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Trial registered on ANZCTR


Registration number
ACTRN12614000290695
Ethics application status
Approved
Date submitted
7/03/2014
Date registered
19/03/2014
Date last updated
22/08/2022
Date data sharing statement initially provided
20/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Haploidentical stem cell transplantation with iCasp9 T cell addback in patients with poor risk haematological malignancies
Scientific title
A phase I study of haploidentical haematopoietic stem cell transplantation with add-back of donor T cells transduced with inducible caspase 9 suicide gene in patients with poor risk haematological malignancies
Secondary ID [1] 284141 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Patients with high risk acute leukaemia, myelodysplastic syndrome or chronic myeloid leukaemia, who lack a suitable fully human leukocyte antigen (HLA)-matched or single-antigen mismatched donor.

 291226 0
Condition category
Condition code
Cancer 291571 291571 0 0
Leukaemia - Acute leukaemia
Cancer 291572 291572 0 0
Leukaemia - Chronic leukaemia
Blood 291690 291690 0 0
Haematological diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The patients will undergo myeloablative conditioning consisting of total body irradiation 8 Gy (lung shielded to 4 Gy) on day -9, intravenous thiotepa (5 mg/kg/day) on days -8 and -7; intravenous fludarabine (40 mg/m2/day) from day -7 to day -3; and intravenous rabbit antithymocyte globulin (Thymoglobuline; 1.5mg/kg/day) on days -5 to -2.
Donor mobilised peripheral blood stem cells are CD34+-selected and infused fresh on day 0 without post transplant immunosuppression.
On day +21 or later, patients are given a single intravenous infusion of iCasp9-transduced T cells, which are generated from unmobilised donor peripheral blood using a clinical grade retroviral vector. The iCasp9 T cell dose is increased in cohort size of two: 5x10e5/kg, 1x10e6/kg, 5x10e6/kg and 1x10e7/kg. Patients who develop grade II or above acute Graft Versus Host Disease (GVHD)are treated with an intravenous infusion of AP1903. AP1903 is a chemical dimeriser that triggers the apoptotic death of iCasp9-transduced T cells. Up to four doses of AP1903 can be given if necessary.
Intervention code [1] 288861 0
Treatment: Other
Comparator / control treatment
None
Control group
Uncontrolled

Outcomes
Primary outcome [1] 291546 0
Overall survival (OS)
Timepoint [1] 291546 0
1 year
Primary outcome [2] 291547 0
The maximum tolerated dose (MTD) for iCasp9-transduced T cell addback that will result in no more than 25% acute GVHD grade III or IV. Acute GVHD will be assessed clinically and graded using the Seattle (Glucksberg) criteria. The MTD is determined by a modified continual reassessment method (mCRM) using a cohort size of 2 patients per dose.
Timepoint [2] 291547 0
Acute GVHD is assessed up to 100 days post T cell addback. Only patients who survive at least 28 days post T cell addback are evaluable unless acute GVHD grade III or IV occurred prior to day 28.
Secondary outcome [1] 307032 0
Progression free survival (PFS)
Timepoint [1] 307032 0
1 year
Secondary outcome [2] 307033 0
Transplant related mortality (TRM)
Timepoint [2] 307033 0
1 year
Secondary outcome [3] 307034 0
Incidence of and time to engraftment. This is assessed by daily full blood counts (laboratory test) until such time when the neutrophil count has reached >0.5x10e9/L on 3 consecutive days and platelet >20x10e9/L (unsupported) for 5 consecutive days.
Timepoint [3] 307034 0
1 year
Secondary outcome [4] 307035 0
Incidence of infection. This is assessed clinically and by laboratory test (culture from blood, urine, faeces, other sample sites, if indicated).
Timepoint [4] 307035 0
1 year
Secondary outcome [5] 307036 0
Incidence of acute GVHD. This is assessed by clinical examination and laboratory tests (blood test and, if indicated, biopsy) and graded according to the Seattle (Glucksberg) acute GVHD criteria.
Timepoint [5] 307036 0
100 days after iCasp9 T cell addback
Secondary outcome [6] 307037 0
Incidence of chronic GVHD. This is assessed by clinical examination and laboratory tests (blood test and, if indicated, biopsy) and graded according to the Seattle chronic GVHD criteria.
Timepoint [6] 307037 0
1 year
Secondary outcome [7] 307038 0
Time to immune reconstitution. This is assessed by laboratory analysis of blood samples.
Timepoint [7] 307038 0
1 year

Eligibility
Key inclusion criteria
RECIPIENT INCLUSION:
*Lack of a fully HLA-matched or single-antigen mismatched (9/10 matched) related or unrelated donor
*Poor risk haematological malignancy defined as follows:
a.Acute myeloid leukaemia (AML)

i.High risk disease in first complete remission (CR1 )
-high risk features include poor risk cytogenetics, normal cytogenetics with Flt3-ITD mutation, and secondary AML
ii.Primary refractory after 2 induction cycles
iii.Relapsed disease in morphological remission

b.Acute lymphoblastic leukaemia (ALL)
i.CR1 with high risk cytogenetics (includes t(9;22), MLL/11q23 translocation)
ii.Second or greater CR

c.Chronic myeloid leukaemia (CML) beyond first chronic phase (>CP1)

d.Myelodysplastic syndrome (MDS) that is intermediate-2 or high risk according to International Prognostic Scoring system

