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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
20/03/2019
Date data sharing statement initially provided
20/03/2019
Date results information 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
Gender
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
Participant recruitment difficulties
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)
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
Address [1] 288794 0
Level 1
16 Marcus Clarke Street
Canberra ACT 2601
Country [1] 288794 0
Australia
Funding source category [2] 288844 0
Government body
Name [2] 288844 0
Queensland Health
Address [2] 288844 0
Queensland Health Building
147-163 Charlotte Street
Brisbane Queensland 4000 Australia
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
Block 7 - Level 7
Royal Brisbane and Women's Hospital
Butterfield Street
Herston. QLD 4006
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
Purpose
This study is evaluating the safety of haploidentical stem cell transplantation using high dose chemotherapy and radiotherapy, with the infusion of donor stem cells followed by the infusion of genetically modified donor T cells. The genetic modification involves the insertion of a safety switch, called iCasp9, into the donor T cells, which allows the cells to be removed with a drug, AP1903, if the patient develops graft-versus-host disease, which is a life-threatening complication of stem cell transplantation.
Who is it for?
You may be eligible to join this study if you have a poor risk haematological malignancy (leukaemia or myelodysplastic syndrome) that requires treatment with an allogeneic stem cell transplant but do not have a suitable conventional donor, meaning you do not have a fully-matched or single-antigen mismatched (9/10 matched) related or unrelated donor. You should be aged 18 to 59years old and have adequate organ function to undergo an allogeneic stem cell transplant. You should have a suitable first, second or third degree relative who can be your donor.
Trial details
Participants in this study will undergo myeloablative conditioning which involves high dose chemotherapy and radiotherapy. This consists of total body irradiation, thiotepa, fludarabine and rabbit antithymocyte globulin (Thymoglobuline). 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 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. Each patient will receive only a single dose. Patients who develop grade II or above acute Graft Versus Host Disease (GVHD) are treated with an infusion of AP1903. AP1903 is a chemical dimeriser that triggers the apoptotic death of iCasp9-transduced T cells.
Participants will be required to undergo regular assessment to evaluate the safety of this study treatment.
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
Dr 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
Dr 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 other documents available
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary