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Trial registered on ANZCTR


Registration number
ACTRN12611000814976
Ethics application status
Approved
Date submitted
15/07/2011
Date registered
3/08/2011
Date last updated
6/04/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Multicentre trial for the treatment of adolescents aged 15 years and above, and young adults aged up to 40 years, with newly diagnosed Acute Lymphoblastic Leukaemia (ALL)
Scientific title
A phase II trial of an intensive pediatric protocol incorporating post-induction stratification based on minimal residual disease levels for the treatment of adolescents aged 15 years and above, and young adults aged up to 40 years, with newly diagnosed ALL
Secondary ID [1] 262289 0
Nil
Universal Trial Number (UTN)
U1111-1122-4935
Trial acronym
ALLG ALL06
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Untreated ALL aged 15 to 40 years 268002 0
Condition category
Condition code
Cancer 268130 268130 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All patients will commence treatment with Protocol I which is an intensive chemotherapy induction protocol. Various prognostic factors such as cytogenetic abnormalities, initial response to prednisolone, achievement of remission, and MRD levels after induction and consolidation, will determine whether patients continue treatment outlined in Protocol M, or are to be treated on the High Risk protocol, or undergo allogeneic Haemopoietic Cell Transplantation (HCT). Patients removed for allogeneic HCT will be withdrawn from the study, but will continue to be followed, with relapse, disease-free and overall survival data being recorded. PROTOCOL I, Phase 1, Days 1-35: i) Intrathecal Methotrexate (IT MTX) on days 1, 15, 33. ii) Prednisolone (PRED) 60mg/m^2/day orally in 2 divided doses per day on Days 1-7. On Days 8-28 PRED 60mg/m^2/day in 3 divided doses. On Days 29-38: PRED taper in 3 stages every 3 days. Reduce dosage by half at each stage. iii) Vincristine (VCR) 1.5mh/m^2/day IV bolus (maximum single dose 2mg) Days 8, 16, 22 and 29. iv) Daunorubicin (DNR) 30mg/m^2 IV over 1 hr Days 8, 16, 22, 29. v) Pegylated Asparaginase (LINK) 1000U/m^2 IM or IV on Days 8 and 22. PROTOCOL I, Phase 2, Days 36-64: i) Cytarabine (ARA-C) 75mg/m^2/day IV or SC in 4 x 4 day blocks on Days 36, 37, 38, 39; Days 43, 44, 45, 46; Days 50, 51, 52, 53; Days 57, 58, 59, 60. ii) Cyclophosphamide (CPA) 1000mg/m^2/day/IV over 1 hour, Days 36 and 64. iii) 6-Mercaptopurine (MP) 60mg/m^2/day orally on Days 36-63, 28 days total. iv) Intrathecal Methotrexate (IT MTX) on Days 43 and 57 with the second and fourth cytarabine blocks. PROTOCOL M for Standard and Medium Risk only. Scheduled to commence on Day 79 after the start of Protocol 1, provided there is adequate count recovery. i) 6-Mercaptopurine (MP) 25 mg/m^2/day orally over 8 weeks, Days 1-56. ii) High Dose Methotrexate (HD-MTX) 5g/m^2 as a continuous infusion over 24 hours, on Days 8, 22, 36, 50. iii) Intrathecal Methotrexate (IT MTX) administered at 2 hours after the start of the MTX-infusion on Days 8, 22, 36, 50. HIGH RISK PROTOCOL, Block HR-1, normally begins directly after completion of Protocol I. i) Dexamethasone (DEXA) 20mg/m^2/d orally or by IV in 2 divided doses on Days 1-5. ii) Vincristine (VCR) 1.5mg/m^2/daily (maximum single dose 2mg) IV on Days 1 and 6. iii) High Dose Methotrexate (HD-MTX) 5g/m^2, infused IV over 24 hours on Day 1. iv) Cyclophosphamide (CPA) 200mg/m^2/twice daily IV over 1 hour, Days 2-4. v) Cytarabine (HD-ARA-C) 2g/m^2/twice daily, IV over 3 hours on Day 5. vi) Pegylated Asparaginase (ASP) 1000U/m^2 IM or IV on Day 6. vii) Intrathecal Methotrexate (MTX) 12 mg/Cytarabine (ARA-C) 30mg/Hydrocortisone 50mg on Day 1. HIGH RISK PROTOCOL, Block HR-2: The doses and scheduling of i) DEXA ii) HD-MTX/LCV-Rescue iii) ASP iv) MTX/ARA-C/HYDROCORTISONE IT are the same as in block HR-1. Additional therapy in HR2: v) Vindesine (VDS) 3mg/m^2/daily (maximum single dose 5mg) IV on Days 1 and 6. vi) Ifosfamide (IFO) 800mg/m^2/twice daily IV over 1 hour on Days 2-4. vii) Daunorubicin (DNR) 30mg/m^2/daily IV over 1 hour on Day 5. HIGH RISK PROTOCOL, Block HR-3: i) DEXA ii) ASP as in block HR-1. Additional therapy in HR-3: iii) Cytarabine (HD-ARA-C) 2g/m^2/twice daily IV over 3 hours, Days 1-2. iv) Etoposide (VP-16) 100mg/m^2/twice daily IV over 1 hour every 12 hours, Days 3-5. v) Intrathecal Methotrexate, Cytarabine, Hydrocortisone (MTX/ARA-C/HYDROCORTISONE IT) on Day 5. PROTOCOL II, Phase 1, Days 1-35: i) Dexamethasone (DEXA) 10mg/m^2/day orally in 2-3 divided doses, Days 1-21. From Day 22 on, reduce the dose every 3 days by half and stop on Day 29. ii) Vincristine (VCR) 1.5mg/m^2/day IV bolus (maximum single dose 2mg) on Days 8, 15, 22, 29. iii) Doxorubicin (DOX): 30mg/m^2/day IV over 1 hour on Days 8, 15, 22, 29. iv) Pegylated L’Asparaginase 1000U/m^2 IM or IV on Day1. v) Intrathecal Methotrexate (IT MTX) on Days 1, 18 ONLY IF CNS disease at diagnosis. PROTOCOL II, Phase 2, Days 36-50: i) Cytarabine (ARA-C) 75mg/m^2/day IV or SC in 2 x 4 day blocks. Days 36, 37, 38, 39 and Days 43, 44, 45, 46. ii) Cyclophosphamide (CPA) 1000mg/m^2 IV over 1 hour, Day 36. iii) 6-Thioguanine (6-TG) 60mg/m^2/day orally, Day 36-49, a total of 14 days. iv) Intrathecal Methotrexate (IT MTX) at the same time as the first dose of Cytarabine in Block 1 (Day 36) and Block 2 (Day 43). MAINTENANCE THERAPY begins 2 weeks after the end of Protocol II. Total therapy, calculated from the start of Protocol I, is 24 months for all patients. i) 6-Mercapoturine (MP) 50mg/m^2/day orally. ii) Methotrexate (MTX) 20mg/m^2/week, orally once a week at night.
Intervention code [1] 266871 0
Treatment: Drugs
Comparator / control treatment
Paediatric patients diagnosed with the same condition who were treated as part of a different ALLG study (ANZCHOG study 8, ANZCTR registration number ACTRN12607000302459)
Control group
Historical

