Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622001232729
Ethics application status
Approved
Date submitted
24/06/2022
Date registered
12/09/2022
Date last updated
26/11/2023
Date data sharing statement initially provided
12/09/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
A multi-centre phase II, Australian and New Zealand, exploratory study of amendments to conditioning regimens in haplo-identical stem cell transplantation
Scientific title
A multi-centre phase II, Australian and New Zealand, exploratory study of amendments to conditioning regimens in haplo-identical stem cell transplantation
Secondary ID [1] 306634 0
NONE
Universal Trial Number (UTN)
Trial acronym
The ANZHIT-2 study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Myeloid Leukaemia 325551 0
Chronic Myeloid Leukaemia 325552 0
Acute Lymphoblastic Leukaemia 325553 0
Non Hodgkin's Disease 325554 0
Hodgkin's Disease 325555 0
transformed AML/ MDS 325780 0
Myeloproliferative Disorders 325781 0
Condition category
Condition code
Blood 322924 322924 0 0
Haematological diseases
Cancer 322925 322925 0 0
Hodgkin's
Cancer 322926 322926 0 0
Leukaemia - Acute leukaemia
Cancer 322927 322927 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
Cancer 322928 322928 0 0
Leukaemia - Chronic leukaemia
Cancer 322929 322929 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a multi-centre Phase II exploratory trial in haploidentical stem cell transplantation consisting of two distinct sub studies (Reduced Intensity Conditioning (RIC) and Myeloablative Conditioning (MAC). Patients at the discretion of their treating stem cell transplant specialist will be assigned to either RIC or MAC sub-study on the completion of assessments to determining their level of physical well-being.

Regardless which arm you are enrolled in, patients will have central venous access performed upon admission to hospital as per institutional guidelines. Intravenous fluids and supportive care with anti-microbials, ganciclovir, anti-emetics, allopurinol, trimethoprim/co-trimoxazole will be administered according to local allogeneic stem cell transplant protocols. Once they are admitted into hospital for the transplant, patients will receive medication to treat any side effects they are experiencing and nutritional support as well as prophylaxis anti- viral/ bacteria according to the patients local institutional guidelines. In addition, Day 0 is the day the patient will receive the donor stem cells known as day of transplant.

If a patient's stem cell transplant specialist has selected to use MYELOABLATIVE CONDITIONING REGIMENS (MAC) they will be enrolled into Fludarabine/Treosulfan protocol (cohort 1) or Fludarabine/TBI 1200cGy protocol (cohort 2).

A patient enrolled into the Fludarabine/Treosulfan protocol (cohort 1) will be given the following regimen.
• Fludarabine will be administered intravenously once a day at a dose of 30mg/m2 over 60 minutes on days -6, -5, -4, -3, -2.
• Treosulfan will be administered intravenously as a two hour infusion at a dose of 14g/m2 on days -4 to day-2 prior to fludarabine
• Cyclophosphamide will be given intravenously as post -transplant Graft Versus Host Disease (GVHD) prophylaxis on Day +3 and Day +4 at a dose of 50mg/kg. Mesna will be administered as per institutional guidelines. The cyclophosphamide will be given as a one hour infusion with pre and post intravenous fluids as per institutional guidelines.
• Cyclosporine 1.5mg/kg will be given twice a day as an intravenous infusion over 2 hours from Day +5 onwards until the donor stem cells have started to function and the patient is able to tolerate oral cyclosporine. The dose of oral cyclosporine will be re-assessed at Day +60 and weaned if possible to cease at D90 - D120 provided no Acute GVHD grade II-IV occurs.
• Mycophenolate will be given orally or IV at a dose of 15mg/kg three times a day (rounded to the nearest 250mg) from Day +5 to Day +35.