*Life expectancy greater than 3 months
*Eastern Cooperative Oncology Group (ECOG) performance status less than 2 (Karnofsky more than 50%)
*Adequate organ function for allogeneic stem cell transplantation: bilirubin less than or equal to 30 micrometre, creatinine clearance more than or equal to 50ml/min/1.73m2, DLCOc more than or equal to 50% predicted, or left ventricular ejection fraction ( LVEF) more than or equal to 50%

*Able and willing to provide written informed consent
DONOR ELIGIBILITY:
*5/10 to 8/10 HLA-matched family member (first, second or third degree relative) aged 18-65 years old
*Seronegativity for Hepatitis B surface Ag, Hepatitis C antibody, and HIV antibody
*Able and willing to undergo venesection and/or additional apheresis procedure to donate T cells for post-transplant add-back
Minimum age
18 Years
Maximum age
59 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
RECIPIENT EXCLUSION:
*Active, uncontrolled infection
*Inadequate organ function for allogeneic stem cell transplantation: bilirubin more than 30 micrometre, creatinine clearance less than 50ml/min/1.73m2, DLCOc less than 50% predicted, or LVEF less than 50%
*Seropositivity for Hepatitis B surface Ag, Hepatitis C antibody, or HIV antibody
*Pregnant or breastfeeding, or patient with reproductive potential who is not willing to use adequate contraceptive precautions in the judgement of the investigator.
*Psychiatric illness or social circumstances that would limit compliance with study requirements

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
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
Slow recruitment
Date of first participant enrolment
Anticipated
1/05/2014
Actual
5/12/2014
Date of last participant enrolment
Anticipated
Actual
10/07/2015
Date of last data collection
Anticipated
5/12/2029
Actual
Sample size
Target
12
Accrual to date
Final
3
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 2178 0
Royal Brisbane & Womens Hospital - Herston

Funding & Sponsors
Funding source category [1] 288794 0
Government body
Name [1] 288794 0
NHMRC
Country [1] 288794 0
Australia
Funding source category [2] 288844 0
Government body
Name [2] 288844 0
Queensland Health
Country [2] 288844 0
Australia
Primary sponsor type
Hospital
Name
Metro North Hospital and Health Service - Royal Brisbane and Womens’ Hospital
Address
Butterfield Street,
Herston.
Brisbane. QLD 4006
Country
Australia
Secondary sponsor category [1] 287490 0
Other
Name [1] 287490 0
QIMR Berghofer Medical Research Institute
Address [1] 287490 0
Clive Berghofer Cancer Research Centre
Herson Road,
Herston.QLD 4006
Country [1] 287490 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290637 0
Royal Brisbane and Women's Hospital - Human Reseach Ethics Committee
Ethics committee address [1] 290637 0
Ethics committee country [1] 290637 0
Australia
Date submitted for ethics approval [1] 290637 0
Approval date [1] 290637 0
09/10/2013
Ethics approval number [1] 290637 0
HREC/13/QRBW/135

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 46446 0
Dr Siok Tey
Address 46446 0
QIMR Berghofer Medical Research Institute
300 Herston Road,
Herston. QLD. 4006
Country 46446 0
Australia
Phone 46446 0
+617 3362 0222
Fax 46446 0
Email 46446 0
Siok.Tey@qimrberghofer.edu.au
Contact person for public queries
Name 46447 0
Siok Tey
Address 46447 0
Cancer Care Services
Royal Brisbane and Women's Hospital
Ground Floor
Building 34
Butterfield Street,
Herston, Brisbane
QLD. 4029
Country 46447 0
Australia
Phone 46447 0
+617 33620222
Fax 46447 0
Email 46447 0
Siok.Tey@qimrberghofer.edu.au
Contact person for scientific queries
Name 46448 0
Siok Tey
Address 46448 0
QIMR Berghofer Medical Research Institute
300 Herston Road,
Herston, QLD. 4006
Country 46448 0
Australia
Phone 46448 0
+617 33620222
Fax 46448 0
Email 46448 0
Siok.Tey@qimrberghofer.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
As per privacy laws and requirements


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseAdoptive T cell therapy following haploidentical hematopoietic stem cell transplantation.2019https://dx.doi.org/10.3389/fimmu.2019.01854
Dimensions AIPhase I Trial of Inducible Caspase 9 T Cells in Adult Stem Cell Transplant Demonstrates Massive Clonotypic Proliferative Potential and Long-term Persistence of Transgenic T Cells2019https://doi.org/10.1158/1078-0432.ccr-18-3069
EmbaseEngineering next-generation car-t cells for better toxicity management.2020https://dx.doi.org/10.3390/ijms21228620
N.B. These documents automatically identified may not have been verified by the study sponsor.