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Trial registered on ANZCTR


Registration number
ACTRN12617000151336
Ethics application status
Approved
Date submitted
16/09/2015
Date registered
27/01/2017
Date last updated
17/05/2019
Date data sharing statement initially provided
17/05/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
A phase II study of haploidentical peripheral blood stem cell transplantation with post-transplant cyclophosphamide as Graft versus Host Disease (GVHD) prophylaxis
Scientific title
A phase II study of haploidentical peripheral blood stem cell transplantation with post-transplant cyclophosphamide as Graft versus Host Disease (GVHD) prophylaxis
Secondary ID [1] 287474 0
none
Universal Trial Number (UTN)
U1111-1174-5033
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Myeloid Leukaemia in first or second complete remission 296206 0
Chronic Myeloid Leukaemia prior to acute or blast transformation 296208 0
acute Lymphoblastic Leukaemia in first or second complete remission 296209 0
Non Hodgkin's Disease in remission 296210 0
for Hodgkins Disease in remission 296211 0
Myeloproliferative disease 296212 0
Patient requiring a haplo-identical stem cell tranplant for Myelodysplastic syndrome with less than or equal 2 CIBMTR risk factors 296213 0
transformed Acute Myeloid Leukaemia with less than or equal 2 CIBMTR risk factors 296214 0
MDSIPSS 296215 0
Acute Myeloid Leukaemia refractory disease with less than or equal 2 CIBMTR 296216 0
Condition category
Condition code
Blood 296485 296485 0 0
Haematological diseases
Cancer 296486 296486 0 0
Leukaemia - Chronic leukaemia
Cancer 296497 296497 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study involves the use of cyclophosphamide post stem cell infusion as prophylactic treatment for Graft versus Host disease. Cyclophosphamide will be used in one of 2 available conditioning treatments; Non-myeloabative and Myeloablative conditioning treatment.

The conditioning treatment selected is determined by the transplant specialist.

Arm 1.Patients undergoing myeloablative allogeneic peripheral blood stem cell transplantation using intravenous Fludarabine 40mg/m2 daily for 5 day from day -6 to day -2. Busulphan will be administered intravenously at a dose of 3.2mg/kg/day for 4 days from days -5 to day -2. Graft Versus Host Disease prophylaxis consisting of post-transplant intravenous cyclophosphamide 50mg/kg will be given for 2 days on Day +3 to day +4 with cyclosporin and mycophenolate commencing on D+5.. Cyclosporine at 1.5mg/kg given twice a day intravenously from Day +5 onwards until the patients has engrafted and is able to tolerate oral cyclosporine. The dose of oral cyclosporine will be re-assessed by their treating physician at Day +60. Mycophenolate mofetil at 15 mg/kg given three times per day taken oral tablet will be started on day +5. Cyclosporin and Mycophenolate will be stopped as directed per treating physician

Arm 2. Patients undergoing non-myeloablative transplantation will receive intravenous Fludarabine 30 mg/m2 daily for 5 day from days -6 to day -2 with Intravenous cyclophosphamide 29 mg/kg, given daily for 2 days on day -6 to day -5 in combination with Total body irradiation 200cGy given once on day -1. Graft Versus Host Disease prophylaxis consisting of post- transplant intravenous cyclophosphamide 50mg/kg gien daily for 2 days on on Day +3 and Day +4, Tacrolimus tablets will be given orally in 2 divided doses daily to target blood levels of 5-15 ng/ml from day +5 and re-assessed at Day +60. Dose is determined by treating physician. Mycophenolate mofetil 15 mg/kg given three times per day taken oral tablet will be started on day +5. Tacrolimus and Mycophenolate will be stopped as directed per treating physician.
Intervention code [1] 292857 0
Treatment: Drugs
Intervention code [2] 292868 0
Treatment: Other
Comparator / control treatment
none
Control group
Uncontrolled

Outcomes
Primary outcome [1] 296112 0
To examine rates of disease-free survival in patients receiving haploidentical peripheral blood stem cell grafts after either myeloablative or non-myeloablative conditioning therapy
Timepoint [1] 296112 0
24 months after stem cell transplantation
Secondary outcome [1] 317534 0
To assess rates of acute Graft Versus Host Disease using CIBMTR CRITERIA
Timepoint [1] 317534 0
day +140 after stem cell transplantation
Secondary outcome [2] 317535 0
To assess rates of disease relapse using blood tests, Medical imaging and/or bone marrow biospys
Timepoint [2] 317535 0
2 year after stem cell transplantation
Secondary outcome [3] 317536 0
To assess rates of non-relapse morbidity (NRM) and mortality in recipients of haploidentical transplants using medical records
Timepoint [3] 317536 0
100 days, 1 year and 2 years after stem cell transplantation
Secondary outcome [4] 317537 0
To assess rates of chronic GVHD as per NIH criteria
Timepoint [4] 317537 0
1 and 2 years after stem cell transplantation
Secondary outcome [5] 317538 0
to assess rates of engraftment through blood tests and bone marrow biospys
Timepoint [5] 317538 0
day +40 after stem cell transplantation
Secondary outcome [6] 317539 0
To assess rates of disease-free survival using blood tests with/without bone marrow biospys, medical imaging and medcial records
Timepoint [6] 317539 0
100 days, 1 year and 2 years after stem cell transplantation
Secondary outcome [7] 317540 0
To assess morbidity associated with myeloablative haploidentical transplants with a particular emphasis on viral infection (BK virus associated hemorrhagic cystitis and CMV infection)
Timepoint [7] 317540 0
day +140 after stem cell transplantation
Secondary outcome [8] 317541 0
To compare the relative outcome measures of haploidentical transplants to standard sibling and unrelated transplants during the same period in the participating centres using medical records
Timepoint [8] 317541 0
day 0 to 2 years after stem cell transplantation

