complete left bundle branch block (LBBB) History of long QT Syndrome or a family member with this condition QTc >470 ms (average of triplicate ECG recordings); a consistent method of QTc calculation must be used for each patients QTc measurements. QTcF (Fridericias formula) is preferred. Serum potassium, magnesium, and calcium levels not outside the laboratorys reference range Current IMPs Gemtuzumab Ozogamicin (Mylotarg)
Cladribine Quizartinib (AC220) Ganetespib Note: Standard chemotherapy drugs are not IMPs Treatments & schedules see section 9 in the protocol Course 1 All patients (Patients with known poor risk cytogenetics at diagnosis will receive DA only) DA plus Mylotarg 1 schedule Daunorubicin 60mg/m2 daily by IV infusion on days 1, 3 and 5 (3 doses) Cytosine Arabinoside 100 mg/m2 12-hourly by i.v. push on days 1 10 inclusive (20 doses) Mylotarg (GO) 3mg/m2 on day 1 of DA chemotherapy DA plus Mylotarg 2 schedule
Daunorubicin 60mg/m2 daily by i.v. infusion on days 1, 3 and 5 (3 doses) Cytosine Arabinoside 100 mg/m2 12-hourly by i.v. push on days 1 10 inclusive (20 doses) Mylotarg (GO) 3mg/m2 (capped at a maximum of 5mg per dose for patients with BSA above 1.67 m2) on days 1 and 4 of DA chemotherapy Treatments & schedules MRD-ve Patients Course 2 (2 vs 3 randomisation) DA 3+8 Daunorubicin 50 mg/m2 daily by i.v. infusion on days 1, 3 and 5 (3 doses) Cytosine Arabinoside 100 mg/m2 12-hourly by i.v. push on days 1 8 inclusive (16 doses) Course 3 (if applicable) DA 2+5
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) Treatments & schedules - MRD+ve/unknown Patients FLAG-Ida or Mini FLAG-Ida Therapy Course 2 For patients aged 60-69 years FLAG-Ida Fludarabine 30 mg/m2 daily i.v. on days 2-6 inclusive (5 doses) Cytosine Arabinoside 1 g/m2 daily over 4 hours, starting 4 hours after Fludarabine on days 2-6 inclusive (5 doses). G-CSF [Lenograstim 263 mg (1 vial)] s.c. daily days 1-7 inclusive (7 doses). Idarubicin x 8mg/m2 i.v. daily on days 4, 5 and 6 For patients aged 70+ years - Mini FLAG-Ida Fludarabine 25 mg/m2 daily i.v. on days 2-5 inclusive (4 doses) Cytosine Arabinoside 1 g/m2 daily over 4 hours, starting 4 hours after Fludarabine on days 2-5 inclusive (4 doses)
G-CSF [Lenograstim* 263mg (1 vial)] s.c. daily days 1-6 inclusive (6 doses). Idarubicin 5 mg/m2 i.v. daily on days 3, 4 and 5 (3 doses) Treatments & schedules Course 3 Mini FLAG-Ida (for all patients) Fludarabine 25 mg/m2 daily i.v. on days 2-5 inclusive (4 doses) Cytosine Arabinoside 1 g/m2 daily over 4 hours, starting 4 hours after Fludarabine on days 2-5 inclusive (4 doses) G-CSF [Lenograstim* 263mg (1 vial)] s.c. daily days 1-6 inclusive (6 doses). Idarubicin 5 mg/m2 i.v. daily on days 3, 4 and 5 (3 doses)
G-CSF: Lenograstim is recommended in this regime but is not obligatory Treatments & schedules DAC Therapy Course 2: DAC 3+8+5 Daunorubicin 50 mg/m2 daily by i.v. infusion on days 1, 3 and 5 (3 doses) Cytosine Arabinoside 100 mg/m2 12-hourly by i.v. push on days 1 8 inclusive (16 doses) Cladribine 5mg/m2 daily on days 1-5 inclusive by subcutaneous injection (capped at a maximum of 10mg per dose) Course 3: DAC 2+5+5 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) Cladribine 5mg/m2 daily on days 1-5 inclusive by subcutaneous injection (capped at a
maximum of 10mg per dose) Please note: Daily monitoring of creatinine is required during cladribine therapy Treatments & schedules DA Therapy Course 2: DA 3+8 Daunorubicin 50 mg/m2 daily by i.v. infusion on days 1, 3 and 5 (3 doses) Cytosine Arabinoside 100 mg/m2 12-hourly by i.v. push on days 1 8 inclusive (16 doses) Course 3: DA 2+5 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) IMP Specifics I Mylotarg
Supplied as an amber glass vial containing 5mg of Mylotarg lyophilised powder Light-sensitive and must be protected from direct and indirect sunlight and unshielded fluorescent light Reconstitute as per pharmacy manual Diluted drug solution may be stored for up to 16 hours at room temperature Administered as a 2 hour intravenous infusion (DO NOT administer as an intravenous push or bolus). Mylotarg will be given at a dose of 3mg/m2 on day 1 of course 1 for patients in arm A (1 dose of Mylotarg) and at a dose of 3mg/m2 on days 1 and 4 of course 1 for patients in arm B (2 doses of Mylotarg). IMP Specifics II Cladribine Cladribine (Litak) is a 2mg/ml solution for injection Supplied in a type 1 glass vial with rubber stopper and flip off aluminium cap
