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Trial registered on ANZCTR


Registration number
ACTRN12617001174370
Ethics application status
Approved
Date submitted
20/07/2017
Date registered
10/08/2017
Date last updated
9/10/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Use of parental stem cells for children requiring a bone marrow transplant
Scientific title
TCR a+ß+/CD19+ cell depleted haploidentical donor stem cell transplantation for paediatric patients
Secondary ID [1] 292442 0
Nil known
Universal Trial Number (UTN)
U1111-1199-3727
Trial acronym
Paßlo (Paediatric aß haploidentical transplantation)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Haematological malignancy
304053 0
Bone marrow failure 304145 0
Primary immunodeficiency 304225 0
Inherited metabolic disorder 304226 0
Condition category
Condition code
Cancer 303379 303379 0 0
Children's - Leukaemia & Lymphoma
Cancer 303384 303384 0 0
Children's - Other
Human Genetics and Inherited Disorders 303576 303576 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1 - Group receiving investigational device
Patients will receive a TCR a+ß+/CD19+ cell depleted graft from a haploidentical parental donor. Candidates will only be eligible for Arm 1 of the study if there are no suitable human leucocyte antigen (HLA) matched readily available donors, and no suitably matched umbilical cord blood units available.

Conditioning therapy used will be dependent on HSCT indication. GVHD prophylaxis will include in vivo serotherapy (ATG) (once daily IV dose of 2.5mg/kg for 3 days) and mycophenolate mofetil in non-malignant patients (15mg/kg 3 times a day -2 to day +30, given initially IV with an option to switch to orally dependent on patient tolerability).

Donor product will be peripheral blood stem cells collected via G-CSF stimulated apheresis. Apheresis will be performed as per FACT guidelines, national standards and individual institution protocols. All donor products will be processed in FACT accredited Bone Marrow Transplant laboratories. Fresh donor product will undergo TCR aß+ depletion and CD19+ depletion using Miltenyi CliniMACS® paramagnetic bead technology. The target CD34+ dose will be 10 x10^6/kg recipient weight, with a recommended minimal dose of 5 x 10^6/kg.

Patients on Arm 1 will be assessed for neutrophil and platelet engraftment, transplant related mortality, graft versus host disease, relapse and overall survival. They will also be assessed for immune reconstitution, economic and quality of life outcomes.

Arm 2 – Control group
Candidates for Arm 2 will be patients undergoing alternate donor HSCT, defined as any donor that is not an HLA matched sibling (e.g., volunteer donor, matched umbilical cord blood units).

Economic and Quality of Life outcomes will be measured for these patients post-transplant.
Intervention code [1] 298621 0
Treatment: Devices
Intervention code [2] 298812 0
Treatment: Other
Comparator / control treatment
HSCTs administered to the control group will not be a+ß+/CD19+ HSCTs. Patients will be undergoing alternate donor HSCT, defined as any donor that is not an HLA matched sibling (e.g., volunteer donor, matched umbilical cord blood units).

Control group
Active

Outcomes
Primary outcome [1] 302764 0
Determine the incidence of donor derived neutrophil recovery post a+ß+/CD19+ HSCT (defined as an absolute neutrophil count >500 x10^6/L for 3 consecutive days).
Timepoint [1] 302764 0
Patients will undergo regular clinical assessment post HSCT as inpatients, and then be reviewed at a minimum of weekly in an outpatient setting for at least the first 100 days post transplant.
The incidence of donor derived neutrophil recovery post a+ß+/CD19+ HSCT will be assessed at day 28 post transplant.
Primary outcome [2] 302765 0
Evaluate the cost of a+ß+/CD19+ HSCT compared to other alternate donor HSCT.

This aspect of the study will assess the equipment, personnel and time resources involved for the acquisition and delivery of a donor product. For each activity, eCRFs will be utilised to collect data from each participating site for each patient on the time and personnel involved in the relevant activity, as well as the quantities of any relevant consumables used (e.g. G-CSF for donor cell mobilisation).

This aspect of the study will also assess post-transplant health service utilisation, which will be based on two key aspects:
1) The use of hospital services. This will be assessed via the completion of an eCRF at study sites for inpatient hospital procedures, and will collect information on the timing and reason for each hospitalisation.
2) The use of medical and pharmaceutical services. For this purpose, patients (or parents/guardians) will be consented to access their Medicare data to allow for information on their medical service use (MBS) and pharmaceutical services (PBS).
Timepoint [2] 302765 0
1. The initial 12 month within trial period
2. Subsequent patient follow-up (up to five years post HSCT)
Secondary outcome [1] 336942 0
Determine the incidence of platelet engraftment (defined as a platelet count >20 x109/L for 7 consecutive days without requiring transfusion).
Timepoint [1] 336942 0
To confirm platelet engraftment, patients will undergo regular clinical assessment post HSCT as inpatients, and then be reviewed at a minimum of weekly in an outpatient setting for at least the first 100 days post transplant.