Eligibility
Key inclusion criteria
1. Patients 16 – 70 years of age

2. Recipients must have a haematological malignancy with a significant risk of relapse (as measured by the Disease Risk Index), where allogeneic transplant is indicated.

3. Adults without a readily available matched related or unrelated donor.

4. Patients must have a first-degree relative who are 3/6 to 4/6 HLA matched.

5. Patients with an HCT-CI/age > or equal to 3 will receive non-myeloablative conditioning.

6. Adequate cardiac (LVEF >50%), pulmonary (DLCO/VA >50%) and renal function (Creatinine Clearance >60ml/min).

7. Informed written consent.

8. Haematological malignancies may be (but are not limited to):
a. AMLCR1 (high risk cytogenetics, FLT-3 positive), CR2
b. AML refractory disease with less than or equal 2 CIBMTR adverse risk factors.
c. tAML/MDS: with less than or equal 2 CIBMTR adverse risk factors
d. MDSIPSS Int-2/High risk
e. MPD eligible for HSCT
f. CML prior AP/BT in CP2; inadequate response to treatment of CP CML:
g. ALL CR1 (high risk cytogenetics or MRD+ve), CR2
h. Lymphoma (NHL or HL) in remission
Minimum age
16 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1.Pregnancy.

2. Positive serology for HIV.

3. Refractory Central Nervous System (CNS) disease.

4. Serious organ dysfunction: LVEF <50%, FEV1, FVC, DLCO <50%of predicted, LFT > 5 x the upper limit of normal, or creatinine clearance < 40 ml/min .

5. Life expectancy less than 60 days.

6. Unable or unwilling to provide written informed consent

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
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The primary endpoint will be disease-free survival at 24 months.

Secondary endpoints to be analysed will be:
1. 2 year relapse rates will be described using the Kaplan-Meier curve
2. rates of engraftment
3. acute GVHD will be described as incidence of grade I-IV disease, as well as grades III and IV
4. rate of chronic GVHD at 2 years
5. non-relapse mortality at 100 days, 1 year and 2 years

6. The following covariates will be tested for association with OS and NRM in both univariate and, if appropriate, multivariate analyses:

7. Patient:
a. Age (median >,< or age .40)
b. Disease Risk Index
c. Sex
d. Karnofsky performance status
e. number of previous chemotherapy regimens
f. previous autologous HCT
g. co-morbid conditions
h. CMV status
i. Diagnosis
j. Disease status – AML CR1, CR2, ALL CR1, CML chronic phase, all MDS except RAEB = good
k. Time from Dx to HSCT (median>,<)
l. cytogenetics at diagnosis

8.Donor:
a Age
b sex
c CMV status

9. Transplant:
a. CD34 dose (median >,< or > 5 x 10^6/kg))
b. Conditioning type
c. transplant year (before median follow up)
d. recipient cytomegalovirus (CMV) status

10. Other:
a. presence of acute and chronic GVHD (time-dependent variables)
A minium number of patients in each group are being enrolled to enable an anlysis to be performed.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
27/08/2015
Date of last participant enrolment
Anticipated
30/12/2019
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
70
Accrual to date
56
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 4342 0
Westmead Hospital - Westmead
Recruitment hospital [2] 4343 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [3] 4344 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [4] 4345 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [5] 4346 0
Royal Melbourne Hospital - Royal Park campus - Parkville
Recruitment postcode(s) [1] 10570 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 10572 0
2050 - Camperdown
Recruitment postcode(s) [3] 10571 0
2065 - St Leonards
Recruitment postcode(s) [4] 10569 0
2145 - Westmead
Recruitment postcode(s) [5] 10573 0
3050 - Royal Melbourne Hospital
Recruitment outside Australia
Country [1] 7168 0
New Zealand
State/province [1] 7168 0
Auckland

