nopho-dbh aml 2012 protocol€¦ · reference lab . 1. review bm cytomorphology 2. flow cytometry...
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NOPHO-DBH AML 2012 Protocol
Research study for treatment of children and adolescents with acute myeloid leukaemia
Initiation presentation based on protocol version 2.1 dd 17/01/2013
Teleconference Study Initiation Belgium 20th of May 2014
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Sponsor: Vastra Gotaland Regionen Regionens Hus 462 80 Vanersborg Sweden
International Study Coordinators: Jonas Abrahamsson
Belgian National Coordinator:
Principal Investigator: Prof. Dr. Barbara De Moerloose Study coordinators: Maaike Van Hoecke and Rein Demuynck Contact: Tel: 0032 9 332 35 47 Fax: 0032 9 332 49 86
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Checklist at diagnosis
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AML2012 Overview
MEC
DxEC
R1 BM d22* R2
ADxE
FLADx
HAM HA3E FLA BM**
SCT for HR
CR
No CR
Salvage therapy
MEC
DxEC
R1 BM d22* R2
ADxE
FLADx
HAM HA3E FLA BM**
SCT for HR
CR
No CR
Salvage therapy
HA3E FLA Inv(16) and SR
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Objectives & endpoints of 1st study
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1st induction standard arm: MEC
Children < 1y or < 10kg Cytarabine 6.7 mg/kg Etoposide 5 mg/kg Mitoxantrone 0.17 mg/kg
Mtx it*
Cytarabine 200 mg/m2 12h ci iv
Etoposide 150 mg/m2 iv
Mitoxantrone 5 mg/m2 iv
Day 6-12
Day 6-10 Inf 1 hour
Day 1-5 Inf 2 hours
Day 1 2 3 4 5 6 7 8 9 10 11 12
MEC
Mtx it age-adjusted <1y 6 mg 1-<2y 8 mg 2-<3y 10 mg ≥ 3y 12 mg
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1st induction experimental arm: DxEC
Children < 1y or < 10kg Cytarabine 6.7 mg/kg Etoposide 5 mg/kg Daunoxome 2 mg/kg
Mtx it*
Cytarabine 200 mg/m2 12h ci iv
Etoposide 150 mg/m2 iv
Daunoxome 60 mg/m2 iv
Day 6-12
Day 6, 8 and 10 Inf 1 hours
Day 1-5 Inf 2 hours
Day 1 2 3 4 5 6 7 8 9 10 11 12
DxEC
Mtx it age-adjusted <1y 6 mg 1-<2y 8 mg 2-<3y 10 mg ≥ 3y 12 mg
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Objectives & endpoints of 2nd study
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2nd induction standard arm: ADxE
Children < 1y or < 10kg Cytarabine 3.3 mg/kg Etoposide 5 mg/kg Daunoxome 2 mg/kg
Mtx it
Cytarabine 100 mg/m2 iv
Etoposide 150 mg/m2 iv
Daunoxome 60 mg/m2 iv
Day 3-8, 30 min inf, every 12h
Day 2,4,6 1 hour inf
Day 6,7,8 2 hour
Day 1 2 3 4 5 6 7 8
Cytarabine 100 mg/m2 ci Day 1,2
ADxE
Mtx it age-adjusted <1y 6 mg 1-<2y 8 mg 2-<3y 10 mg ≥ 3y 12 mg
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2nd induction experimental arm: FLADx
Children < 1y or < 10kg Cytarabine 67 mg/kg Fludarabine 1 mg/kg Daunoxome 2 mg/kg
Fludarabine 30 mg/m2 iv (30min)
Cytarabine 2000 mg/m2 inf (3h)
Daunoxome 60 mg/m2 iv inf (1h)
Day
Day 1-5
Day 1-5 4h after fludarabine
Day 2,4,6 immediately after fludarabine
Mtx it
1 5 6 4 3 2
FLADx
Mtx it age-adjusted <1y 6 mg 1-<2y 8 mg 2-<3y 10 mg ≥ 3y 12 mg
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Overview of consolidation
HAM HA3E FLA
SCT HAM
Standard risk
High risk
No donor
HA3E FLA Inv(16)
Note that SR patients with Inv(16) only receive two consolidation
blocks
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HAM
Children < 1y or < 10 kg Cytarabine 33 mg/kg Mitoxantrone 0.33 mg/kg
Cytarabine 1000 mg/m2 inf (2h)
Mitoxantrone 10 mg/m2 iv inf (1 hour) Day 1-3 every 12 hours
Day 3,4,5
Mtx it
Day 1 5 4 3 2
HAM
Mtx it age-adjusted <1y 6 mg 1-<2y 8 mg 2-<3y 10 mg ≥ 3y 12 mg
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HA3E
Children < 1y or < 10 kg Cytarabine 67 mg/kg Fludarabine 1 mg/kg Daunoxome 2 mg/kg
Cytarabine 3000 mg/m2 inf (2h)
Etoposide 100 mg/m2 inf (1h)
Day 1-3 every 12 hours
Day 1-5
MTX it
Day 1 5 4 3 2
HA3E
Mtx it age-adjusted <1y 6 mg 1-<2y 8 mg 2-<3y 10 mg ≥ 3y 12 mg
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FLA
