Transcript Welcome to the AML LI1 initiation

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
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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, we’ll 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 patient’s QTc measurements. QTcF (Fridericia’s formula) is preferred.
• Serum potassium, magnesium, and calcium levels not outside the laboratory’s reference
range
Current IMPs
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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:
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Copy of your signed agreement
Training log & initiation attendance certificates
Correspondence about clinical queries
Details of amendments
• Periodically, we’ll 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
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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
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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
&
Pharmacovigilance
Helen Clark (Tues – Fri)
[email protected]
029 2074 8976
Sarah Burns (Mon – Wed)
[email protected]
029 2184 7942
Data Manager
Nuria Marquez Almunia
[email protected]
029 2074 6413
Trials Office
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 you’ll receive from us
• Log in details for the randomisation system and
website (we can’t 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?