Funding & Sponsors
Funding source category [1] 292050 0
Charities/Societies/Foundations
Name [1] 292050 0
Arrow Bone Marrow Transplant Foundation
Country [1] 292050 0
Australia
Primary sponsor type
Hospital
Name
St Vincent's Hospital Sydney
Address
390 Victoria St, Darlinghurst NSW 2010
Country
Australia
Secondary sponsor category [1] 290730 0
Hospital
Name [1] 290730 0
Royal prince Alfred Hospital,
Address [1] 290730 0
Level 11, KGV Building, Missenden Road,
Camperdown NSW 2050
Country [1] 290730 0
Australia
Secondary sponsor category [2] 292668 0
Hospital
Name [2] 292668 0
Royal Melbourne Hospital
Address [2] 292668 0
Melbourne Heath- The Royal Melborne Hospital, Grattan St Parkville, VIC, 3050
Country [2] 292668 0
Australia
Secondary sponsor category [3] 292669 0
Hospital
Name [3] 292669 0
Royal North Shore Hospital
Address [3] 292669 0
Pacific Highway,
St leonards NSW 2065
Country [3] 292669 0
Australia
Secondary sponsor category [4] 292670 0
Hospital
Name [4] 292670 0
Westmead Hospital
Address [4] 292670 0
Cnr Hawkesbury and Darcy Roads,
Westmead NSW 2145
Country [4] 292670 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293533 0
St Vincent's Hospital Human Research Ethics committee
Ethics committee address [1] 293533 0
St Vincent's Hospital Sydney
390 Victoria St
Darlinghurst 2010
Ethics committee country [1] 293533 0
Australia
Date submitted for ethics approval [1] 293533 0
05/05/2015
Approval date [1] 293533 0
28/07/2015
Ethics approval number [1] 293533 0
HREC/15/SVH/150

Summary
Brief summary
This study will assess the use of cyclophosphamide post stem cell infusion as preventative treatment for Graft versus Host disease in patients requiring a haplo-identical stem cell transplant. Who is it for? You may be eligible to join this study if you are 16 – 70 years of age and have haematological malignancies requiring allogeneic transplantation, but have no readily available fully HLA-matched related or unrelated donors. Study details All patients will receive peripheral blood stem cell transplant from haploidentical relatives. Patients will either undergo myeloablative or non- myeloablative conditioning treatments prior to receiving stem cell transplants. The conditioning treatment selected is determined by the transplant specialist. Two groups will then receive a treatment aimed at prevention of Graft versus Host disease after stem cell transplant. If you receive myeloablative conditioning treatment, your post-transplant treatment will include cyclophosphamide 50mg/kg administered on day 3 and day 4 after transplant with cyclosporine [dose calculated on body weight] and mycophenolate [dose calculated on body weight ] commencing on day 5 after transplant. If you receive non- myeloablative conditioning treatment, your post-transplant treatment will include cyclophosphamide 50mg/kg administered on day 3 and day 4 after transplant with tacrolimus [dose calculated on body weight] and mycophenolate [dose calculated on body weight] commencing on day 5 after transplant. Total duration of treatment will depend if graft versus host diseas develops and how severe. It is anticiapted adding cyclophosphamide post stem cell infusion will prevent Graft versus Host disease or affect the rate of acute and chronic Graft versus Host disease
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 60346 0
A/Prof John Moore
Address 60346 0
St Vincent's Hospital, Sydney
390 Victoria St
Darlinghurst 2010
Country 60346 0
Australia
Phone 60346 0
61 2 93555656
Fax 60346 0
61 2 93555602
Email 60346 0
SVHSCancer.Research@svha.org.au
Contact person for public queries
Name 60347 0
Ms Patricia Plenge
Address 60347 0
St Vincent's Hospital, Sydney
390 Victoria St
Darlinghurst 2010
Country 60347 0
Australia
Phone 60347 0
61 2 93555613
Fax 60347 0
61 2 93555735
Email 60347 0
SVHS.CancerResearch@svha.org.au
Contact person for scientific queries
Name 60348 0
Ms Patricia Plenge
Address 60348 0
St Vincent's Hospital, Sydney
390 Victoria St
Darlinghurst 2010
Country 60348 0
Australia
Phone 60348 0
61 2 93555613
Fax 60348 0
61 2 93555735
Email 60348 0
SVHS.CancerResearch@svha.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
not ethics approve to do so


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
EmbaseA Prospective Haploidentical Peripheral Blood Stem Cell Transplant Study Using a Pre-Defined Conditioning Regimen Intensity Based on Age and the Hematopoietic Cell Transplantation Comorbidity Index- Anzhit 1: Encouraging Preliminary Survival Outcomes at One Year Follow up.2020https://dx.doi.org/10.1182/blood-2020-142131
EmbaseEarly cessation of calcineurin inhibitors is feasible post-haploidentical blood stem cell transplant: the ANZHIT 1 study.2023https://dx.doi.org/10.1182/bloodadvances.2023009840
N.B. These documents automatically identified may not have been verified by the study sponsor.