The incidence of platelet engraftment will be assessed at 100 days post a+ß+/CD19+ HSCT.
Secondary outcome [2] 336943 0
The time to neutrophil and platelet engraftment in a+ß+/CD19+ HSCT will be evaluated by clinician definition and prospective data captured on the study database.
Timepoint [2] 336943 0
Patients will undergo regular clinical assessment post HSCT as inpatients, and then be reviewed at a minimum of weekly in an outpatient setting for at least the first 100 days post transplant.
Secondary outcome [3] 336944 0
Determine the incidence of graft versus host disease (GVHD) grade II-IV as per published criteria (1994 Consensus Conference on Acute GVHD Grading).
Timepoint [3] 336944 0
At 100 days days post a+ß+/CD19+ HSCT.
Secondary outcome [4] 336945 0
Determine the incidence of graft versus host disease (GVHD) grade III-IV as per published criteria (National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease).
Timepoint [4] 336945 0
At 100 days post a+ß+/CD19+ HSCT.
Secondary outcome [5] 336946 0
Determine transplant related mortality post a+ß+/CD19+ HSCT by review of data captured on the study database.
Timepoint [5] 336946 0
At 100 days and 365 days post a+ß+/CD19+ HSCT.
Secondary outcome [6] 336947 0
Determine the overall survival post a+ß+/CD19+ HSCT.
Timepoint [6] 336947 0
At 2 years post a+ß+/CD19+ HSCT.
Secondary outcome [7] 337553 0
Evaluate time to full immune reconstitution in a+ß+/CD19+ HSCT.

Immune reconstitution will be assessed by formal measurement of lymphocyte subsets, including TCR a+ß+ and TCR g+d+ cells. Immunoglobulin levels (IgG, IgM, IgA) will also be performed at the same time points.
Timepoint [7] 337553 0
At 1 month, 3 months, 6 months, 1 year and 2 years post HSCT.
Secondary outcome [8] 337554 0
Explore the pattern of chimerism post a+ß+/CD19+ HSCT (assessed by whole blood chimerism evaluation).
Timepoint [8] 337554 0
At day 30 post HSCT, and then further assessment at day 90, day 180, 1 year and 2 years post HSCT. Lineage specific chimerism, including myeloid, B cell, T cell and NK cell lineages will be performed from day 90 where possible.
Secondary outcome [9] 337591 0
Quality of Life post HSCT will be assessed via the Paediatric Quality of Life (CHU9D) questionnaire and the Pediatric Quality of Life Inventory (cancer module).
Timepoint [9] 337591 0
Questionnaires will be completed prior to transplant, at 3 months, 6 months, 12 months, and then annually until 5 years post transplant.
Secondary outcome [10] 337612 0
Carer burden post HSCT will be assessed via the Parent/Carer Impact Form (modified Work Productivity and Activity Impairment Questionnaire) (WPAI-GH) and the Care related Quality of Life (CarerQoL-7D) questionnaire.
Timepoint [10] 337612 0
Questionnaires will be completed prior to transplant, at 3 months, 6 months, 12 months, and then annually until 5 years post transplant.

Eligibility
Key inclusion criteria
A patient must meet the following criteria to be eligible for inclusion of Arm 1 of the study:
• Aged between 3 months and 18 years
• The availability of a HLA matched haploidentical donor greater or equal to 5/10
• Absence of readily available matched sibling donor
• Absence of other readily available non-related donors:
- Unrelated volunteer donors; HLA match less than 9/10
- UCB units with adequate cell dose; HLA match less than 5/6 on low resolution typing or HLA match less than 6/8 on high resolution typing (8/8 HLA match for non malignant patients)
• Adequate organ function
• Female patients of child bearing age are not pregnant
• Written consent of the patient’s legal guardian, and assent from the patient if age appropriate

All potential parent donors must undergo high resolution HLA typing, and assessment as to their fitness to undergo peripheral blood stem cell collection via G-CSF stimulated apheresis.