Outcomes
Primary outcome [1] 269092 0
The primary objective of this study is to determine whether a modified form of the BFM-2000 protocol can be administered to patients with newly diagnosed and untreated ALL aged between 15 and 40 years in a comparable timeframe to patients under 15 years of age.

All patients will commence treatment with Protocol 1, which is an intensive chemotherapy induction protocol. Various prognostic factors such as cytogenetic abnormalities, initial response to prednisolone, achievement of remission, and MRD levels after induction and consolidation, will determine whether patients continue treatment outlined in Protocol M, or are to be treated on the High Risk protocol, or undergo allogeneic HCT. Patients removed for allogeneic HCT will be withdrawn from the study, but will continue to be followed, with relapse, disease-free and overall survival data being recorded.
Timepoint [1] 269092 0
The primary end-point will be the proportion of patients starting protocol M by day 94 after commencing therapy, or in the case of patients stratified to receive high risk treatment, the start of HR block 1.
Secondary outcome [1] 276913 0
To evaluate the complete remission (CR) rates, disease-free survival (DFS) and overall survival (OS) of patients treated on this protocol and to compare with results reported in a similar age group using protocols designed for use in adult patients.
Timepoint [1] 276913 0
when all patients have reached day 94 of treatment (time point for primary endpoint) and when all patients have completed 2 years follow up post treatment
Secondary outcome [2] 276914 0
To evaluate toxicity, both hematologic and non-hematologic.
Timepoint [2] 276914 0
On-going, until completion of treatment.
Secondary outcome [3] 276915 0
To compare the proportions of AYA patients with standard, medium, and high risk disease to pediatric ALL, and to evaluate outcomes within these risk groups.