If patients are enrolled instead into the Fludarabine/TBI 1200cGy protocol (cohort 2), they
will receive the following regimen:
• Fludarabine will be administered intravenously daily at a dose of 30mg/m2 over 60 minutes on Days -7, D-6 and D-5.
• Total Body irradiation (TBI) will be administered daily at a dose of 150cGy from D-4 to D-1 (total dose 1200cGy).
• Cyclophosphamide will be given intravenously daily as post -transplant GVHD prophylaxis on D+3 and D+4 at a dose of 50mg/kg. Mesna will be administered as per institutional guidelines. The cyclophosphamide will be given as a one hour infusion with pre and post intravenous fluids as per institutional guidelines.
• Cyclosporine 1.5mg/kg will be given twice a day as an intravenous infusion over 2 hours 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 at Day +60 and weaned, if possible, to cease between D+90-D+120 provided no Acute GVHD grade II-IV occurs.
• Mycophenolate will be given orally or IV at a dose of 15mg/kg three times a day (rounded to the nearest 250mg) from Day+5 to Day+35

Patients who are assessed as not suitable for MAC regimen will be offered/ enrolled into The Reduced intensity conditioning (RIC) sub-study. The Reduced intensity conditioning (RIC) sub-study contains two sequential cohorts. The first cohort will use radiation therapy called total body irradiation with Fludarabine. Once 25 patients have being enrolled in the first treatment arm, enrolled in the second treatment arm will commence. The second treatment arm will use Fludarabine with treosulfan and post transplant cyclophosphamide as Graft Versus Host Disease (GVHD) prophylaxis

Once 25 patients have being enrolled in the first treatment arm, enrolled in the second treatment arm will commence. The second treatment arm will
Treatment Arm # 1: Fludarabine/TBI 400cGy.
A maximum of 52 patients will be accrued in the first treatment arm and
• Fludarabine will be given intravenously daily at 30 mg/m2 on days -6, -5, -4, -3, and -2 (total dose 150 mg/m2)
• Cyclophosphamide will be administered daily at a dose of 14.5 mg/kg intravenously on days -6 and -5
• Total body irradiation will be given 200 cGy fraction daily for two doses on Day -2 and Day-1
• Cyclophosphamide will be administered daily at a dose of 50 mg/kg intravenously as post-transplant GHVD prophylaxis on days +3 and +4. Mesna will also be administered as per institutional guidelines. The cyclophosphamide will be given as a one hour infusion with pre and post intravenous fluids as per institutional guidelines.
• Tacrolimus in 2 divided oral doses per day until the drug level reaches a target of 5-15 ng/ml will be started on day +5. This will be assessed by blood test taken daily. The dose of oral tacrolimus will be re-assessed at Day +60 and weaned, if possible, to cease at D90-D120 provided no Acute Graft Versus Host Disease grade II-IV occurs.
• Mycophenolate mofetil taken orally three times a day at 15 mg/kg will be start on day +5 and cease on D35..

Once RIC treatment arm #1 has reached it maximum numbers and participants enrolled have tolerated the treatment, a maximum of 25 patients will be enrolment into Treatment Arm # 2 using Fludarabine/Treosulfan. Patients in this treatment arm will receive:
• Fludarabine will be given intravenously daily at 30 mg/m2 on days -6, -5, -4, -3, and -2 (total dose 150 mg/m2)
• Treosulfan will be given intravenously daily at 10mg/m2 as a 2 hour infusion on days -4, -3,-2, and D-1 prior to fludarabine
• Cyclophosphamide will be administered daily at a dose of 50 mg/kg intravenously as post-transplant GHVD prophylaxis on days +3 and +4. Mesna will also be administered as per institutional guidelines. The cyclophosphamide will be given as a one hour infusion with pre and post intravenous fluids as per institutional guidelines.
• Tacrolimus in 2 divided oral doses per day until the drug level reaches a target of 5-15 ng/ml will be started on day +5. This will be assessed by blood test taken daily. The dose of oral tacrolimus will be re-assessed at Day +60 and weaned, if possible, to cease at D90-D120 provided no Acute Graft Versus Host Disease grade II-IV occurs.
• Mycophenolate mofetil taken orally three times a day at 15 mg/kg will be starton day +5 and cease on D35.

Regardless which arm a patient is enrolled into, they are admitted into hospital for the transplant, patients will receive medication to treat any side effects they are experiencing and nutritional support as well as prophylaxis anti- viral/ bacteria according to the patients local institutional guidelines. Weekly monitoring of CMV and EBV infection will take place from Day+21 until Day +90. All patients will have weekly clinical assessment done by the treating physician or team following discharge along with routine blood tests up to day +100. Subsequently, formal follow-up for trial assessments will occur on Day +180 then yearly from year 1-5 post HSCT. Formal disease assessment will be made at Day +28-42 (post BMAT), Day +100, Day +180, then yearly from Year 1-5. using local institutional guidelines.
Intervention code [1] 323218 0
Treatment: Other
Intervention code [2] 323219 0
Treatment: Drugs
Comparator / control treatment
No control group - the treatment groups will be compared with each other and on their own therefore, please refer to the section above titled 'description of intervention'
This study will be analysing the effects of using cyclophosphamide post-transplant on graft versus host disease within applicable group as well as between each regimen. In addition, the two treatment arms will be compared to each other within each sub-study.
Control group
Active

Outcomes
Primary outcome [1] 330891 0
To assess Transplant Related Mortality (TRM) when the dose of Total Body Irradiation is increased from the current standard practice of 200cGy to 400cGy for the Reduced Intensity Conditioning regimen by reviewing patient medical records.
Timepoint [1] 330891 0
Reviewed at Day 100 and 2yrs after transplant
Primary outcome [2] 330892 0
To assess Transplant Related Mortality (TRM) when busulfan is replaced with treosulfan or Total Body irradiation (TBI) 1200cGy in the MAC regimen by reviewing patient medical records.
Timepoint [2] 330892 0
Reviewed at Day 100 and 2yrs after transplant
Primary outcome [3] 330893 0
To assess TRM when treosulfan is used as conditioning in the RIC arm by reviewing patient medical records.
Timepoint [3] 330893 0
Reviewed at Day 100 and 2yrs after transplant
Secondary outcome [1] 407931 0
measure overall survival post-transplant assessed by review of patient medical records.
Timepoint [1] 407931 0
Reviewed at 2yrs after transplant
Secondary outcome [2] 407933 0
Measure the proportion of patients who cease Calcineurin inhibitors (CNIs) immunosuppression using patient medical records.
Timepoint [2] 407933 0
reviewed between Day + 90 to Day 120 after transplant
Secondary outcome [3] 407934 0
measure incidence of relapse post transplant by reviewing patient medical records.
Timepoint [3] 407934 0
Measured at 1 yr and 2 yr after transplant
Secondary outcome [4] 407935 0
measure cumulative incidence of acute GVHD by reviewing patient medical records.
Timepoint [4] 407935 0
Measured at Day + 100 after transplant
Secondary outcome [5] 407936 0
measure cumulative incidence of chronic GVHD post transplant by reviewing patient medical records.
Timepoint [5] 407936 0
Reviewed at Day 120, Day 180, 1 yr after transplant then yearly for total 5 years
Secondary outcome [6] 407938 0
Measure GvHD and Relapse-free (GRF) Survival without GVHD by reviewing patient medical records.
Timepoint [6] 407938 0
Measured at 2 yr after transplant
Secondary outcome [7] 407939 0
measure minimal residual disease (MRD) post-transplant by reviewing patient medical records.
Timepoint [7] 407939 0
Measured at 1 yr and 2 yr after transplant
Secondary outcome [8] 412773 0
Overall disease free survival at 2 years post-transplant assessed by reviewing patient medical records.
Timepoint [8] 412773 0
Measured at 2 yr after transplant