Minimum age
3 Months
Maximum age
18 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Patient has undergone HSCT within the last 180 days
• Evidence of HIV infection
• Current uncontrolled bacterial or fungal infection
• The treatment protocol in part or in its entirety is declined by either the patient or their legal guardian

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
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)
NSW,QLD,WA,VIC
Recruitment hospital [1] 8547 0
Sydney Children's Hospital - Randwick
Recruitment hospital [2] 8548 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [3] 8549 0
Lady Cilento Children's Hospital - South Brisbane
Recruitment hospital [4] 8550 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [5] 8551 0
Princess Margaret Hospital - Subiaco
Recruitment postcode(s) [1] 16644 0
2031 - Randwick
Recruitment postcode(s) [2] 16645 0
2145 - Westmead
Recruitment postcode(s) [3] 16646 0
4101 - South Brisbane
Recruitment postcode(s) [4] 16647 0
3052 - Parkville
Recruitment postcode(s) [5] 16648 0
6008 - Subiaco
Recruitment outside Australia
Country [1] 9060 0
New Zealand
State/province [1] 9060 0
Auckland

Funding & Sponsors
Funding source category [1] 297015 0
Other Collaborative groups
Name [1] 297015 0
Australian and New Zealand Children's Haematology/Oncology Group (ANZCHOG)
Address [1] 297015 0
ANZCHOG Concept Validation Scheme
Hudson Institute
27-31 Wright Street
Clayton, VIC 3168
Country [1] 297015 0
Australia
Funding source category [2] 297043 0
Commercial sector/Industry
Name [2] 297043 0
Miltenyi Biotech
Address [2] 297043 0
Miltenyi Biotech GmbH
Friedrich-Ebert-Straße 68
51429 Bergisch Gladbach,
Germany



Country [2] 297043 0
Germany
Funding source category [3] 297044 0
Charities/Societies/Foundations
Name [3] 297044 0
Tour de Cure Ltd.
Address [3] 297044 0
Tour de Cure Ltd.
Suite 2 (Level 1),
Building B,
14 Rodborough Road,
Frenchs Forest NSW 2086

Country [3] 297044 0
Australia
Funding source category [4] 297084 0
Charities/Societies/Foundations
Name [4] 297084 0
Children's Cancer Foundation
Address [4] 297084 0
Level 4,
4 Freshwater Place,
Southbank VIC 3006
Country [4] 297084 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Kids Oncology And Leukaemia TriAls (KOALA)
Address
Kids Cancer Centre,
Sydney Children’s Hospital,
High Street,
Randwick, NSW Australia 2031
Country
Australia
Secondary sponsor category [1] 296176 0
None
Name [1] 296176 0
Address [1] 296176 0
Country [1] 296176 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298198 0
Children’s Health Queensland Hospital and Health Service Human Research Ethics Committee (EC00175)
Ethics committee address [1] 298198 0
Ethics committee country [1] 298198 0
Australia
Date submitted for ethics approval [1] 298198 0
11/03/2017
Approval date [1] 298198 0
07/06/2017
Ethics approval number [1] 298198 0
HREC/17/QRCH/48

Summary
Brief summary
The primary purpose of this trial is to evaluate the efficacy of using parent donors for bone marrow transplants in children, using a particular processing method of the donor blood cells (TCR a+ß+/CD19+ cell depletion) compared to those receiving a standard bone marrow transplant from another donor, We also want to compare cost to the health system of TCR a+ß+/CD19+ cell depletion with that of standard bone marrow transplant procedures,

Who is it for?
Patients may be eligible to enrol in this trial if they are aged 3 months to 18 years of age, have been diagnosed with haematological malignancies or non malignant disorders requiring a bone marrow transplant, and have an eligible parent donor.

Study details
Patients who have no fully matched brothers or sisters, and no well matched volunteer donors or umbilical cord blood units available will receive a TCR a+ß+/CD19+ cell depleted graft from a parent donor. Control patients will receive a standard bone marrow transplant from another donor (e.g., volunteer donor) as per institutional practice.

Patients will undergo clinical assessments at regular intervals for two years following the transplant to evaluate the efficacy of the treatment. Further information, such as quality of life and carer burden, will be collected for up to 5 years following the transplant.

It is hoped that the findings from this trial will provide information on whether parent donor cells undergoing specialised cell processing can be effectively used for bone marrow transplants in children with haematological malignancies or non malignant disorders.

Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 76302 0
Dr Richard Mitchell
Address 76302 0
Kids Cancer Centre
Level 1, Sydney Children's Hospital
High St, Randwick, NSW 2031
Country 76302 0
Australia
Phone 76302 0
+612 9382 1690
Fax 76302 0
Email 76302 0
richard.mitchell@unsw.edu.au
Contact person for public queries
Name 76303 0
Ms Emma McCormack
Address 76303 0
Kids Cancer Centre
Level 1, Sydney Children's Hospital
High St, Randwick, NSW 2031
Country 76303 0
Australia
Phone 76303 0
+612 9382 3102
Fax 76303 0
Email 76303 0
emma.mccormack@health.nsw.gov.au
Contact person for scientific queries
Name 76304 0
Dr Richard Mitchell
Address 76304 0
Kids Cancer Centre
Level 1, Sydney Children's Hospital
High St, Randwick, NSW 2031
Country 76304 0
Australia
Phone 76304 0
+612 9382 1690
Fax 76304 0
Email 76304 0
richard.mitchell@unsw.edu.au

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