Transcript Randomisation & Stratification

Leukaemia for
shared care centres
Workshop session
Caroline Osborne & Julia Hitchin (Alder Hey)
NPPG conference
11th November 2012
Workshop content
 Presentation
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Children’s Cancer Measures
Shared care levels for POSCUs
Clinical Trial Issues
Background – other trial results (UK and international)
Objectives of UKALL 2011
UKALL 2011 trial summary
IMPs/NIMPs
Pharmacy responsibilities
 UKALL
2011 Prescription verification
exercise
 Open discussion
Aims of session
 Have
an understanding of the UKALL
2011 clinical trial
 Understand the implications of this trial for
your POSCU
 Be aware of your responsibilities in
dispensing for this clinical trial
Children’s Cancer Measures

2005 NICE Improving Outcomes Guidance in
Children and Young People with Cancer
 2009 Manual for Cancer Services , Children’s
Cancer Measures. Part of National Cancer Peer
Review Programme.
 2011 - V2.1
 Birth to 16 years
Children’s Cancer Measures
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Principle Treatment Centre (PTC) – 20, linked to
CCLG
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Paediatric Oncology Shared Care Unit (POSCUs)
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Self assessment, Internal Validation, external
review
Shared care levels for POSCUs
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Level 1
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Level 2
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Supportive care
Out patient Oral chemo
Out patient IV bolus
As level 1 PLUS
Day case infusional chemo
Level 3
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As level 2 plus inpatient 24 hour chemotherapy
Everything except diagnosis, trial enrolment, BMT etc
Clinical Trial Issues
 IMP