The outcomes listed here will be evaluated within these risk groups.
Timepoint [3] 276915 0
when all patients have reached day 94 of treatment (time point for primary endpoint) and when all patients have completed 2 years follow up post treatment
Secondary outcome [4] 276916 0
To assess the level of minimal residual disease (MRD) after induction chemotherapy and compare this with levels reported in a similar age group using adult protocols.

MRD analysis will be performed on peripheral blood and bone marrow samples.

MRD levels will be measured by quantitative polymerase chain reaction (PCR) and flow cytometric techniques, which can detect small numbers of residual leukemic cells surviving in the bone marrow after initial treatment.
Timepoint [4] 276916 0
Completion of Induction Chemotherapy.
Secondary outcome [5] 276917 0
To conduct correlative laboratory scientific studies on blood and bone marrow samples taken from patients enrolled on this study.
Timepoint [5] 276917 0
End of Study.
Secondary outcome [6] 276918 0
To assess the impact of treatment on physical, functional, emotional and social wellbeing via HRQOL assessment at the beginning and end of each phase of treatment.
Timepoint [6] 276918 0
At the start and end of each phase on treatment.
Secondary outcome [7] 276919 0
To provide an indication of fertility status after treatment.

The following fertility assessments will occur during follow-up:

For women:
Follicle Stimulating Hormone (FSH), Luteinising hormone (LH), estradiol 3 months after the end of therapy, then annually for 5 years

For men:
Semen analysis at the end of therapy, then annually until normal.
Timepoint [7] 276919 0
during Follow-up

Eligibility
Key inclusion criteria
All of the following criteria must be satisfied for registration on the study.
1. A morphological diagnosis of ALL byWHO criteria, confirmed by immunophenotyping and cytogenetics. All clinico-pathological subtypes will be eligible, except for mature B or Burkitt ALL (L3).
2. Has provided written, informed consent
3. Available for follow up for at least 3 years
4. Males capable of parenting a child and women of childbearing potential must be using a medically acceptable and adequate method of contraception while undergoing protocol treatment and for 28 days following the last dose of protocol treatment. Note: due to a potentially increased risk of thrombosis in asparaginase containing regimens, cessation of the combined oral contraceptive in female patients should be considered and an alternative medically appropriate form of contraception be instituted.
5. Bone marrow blast count >/= 20%
6. Adequate renal and hepatic function at Screening as defined by:
a. Total bilirubin <2.5 x ULN unless medically correctable
b. Serum creatinine less than or equal to 200 micromol/L unless medically correctable
7. Normal left ventricular ejection fraction, according to institutional criteria. If the clinical circumstances require that treatment must be given urgently before this can be ascertained, the absence of clinical cardiac impairment is acceptable, provided that a normal left ventricular ejection fraction is confirmed prior to the first consolidation cycle.
8. An ECOG performance status score of 0-3 at Screening
Minimum age
15 Years
Maximum age
40 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Presence of any of the following criteria will exclude the subject from registration on the study.
1. Subjects aged less than 15 or more than 40 years at Screening
2. Patients known to have Philadelphia chromosome-positive disease
3. Presence of serious cardiac, pulmonary, hepatic or renal disease.
4. Previous treatment for ALL or history of cancer (other than basal cell skin cancer or carcinoma of the cervix in situ, or other localised cancer treated by surgical excision only more than 5 years earlier without evidence of recurrence in the intervening period).
5. Contraindication to the use of the study drugs.
6. Positive for HIV, or evidence of uncontrolled Hepatitis B or C infection
7. Severe active infection
8. Has any other clinically important abnormalities as determined by the investigator that may interfere with his or her participation in or compliance with the study
9. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. This condition must be discussed with the patient prior to signing consent and registration in the trial.
Pregnancy-Women who are pregnant at the time of diagnosis will not be excluded from the trial per se. The specific circumstances will require discussion between the patient, the hematologist responsible for her care, and the attending obstetrician. The management plan should then be discussed with one of the study

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The patients will be screened and enrolled by their treating physician.