Eligibility
Key inclusion criteria
• Informed written consent.
• Patients 16 to 75 years of age
• Recipients must have a haematological malignancy with a significant risk of relapse (as measured by the Disease Risk Index13 (validated stratification system where allogeneic transplant is indicated).
• Adults without a matched related or unrelated donor or where the time for the donor cells to arrive places the patient at a high risk of relapse.
• Patients must have a first-degree relative who are 3out of 6 to 4out of 6 HLA matched (i.e. haploidentical)
• Adequate cardiac (LVEF greater than 50%), pulmonary (DLCO/VA greater than 50%) and renal function (Creatinine Clearance greater than 60ml per min).
• Patients with creatinine clearance between 41 to less than 60 ml per min will be assessed by their treating transplant specialist and if deemed suitable, can enrolled into the study.
• Haematological malignancies may be (but are not limited to):
- Acute Myeloid Leukemia (with high risk cytogenetics/mutations) in first complete remissionAMLCR1 (high risk cytogenetics or mutations),
- Acute Myeloid Leukemia (with high risk cytogenetics) in second complete remission
- Acute Myeloid Leukemia (with refractory disease with at least 2 adverse risk factors as per Centre for International Blood and Marrow Transplant Research.
- transformed Acute Myeloid Leukemia/Myeloid Dysplastic Syndrome
- Myeloid Dysplastic Syndrome with Intermediate level 2 as per International Prognostic Score System IPSS Int-2
- Myeloid Dysplastic Syndrome with high risk as per International Prognostic Score System
- Myeloproliferative Disease - eligible for HSCT – High DIPSS
_ Chronic Myeloid Leukemia with inadequate response to treatment
- Chronic Myeloid Leukemia in second chronic phase (CML prior Accelerated Phase or Blast Transformation)
- Acute Lymphoblastic Leukemia (with high risk cytogenetics) in first complete remission
- Acute Lymphoblastic Leukemia (with Minimal Residual Disease) in first complete remission
- Acute Lymphoblastic Leukemia in second complete response
- Hodgkin's Lymphoma in remission
- Non-Hodgkin's Lymphoma in remission
Minimum age
16 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Pregnancy.
• Positive serology for HIV.
• Refractory Central Nervous System (CNS) disease.
• Refractory lymphoma
• Serious organ dysfunction: LVEF less than 50%, FEV1, FVC, DLCO less than 50% of predicted, LFT greater than 5 times the upper limit of normal, or creatinine clearance less than 40 ml per min.
• Life expectancy less than 60 days.
• Unable or unwilling to provide written informed consent
• Previous adverse reaction to the treosulfan, fludarabine or cyclophosphamide
• 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.
• 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.
• Prior Allogeneic stem cell transplant

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
Other design features
This study has two sub-studies; Reduced Intensity Conditioning (RIC) and Myeloablative Conditioning (MAC)
Patients who are eligible for the Myeloablative Conditioning (MAC) are enrolled at the discretion of their treating transplant physician (Investigator) into one of the two MAC regimens which are being run concurrently. 30 to 50 patient will be enrolled in total