= Investigational Medicinal Product
a pharmaceutical form of an active substance or
placebo being tested or used as a reference in a
clinical trial, including products already with a
marketing authorisation but used or assembled in a
way different from the authorised form, or when used
for an unauthorised indication, or when used to gain
further information about the authorised form
 NIMP
= Non-Investigational Medicinal
Product (i.e. any other drug used within
protocol)
IMP management
 IMPs
may be licensed medication that only
becomes IMP once taken off shelf to
dispense OR
 Trial specific products that must be
ordered, stored and recorded specifically
for the trial
 Drug accountability is required for all IMPs
 Labelling – need to attach a trial specific
label (supplied by trial sponsor) to each
container of IMP dispensed as well as
dispensing label
Background
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Results of UKALL 2003 show an improvement in
EFS of 6% (87%)
 Among the best reported to date internationally
 Various recent international trials (COG and
BFM) have been reviewed whilst making the
changes to UKALL 2011
 UKALL 2011 aims to further improve survival
and quality of survival by addressing 4 main
issues apparent from UKALL 2003
UKALL 2003
4 main areas of concern
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Treatment related morbidity and mortality too
high in context of DFS 87%
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100 non-relapse deaths in CR, 25% all patients have
at least 1 SAE
Marked reduction in QoL
TRM commonest during induction and delayed
intensive (Dexamethasone)
Very poor prognosis of early marrow relapse
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<20% survive even after transplant
UKALL 2003
4 main areas of concern
 Concerns
over efficacy and burden of
therapy of CNS prophylaxis (i.e. IT’s)
 Superior
outcome for young adults treated
on paediatric protocol
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Up to age 24. Previously treatment depended
on place of presentation/choice
Needs more uniform approach so all young
adults get treated the same
Aims & Objectives of UKALL 2011
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Reduce toxicity through introduction of short 14day course high dose dexamethasone instead of
conventional 28 day lower dose (randomised)
 More effective CNS prophylaxis and reduce
burden of therapy by introducing high dose IV
methotrexate and by omission of vincristine and
dex pulses (randomised)
 Decrease toxicity and reduce burden of therapy
by administering a single delayed intensification
to all patients (non-randomised)
UKALL 2011
Inclusion
 Age
1 year to < 25 years
 First diagnosis of acute lymphoblastic
leukaemia or:
 Lymphoblastic lymphoma (T-NHL or
precursor negative B-NHL)
Regimen A (Standard risk)
Induction
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B cell precursor ALL < 10 years of age and
highest WCC <50
All Downs syndrome patients
Randomised to standard dexamethasone (IMP)
6mg/m2/day in 2 doses (capped at 10mg/day) for
28 days then taper over next 7 days
OR short dexamethasone (IMP) 10mg/m2/day in
2 doses (not capped & no taper) for 14 days
Weekly vincristine
PEG Asparaginase
Intrathecal Methotrexate
Regimen B (High risk) Induction
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B cell precursor ALL > 10 years of age and/or highest
WCC >50
All T cell ALL and T cell lymphoblastic lymphoma
Randomised to standard dexamethasone (IMP)
6mg/m2/day in 2 doses (capped at 10mg/day) for 28
days then taper over next 7 days
OR short dexamethasone (IMP) 10mg/m2/day in 2
doses (not capped & no taper) for 14 days
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(NB >10 years “short dex” get 2 x 7 day blocks weeks 1 & 3 –
reduced risk osteonecrosis)
Weekly daunorubicin and vincristine
PEG Asparaginase
Intrathecal Methotrexate
Day 29 MRD
risk – continue regimen A or B as
allocated for induction
 Risk – augmented BFM consolidation
regimen C
 No result – determine post induction
therapy based on early response
 Low
Post induction treatment –
Regimen A
Post induction treatment – reg B
Interim maintenance
(standard arm)
 As
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in UKALL 2003 (ALL IMPS)
Dexamethasone 5 day pulse each month
Vincristine monthly
Continuous oral mercaptopurine 75mg/m2/day
for 8 weeks
Oral methotrexate weekly omitting in weeks
when get intrathecals
Intrathecal methotrexate monthly
Protocol M – High Dose
methotrexate (experimental arm)
 ALL
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IMPs
Oral mercaptopurine 25mg/m2/day for 8
weeks (NB much lower dose than elsewhere)
IV Methotrexate 5g/m2 every 14 days for 4
doses
Intrathecal methotrexate – within 2 hours of
start of IV Methotrexate
Delayed Intensive (reg A week 18 – 24)
(reg B week week 20-26) All NIMPs
 As
per UKALL 2003 except no Intrathecals
in part 2
 Part 1 - Vinc, Dox, PEG, IT day 1, Dex
10mg/m2/day for 7 days week 1 & 3
 Part 2 - Cyclo, Cytarabine, oral
Mercaptopurine 60mg/m2/day for 14 days
Maintenance
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All patients get
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Pulses (randomised to receive or not)
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Dexamethasone (IMP) 6mg/m2/day for 5 days every 4
weeks
Vincristine (IMP) 1.5mg/m2 every 4 weeks
Intrathecals (IMP) (NOT for patients who got
protocol M)
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Oral Mercaptopurine (NIMP) 75mg/m2/day continuous
(adjusted for counts)
Oral Methotrexate (NIMP) 20mg/m2 once a week
(omitted week of IT & adjusted for counts)
IT Methotrexate day 15 of each 12 week cycle
NB Septrin continues throughout
Regimen C
 Induction
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Only for reg A subsequently found to have
high risk cytogenetics OR Downs syndrome
with SER
Continue Dex as randomised
Continue Vinc
Daunorubicin day 16 & 23 (higher dose than
reg B)
Post induction treatment – reg C
Capizzi interim maintenance
(standard arm) (all IMPs)
 As
UKALL 2003
 Vincristine every 10 days with escalating
IV Methotrexate doses
 PEG Asparaginase
 Intrathecal methotrexate
Protocol M-A (experimental arm)
(all IMPs)
 As
reg A/B with addition of Peg Asp
Delayed Intensive – reg C
(weeks 24-31) All NIMPs
 As
per UKALL 2003
 As regimen A/B
Special IMPs
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Mercaptopurine 10mg tabs and PEG
Asparaginase, licensed in Germany, must use
Medice (Medac UK) for both
Methotrexate liquid for IMP is trial specific from
Stockport
In NIMP phase use special from Stockport
Mercaptopurine suspension – is now a licensed
product (NOVA) but initially this is trial specific
IMP from NOVA
When NIMP must use licensed NOVA product
Pharmacy Responsibilities
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Maintaining pharmacy file and signing relevant
delegation logs
 IMP ordering, ensuring only approved preparations are
used
 IMP storage in controlled temperature environment
 Drug accountability of all IMPs
 Ensure prescription is identified as clinical trial and IMPs
are highlighted
 Identification of IMP by approved trial label in addition to
dispensing label
 Recording returns and safely disposing of them
Useful Links
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NPPG and POP group
Your local cancer network –see the Department
of Health website for a full list www.dh.gov.uk
www.bopawebsite.org – learning centre:
Verification of Chemotherapy Prescriptions in
Paediatrics Module
www.macmillan.org.uk – aimed at public but lots
of useful information
www.cclg.org.uk
www.cquins.nhs.uk – children's cancer
measures