Before the patient can commence day 1 treatment of prednisolone and IT MTX, the investigator should ensure that all of the following requirements are met:
- The patient has signed and dated the screening PICF
- All Screening assessments and investigations have been performed.
- the only exception being that extenuating circumstances prevent the gated heart pool scan or echo pre-treatment to assess cardiac function– in this instance the test must be completed and results known prior to registration to confirm eligibility
- Blood and marrow samples are mandatory for study entry and must be collected before any treatment is commenced.
- All of the required samples have been sent or are in the process of being shipped to the central laboratories for MRD testing and laboratory studies.
If the investigator feels that the patient must commence treatment immediately, (prior to receiving the final screening test results), treatment with prednisolone & IT MTX can commence prior to registration if:
-the treatment specified in this protocol for day 1 to day 7 is standard of care at the treating hospital.
-the patients’ eligibility is confirmed and the patient is registered prior to day 8 of treatment.
The day the prednisolone is commenced is regarded as day 1 of the protocol. Registrations will not be accepted once day 8 systemic chemotherapy has commenced

All patients will commence treatment with Protocol 1 which is an intensive chemotherapy induction protocol. Various prognostic factors such as cytogenetic abnormalities, initial response to prednisolone, achievement of remission, and MRD levels after induction and consolidation, will determine whether patients continue treatment outlined in Protocol M, or are to be treated on the High Risk protocol, or undergo allogeneic HCT. Patients removed for allogeneic HCT will be withdrawn from the study treatment, but will continue to be followed, with relapse, disease-free and overall survival data being recorded
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
This is not a randomized study
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Various prognostic factors such as cytogenetic abnormalities, initial response to prednisolone, achievement of remission, and MRD levels after induction and consolidation, will determine whether patients continue treatment outlined in Protocol M, or are to be treated on the High Risk protocol, or undergo allogeneic HCT.
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 8179 0
The Alfred - Prahran
Recruitment hospital [2] 8180 0
The Canberra Hospital - Garran
Recruitment hospital [3] 8181 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [4] 8182 0
Gosford Hospital - Gosford
Recruitment hospital [5] 8183 0
Royal Hobart Hospital - Hobart
Recruitment hospital [6] 8184 0
Liverpool Hospital - Liverpool
Recruitment hospital [7] 8185 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [8] 8186 0
Prince of Wales Hospital - Randwick
Recruitment hospital [9] 8187 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [10] 8188 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [11] 8189 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [12] 8190 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [13] 8191 0
The Townsville Hospital - Douglas
Recruitment hospital [14] 8192 0
Westmead Hospital - Westmead
Recruitment hospital [15] 8193 0
Wollongong Hospital - Wollongong
Recruitment postcode(s) [1] 16241 0
3004 - Prahran
Recruitment postcode(s) [2] 16242 0
2605 - Garran
Recruitment postcode(s) [3] 16243 0
6150 - Murdoch
Recruitment postcode(s) [4] 16244 0
2250 - Gosford
Recruitment postcode(s) [5] 16245 0
7000 - Hobart
Recruitment postcode(s) [6] 16246 0
2170 - Liverpool
Recruitment postcode(s) [7] 16247 0
4102 - Woolloongabba
Recruitment postcode(s) [8] 16248 0
2031 - Randwick
Recruitment postcode(s) [9] 16249 0
5000 - Adelaide
Recruitment postcode(s) [10] 16250 0
2065 - St Leonards
Recruitment postcode(s) [11] 16251 0
2050 - Camperdown
Recruitment postcode(s) [12] 16252 0
6009 - Nedlands
Recruitment postcode(s) [13] 16253 0
4814 - Douglas
Recruitment postcode(s) [14] 16254 0
2145 - Westmead
Recruitment postcode(s) [15] 16255 0
2500 - Wollongong