Each vial contains 10mg of cladribine in 5ml of solution Cladribine is supplied as a ready to use solution for injection Inject as a subcutaneous bolus injection without dilution IMP Specifics III AC220 AC220 is supplied in a tablet formation, each containing 20mg AC220 Packaged in high density polyethylene bottles, containing 30 tablets, with child-resistant caps Patients will take 2 x 20mg AC220 tablets once a day on an empty stomach at least 1 hour before or 2 hours after a meal in the morning Take for 14 days after cycles 2 and 3 of chemotherapy Patients on maintenance AC220 will take AC220 for 28 days for 12 cycles AC220 must be discontinued 48 hours prior to the next course
IMP Specifics IV Ganetespib Supplied as a 300mg/vial (25mg/mL) Each vial contains 12ml of deliverable ganetespib It is a clear, colourless-to-pale yellow solution, essentially free of visible particles Follow the protocol and pharmacy manual preparation guideline Please ensure patients are hydrated Follow guidance in protocol for management of diarrhoea IMP Distribution All IMPs will be delivered by SMPU Seeder stock of Mylotarg will be ordered by HCTU following Green Light procedure HCTU will replenish Mylotarg after site
randomisation HCTU will order course 2 IMP (cladribine and small molecule) All subsequent course IMPs (cladribine and small molecule) will need to be ordered by site. IMP management Request procedure Request forms provided in pharmacy file Shipment of course 1 and 2 requested automatically by HCTU, subsequent courses must be requested by site Accountability Forms available in site file Will be requested annually (approx.) Destruction
Must be authorised by Sponsor Temperature deviations should be reported, along with temp logs Site file & essential documents Site files have been issued to all participating PIs Your file should contain the usual, including: Copy of your signed agreement Training log & initiation attendance certificates Correspondence about clinical queries Details of amendments
Periodically, well ask for confirmation that your site file is up to date Online Randomisation System very similar to AML16 non-intensive and all other AML trials Contact HCTU if in doubt Data & Documentation CRFs similar to AML16 and LI-1 trials Documentation may be filled in online or sent to HCTU Data queries will be issued at regular intervals Please ensure that data is up to date Sample Flow Pre-Treatment
2-4ml* bone marrow in EDTA 20ml* peripheral blood in EDTA EDTA 10 ml of peripheral blood For AC220 Patients only 10ml* peripheral blood in EDTA To be taken on day 14 of each course For Long AC220 Patients To be taken at 2, 4 and 6 months after randomisation For Ganetespib Patients only: 10ml* peripheral blood in EDTA To be taken on day 14 of each course Dr Paul White Department of
Haematology 7th Floor Cardiff University Heath Park Cardiff CF14 4XN At Relapse 2-4ml* bone marrow in EDTA 20ml* peripheral blood in EDTA Please try to ensure that samples arrive in Cardiff within 48 hours of the sample being taken. In the event that a sample is taken on a Friday, please send as normal. *These are optimal quantities if only smaller volumes are available, please send what you can. For further assistance please contact Dr Paul White 029 2074 4524 Enhanced Monitoring
Enhanced monitoring will be required for every patient receiving DA + GO x 2, DAC, AC220, Ganetespib Monitoring will last for 4 weeks in courses 1 and 2 Via telephone or e-mail Quality of Life assessment Key endpoint (see protocol section 2.2) You will be provided with hard copies of QoL questionnaires and FREEPOST envelopes Reminder (at randomisation) for baseline QoL Baseline QoL must be completed before treatment commences Auto-reminders at 3, 6 and 12 months Important to inform HCTU of patient death
Cardiac Monitoring AC220 To be completed at Day 1, Day 7 and Day 14 for cycles 2 4 (no small molecule in cycle 1) PRE-DOSE ECG x3 + 2 HOURS Site Review + 4 HOURS
Site Review ECG x3 ECG x3 DAILY In the event that a concomitant medication is introduced that is known to cause QTc prolongation follow this path from Day 1 of commencing the concomitant medication.