Children < 1y or < 10kg Cytarabine 67 mg/kg Fludarabine 1 mg/kg Daunoxome 2 mg/kg
Fludarabine 30 mg/m2 iv (30min)
Cytarabine 2000 mg/m2 inf (3h)
Day
Day 1-5
Day 1-5 4h after fludarabine
Mtx it
1 5 4 3 2
FLA
Mtx it age-adjusted <1y 6 mg 1-<2y 8 mg 2-<3y 10 mg ≥ 3y 12 mg
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Day 22 BM after course 1
Repeat BM weekly until recovery of ANC and platelets
Start course 2 immediately
Day 22 BM after course 2
Repeat BM weekly until recovery of PB
Salvage therapy If very aplastic BM consider
repeat BM – see protocol text
LC ≥ 5% LC < 5%
LC ≥ 5%
Start course 2 after recovery
LC < 5%
LC ≥ 5%
LC < 5%
LC < 5% and recovery start HAM
LC ≥ 0.1% assign HR
LC ≥ 5% BM + HAM after recovery
LC before HAM ≥ 0.1% assign HR
LC ≥ 15%
LC < 5%
Assign HR
Assign RD
Flow-sheet induction
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Radomisation Timepoints
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Checklist D22 after 1st induction
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Checklist after 2nd induction
Reference Lab
1. Review BM cytomorphology 2. Flow cytometry (MRD) 3. Biobanking 4. No PCR 5. No cytogenetics - please send a copy of
this report
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Induction MRD
Standard risk patients MRD before course 5*
Diagnosis – MRD target search
Day 22 – MRD all patients
Good Response < 5% LC MRD repeated weekly
Start course one
Start course two
Poor Response ? 5% LC Course 2 direct
Start course two after regeneration
MRD before consolidation MRD D22
Poor Response Off protocol
Good Response MRD repeated weekly
Start consolidation after regeneration
High risk patients MRD before SCT
High risk patients
MRD before SCT Standard risk patients MRD before course 5*
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Consolidation MRD
High risk patients MRD before SCT
Standard risk patients MRD before course 5
The exact number of MRD samples cannot be determined but it is expected that 3-4 samples per
patient will be taken during induction
Checklist
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Sample information sheet
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Flow Chart
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Flow Chart
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Database
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SAE/SUSAR reporting
• SAE: toxicity registration (appendix 2) > after each course!
• SUSAR: Death report form (appendix 3) > should be reported within 48h > submitted online in database or by fax
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DAUNOXOME
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National monitoring is provided by Bimetra Clinics.
Visits: TIV At least 1 visit/site Close-out visit
Responsibilities local sites: Do not start without a signed contract. ◦ Signed contract: UZ Brussel, HUDERF, UZ Leuven, UCL
Contact [email protected] after first inclusion
Contact [email protected] after LPLV Trial Master File SAE/SUSAR reporting: online or fax to NOPHO
Leukaemia registry Please provide us the site specific procedure for
granting access to internet/electronic patient files/…
Trial Master File: See ‘table of contents’ for required
documents ◦ Site signature log ◦ Subject screening and enrolment log ◦ Adverse event log ◦ Medication log ◦ Insurance certificate ◦ …
Templates are available
TIV report - List of responsibilities local PI
- Complete table on page 1: ‘local site’ - Sign the TIV report
- Local investigator - Study personnel
- Send scan to [email protected] - File signed document in TMF
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Thanks and good luck!
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Conclusions
• NOPHO DBH AML 2012 is open for inclusion: EC approval 17/04/2014
• Intersite contract signed: UZ Brussel, HUDERF, UZ Leuven, UCL
Contact site
Maaike Van Hoecke: 09/332 11 91
Rein Demuynck: 09/332 11 65