Funding & Sponsors
Funding source category [1] 267461 0
Other Collaborative groups
Name [1] 267461 0
Australasian Leukaemia and Lymphoma Group
Address [1] 267461 0
35 Elizabeth Street, Richmond, Vic 3121
Country [1] 267461 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group
Address
35 Elizabeth Street, Richmond, Vic 3121
Country
Australia
Secondary sponsor category [1] 266506 0
None
Name [1] 266506 0
Address [1] 266506 0
Country [1] 266506 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 269432 0
Northern Sydney Local Health District Human Research Ethics Committee
Ethics committee address [1] 269432 0
Research Business Unit
Level 13, Kolling Building, Royal North Shore Hospital, St Leonards NSW, 2065
Ethics committee country [1] 269432 0
Australia
Date submitted for ethics approval [1] 269432 0
01/08/2011
Approval date [1] 269432 0
25/06/2012
Ethics approval number [1] 269432 0
HREC/12/HAWKE/25
Ethics committee name [2] 297814 0
The Alfred Ethics Committee
Ethics committee address [2] 297814 0
55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [2] 297814 0
Australia
Date submitted for ethics approval [2] 297814 0
Approval date [2] 297814 0
06/08/2013
Ethics approval number [2] 297814 0
130/13
Ethics committee name [3] 297815 0
ACT Government Health Directorate HREC
Ethics committee address [3] 297815 0
Building 10 Level 6 Canberra Hospital
PO Box 11 Woden ACT 2606
Ethics committee country [3] 297815 0
Australia
Date submitted for ethics approval [3] 297815 0
Approval date [3] 297815 0
19/09/2012
Ethics approval number [3] 297815 0
ETH.6.12.116
Ethics committee name [4] 297816 0
Human Research Ethics Committee (Tasmania) Network
Ethics committee address [4] 297816 0
Research Integrity and Ethics Unit (RIEU)
Division of the Deputy Vice Chancellor (Research)
University of Tasmania
Private Bag 1
Hobart Tasmania 7001
Ethics committee country [4] 297816 0
Australia
Date submitted for ethics approval [4] 297816 0
Approval date [4] 297816 0
16/01/2017
Ethics approval number [4] 297816 0
H0015540
Ethics committee name [5] 297817 0
Metro South Human Research Ethics Committee
Ethics committee address [5] 297817 0
PAH Centres for Health Research
Level 7, Translational Research Institute
37 Kent Street
Woolloongabba QLD 4102
Ethics committee country [5] 297817 0
Australia
Date submitted for ethics approval [5] 297817 0
Approval date [5] 297817 0
31/10/2013
Ethics approval number [5] 297817 0
HREC/13/QPAH/363
Ethics committee name [6] 297818 0
Sir Charles Gairdner Group HREC
Ethics committee address [6] 297818 0
Level 2 A Block Hospital Ave, Nedlands, WA 6009
Ethics committee country [6] 297818 0
Australia
Date submitted for ethics approval [6] 297818 0
Approval date [6] 297818 0
26/07/2012
Ethics approval number [6] 297818 0
2011-170
Ethics committee name [7] 297819 0
Research Ethics Committee Royal Adeladie Hospital
Ethics committee address [7] 297819 0
Level 3 Hanson Institute, RAH, North Terrace, Adelaide SA 5000
Ethics committee country [7] 297819 0
Date submitted for ethics approval [7] 297819 0
Approval date [7] 297819 0
25/01/2012
Ethics approval number [7] 297819 0
20111224

Summary
Brief summary
This study will be a national clinical trial that will evaluate the safety and efficacy of a chemotherapy treatment, administered to adolescents and young adults with a newly diagnosed bone marrow cancer, called acute lymphoblastic leukaemia (ALL).

Who is it for?

You may be able to join this study if you are aged between 15 to 40 years and have been recently diagnosed with acute lymphoblastic leukaemia (ALL), for which you have not yet undergone any treatment.

Trial details:

ALL is the most common form of childhood cancer, but in over 80% of children it can be cured with chemotherapy. Adults with ALL do much worse and this trial will examine whether exactly the same treatment given to children can also be given to adults, and if so, are the results as good. In order to determine this, all patients in this trial will be administered the same chemotherapy treatment given to children. Patients' response to this chemotherapy will determine subsequent treatment.

Participants in this trial will be regularly assessed throughout this trial to determine remission rates, survival, toxicity and quality of life.
Trial website
www.allg.org.au
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 32686 0
Dr Matthew Greenwood
Address 32686 0
Haematology Department, Level 5 Acute Services Building, Royal North Shore Hospital Pacific Hwy, St Leonards NSW 2065 Australia
Country 32686 0
Australia
Phone 32686 0
+61 2 9926 4393
Fax 32686 0
Email 32686 0
Matthew.Greenwood@health.nsw.gov.au
Contact person for public queries
Name 15933 0
Miss Amanda Jager
Address 15933 0
Australasian Leukaemia & Lymphoma Group
35 Elizabeth St, Richmond, Vic 3121
Country 15933 0
Australia
Phone 15933 0
+61(0)383739714
Fax 15933 0
Email 15933 0
amanda.jager@allg.org.au
Contact person for scientific queries
Name 6861 0
Dr Dr Matthew Greenwood
Address 6861 0
Haematology Department, Level 5 Acute Services Building, Royal North Shore Hospital Pacific Hwy, St Leonards NSW 2065 Australia
Country 6861 0
Australia
Phone 6861 0
+61 2 9926 4393
Fax 6861 0
+61 2 9926 4070
Email 6861 0
Matthew.Greenwood@health.nsw.gov.au

No data has been provided for results reporting
Summary results
Not applicable