Patients who are eligible for the Reduced Intensity Conditioning (RIC) arm, will be enrolled into one of the RIC regimens. The RIC arm contains two sequential cohorts. Once the first cohort has enrolled 25 participant, cohort 2 will commence enrolment
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
It is anticipated that between 35-50 will be accrued in the MAC sub study (within both cohorts) whilst maximum of 52 patients will be accrued in treatment arm 1 and 25 in treatment arm 2 of the RIC sub study.
A statistical analysis plan will be generated for the study with the following methods utilised:
• Non-relapse mortality at D+100, 12 and 24 months will be calculated using cumulative incidence function with relapse or death (other than TRM) as competing risks.
• Endpoint of GVHD and relapse-free survival (GRFS- survival without acute graft versus host disease grade III-IV, moderate-severe chronic graft versus host disease and relapse)) will be analysed using a cumulative incidence function with death (any cause) as a competing risk
• OS and DFS will be analysed by the Kaplan-Meier method at 12 and 24 months
• Engraftment will be evaluated using CIBMTR criteria. Neutrophil engraftment defined as the date of the first of three consecutive absolute neutrophil count (ANC) of 0.5 × 109/L on different days. Platelet engraftment is the date of the first of three consecutive platelet laboratory results are 20 × 109/L obtained on different days, when no platelet transfusion is given within preceding 7 days. Time to successful engraftment will be analysed using a cumulative incidence function with relapse, and death as competing risks
• Acute GVHD will be described as incidence of maximal grade (I-IV) using MAGIC criteria occurring within first 100 days of transplantation. Time to aGVHD will be analysed using a cumulative incidence function with relapse and death (any cause) as competing risks
• Chronic GVHD will be assessed by using the NIH criteria at 12 and 24 months.
• Cumulative incidence of poor graft function at D+28 and D+100 (2 of out of 3 of the following: PMN less than 0.5, Platelets less than 20, Hb less than 70) will be measured using cumulative incidence functions with death and relapse as competing risks
• Disease relapse will be estimated using cumulative incidence functions with death as a competing risk
• Clinically relevant patient-reported outcomes (PROs) using the FACT-BMT, will be analysed longitudinally to assess the impact of protocol treatments and GVHD on patients’ quality of life from pre-transplant to 12 and 24- months post-transplant
• Successful early cessation of immunosuppressant will be summarized as a binomial proportion with exact confidence limits.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
30/09/2022
Actual
5/09/2023
Date of last participant enrolment
Anticipated
1/12/2025
Actual
Date of last data collection
Anticipated
2/12/2030
Actual
Sample size
Target
127
Accrual to date
5
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 21930 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [2] 21931 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [3] 21932 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [4] 21933 0
Royal Melbourne Hospital - Royal Park campus - Parkville
Recruitment hospital [5] 21934 0
Westmead Hospital - Westmead
Recruitment hospital [6] 21935 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [7] 22043 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [8] 22044 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 37012 0
6150 - Murdoch
Recruitment postcode(s) [2] 37013 0
5000 - Adelaide
Recruitment postcode(s) [3] 37014 0
2065 - St Leonards
Recruitment postcode(s) [4] 37015 0
3052 - Parkville
Recruitment postcode(s) [5] 37016 0
2145 - Westmead
Recruitment postcode(s) [6] 37017 0
2010 - Darlinghurst
Recruitment postcode(s) [7] 37165 0
4029 - Herston
Recruitment postcode(s) [8] 37166 0
3084 - Heidelberg
Recruitment outside Australia
Country [1] 24648 0
New Zealand
State/province [1] 24648 0
Wellington and Auckland

Funding & Sponsors
Funding source category [1] 310961 0
Hospital
Name [1] 310961 0
St Vincent's Hospital, Sydney
Country [1] 310961 0
Australia
Funding source category [2] 311114 0
Charities/Societies/Foundations
Name [2] 311114 0
Arrow Bone Marrow Transplant Foundation
Country [2] 311114 0
Australia
Funding source category [3] 311115 0
Commercial sector/Industry
Name [3] 311115 0
Link (A Clinigen Company)
Country [3] 311115 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] 312448 0
None
Name [1] 312448 0
Address [1] 312448 0
Country [1] 312448 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310520 0
St Vincent's Hospital, Sydney
Ethics committee address [1] 310520 0
Ethics committee country [1] 310520 0
Australia
Date submitted for ethics approval [1] 310520 0
30/05/2022
Approval date [1] 310520 0
21/07/2022
Ethics approval number [1] 310520 0
2022/ETH00741

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

Contacts
Principal investigator
Name 117938 0
A/Prof John Moore
Address 117938 0
St Vincent's Hospital, Sydney
390 Victoria St
Darlinghurst NSW 2010
Country 117938 0
Australia
Phone 117938 0
+61 2 9355 5656
Fax 117938 0
Email 117938 0
[email protected]
Contact person for public queries
Name 117939 0
Patricia Plenge
Address 117939 0
St Vincent's Hospital, Sydney
390 Victoria St
Darlinghurst NSW 2010
Country 117939 0
Australia
Phone 117939 0
+61 2 9355 5656
Fax 117939 0
Email 117939 0
[email protected]
Contact person for scientific queries
Name 117940 0
John Moore
Address 117940 0
St Vincent's Hospital, Sydney
390 Victoria St
Darlinghurst NSW 2010
Country 117940 0
Australia
Phone 117940 0
+61 2 9355 5656
Fax 117940 0
Email 117940 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual participant data will not be available however, a copy of aggregated data may be considered upon application (subject to approval by the CPI)


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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