ECG x3 until QTc <500ms N.B. It is not expected that 40mg AC220 will result in QTc problems but please see section 9.6.6 of protocol should any issues arise. Site Review Within 3 HOURS Site Review ECG x3
IF: Abnormality of concern e.g. value of QTcF increases to >500ms Within 2 HOURS IF: value of QTcF remains >500ms = DLT ECG x3 Please note: ECG machines are not provided in this trial Cardiac Monitoring AC220 Long
To be completed at Day 1, Day 8, Day 15, Day 21 for cycle 1 of AC220 maintenance. Pre-dose on Day 1 only for subsequent cycles. PRE-DOSE ECG x3 within 2 HOURS + 2 HOURS Site Review ECG x3 In the event that a concomitant
medication is introduced that is known to cause QTc prolongation follow this path from Day 1 of commencing the concomitant medication. N.B. If you suspect an abnormality of concern contact HCTU See section 9.6.6 of protocol for details. Site Review IF: Abnormality of concern e.g. value of QTcF increases to >500ms
DAILY ECG x3 until QTc <500ms ECG x3 Within 3 HOURS Site Review ECG x3
IF: value of QTcF remains >500ms = DLT Cardiac Monitoring - Ganetespib To be completed pre-dose on Day 1 for cycles 2 - 4 PRE-DOSE ECG x3 Site Review IF: Abnormality of concern e.g. value of QTcF increases to >470ms
ECG x3 IF: value of QTcF remains >470ms = infusion should be delayed until <470ms QTc should be <470ms prior to each dose or delayed till it falls to <470ms N.B. If you suspect an abnormality of concern contact HCTU See page 66 of protocol for details.
Patients with reported Grade 4 QTc prolongation (QTc >500 ms or >60 ms change from baseline and torsades de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia) or repeated Grade 3 or higher QTc prolongation must discontinue treatment with ganetespib. SAE Reporting What to include in report within 24 hours: What NOT to report (see section 16.2): Patient identifiers (Trial No, DoB, Initials, Sex) * Associated Drugs and treatment dates * Category of event (hospitalisation/death/life threatening etc.) * SAE start date * Details of event * Causality assessment for each individual
associated drug * Details of person reporting PI signature Pre-existing toxicities (only development of these toxicities requires reporting) *once these details are available the reporting clock has started Neutropenic fever and its consequences (unless >42 days post chemo) Death due or associated with persistent or progressive disease (although this should still be recorded, see Section 16.5) Unrelated SAEs 28 days or more after last dose of treatment
SAE Form Site must complete these sections Current Approved Documents
Protocol V3.1 May 2014 PIS1 V2.1 April 2014 PIS2 V1.2 April 2014 PIS3 V2.2 April 2014 PIS4 V3.0 May 2014 PIS5 V2.0 July 2013 GP Letter Course 1 V1.1 July 2013 GP Letter Course 2 Residual Disease V2.2 April 2014 GP Letter Course 2 CR-MRD Neg V2.0 July 2013 GP Letter Course 3 CR-MRD Neg V2.0 July 2013 Contact details For randomisations, data entry, IMP and all other queries relating to AML18: Trial Management &
Drug ordering: 029 2074 6413 Other (data): 029 2074 6413 Email: [email protected] Return address for QoL FREEPOST Dept Haematology, 6th Floor A-B link, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN For site activation Green Light Process What we need from you Fully signed Site Agreement Centre Registration Form R&D approval letter Provide a copy to HCTU
Initiation of key personnel Site Activation Cont What youll receive from us Log in details for the randomisation system and website (we cant do this without your centre registration form) An email stating that you are now open to recruitment Order your seeder supply of Mylotarg Thank you for all your hard work and good luck with your recruitment Any questions?
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