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Trial registered on ANZCTR


Registration number
ACTRN12614000351617
Ethics application status
Approved
Date submitted
17/03/2014
Date registered
2/04/2014
Date last updated
5/06/2019
Date data sharing statement initially provided
5/06/2019
Date results provided
5/06/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Phase III Clinical Study of Allogeneic Stem Cell
Transplantation with Reduced Conditioning (RICT)
versus Best Standard of Care in Acute Myeloid Leukemia
(AML) in First Complete Remission
Scientific title
Phase III Clinical Study of Allogeneic Stem Cell
Transplantation with Reduced Conditioning (RICT)
versus Best Standard of Care in Acute Myeloid Leukemia
(AML) in First Complete Remission
Secondary ID [1] 283359 0
ALLG BMO6 study
Australiasian Leukeamia and Lymphoma Group
Universal Trial Number (UTN)
Trial acronym
RICT in AML
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Myeloid Leukaemia 290256 0
Condition category
Condition code
Cancer 290647 290647 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients in the Control (no transplant) group will be treated as per local practice, whereas patients with an identified and medically approved donor will proceed to Reduced Intensity Conditioning Transplant (RICT).

MSD (Matched Sibling Donor)/RICT and MUD(Matched Unrelated Donor)/RICT groups:

Patients allocated to RICT group should proceed as soon as possible to transplant as the next treatment after achieved remission. Due to medical or logistic factors, consolidation course(s) according to institutional practice may be given. Consequently, patients in the RICT group will (before conditioning) receive a total of 1-3 chemotherapy courses.
If a patient in the RICT group relapses, or if a contraindication to the assigned treatment occurs, the patient will be treated at the discretion of the clinician, but nevertheless reported within the study.

Centers may select any of the conditioning regimens described below and are then asked to consistently use the chosen regimen. Note that busulphan may be given intravenously or orally as per center preference.
Intrathecally administered methotrexate will be given to selected patients as per center routine.
As fludarabine is metabolized partly by a renal mechanism (Malspies Sem Oncol 1990), doses of fludarabine need to be modified if the calculated or assessed renal clearance is below the lower limit of the normal range.
Busulphan (orally or IV) and fludarabine
Fludarabine 30 mg/sqm iv infusion over 30 min;
-on day –8 to day – 4 (=five days) for MSDs
-on day -9 to day -5 or -4 (= five or six days) for MUDs
Busulphan may be administrated orally or intravenously;
-Orally. Total dose 8 mg/kg, given as eight doses of 1 mg/kg each on day –4 (two
doses), day –3 (four doses) and day –2 (two doses).
-Intravenously1. Total dose of Busulphex is 6.4 mg/kg given as two doses of 3.2 mg/kg each, administered over 3 hours, on days -3 and -2.
In-vivo T depletion with ATG, or alemtuzumab, as per local standards is permitted for MUDs
There shall be an interval of = 8 hours between fludarabine and busulphan, and 48 hours between last dose of busulphan and infusion of stem cells.

Fludarabine, carmustine, melfalan
Fludarabine 30 mg/sqm IV infusion over 30 min q d days –8 to -5 (four days)
Carmustin 150 mg/sqm IV infusion over 60 min q d, days –7 and –6 (two days)
Melphalan 110 mg/sqm IV infusion over 30 minutes on day –2.
Alemtuzumab 10 mg (total dose) SQ on day -1.
There shall be an interval of 48 hours between melfalan and the infusion of stem cells.
Supportive measures post transplant
Supportive measures listed below represent basic general recommendations. In principle, centres are
free to follow their local standard guidelines.
Blood transfusion support. Red blood cell and platelet transfusion support will be given using standard procedures at each institution. Blood products should be irradiated and filtered.

Antibacterial prophylaxis. As per center preference

Herpes simplex virusand varicella zoster prophylaxis. As per center preference

Surveillance and pre-emptive treatment of CMV. Test for CMV antigenemia or PCR assay should be performed weekly from day 0, at least until D +100. If positive, appropriate treatment should be given.

Fungal prophylaxis. As per center preference

P. carinii prophylaxis. Trimethoprim-sulfamethoxazol at appropriate dose for a duration of at least one year.

The use of G-CSF in the post-transplant setting should be individualized.

Immunosuppressive therapy
In the RICT setting, there are no data to support any claims of superiority of one regimen over another.
All regimens in use at the participating institutions have been evaluated locally. It is not possible to mandate that one particular regimen should be used. Therefore, this protocol includes the use of eithermethotrexate or mycophenolate mofetil (MMF) in addition to cyclosporine-A (CyA). It is however
recommended that each center uses the same regimen throughout the study.
Cyclosporine-A (CyA)
The dose of CyA should be targeted and adjusted to a serum concentration as per center preference.
The first doses of CyA are given intravenously to try and ensure adequate levels at the time of transplant. If there is nausea and vomiting anytime during CyA treatment the drug should be given intravenously at the appropriate dose. Blood pressure, renal function tests (creatinine, BUN), electrolytes and magnesium need to be followed closely while receiving CyA at full dose.
In principle, cyclosporine should be given IV or orally in full dose from Day –1 until day 60, then be tapered, in the absence of GvHD, and stopped at day +120. However, if GvHD occurs, or if
justified by chimerism data, CyA dose and duration should be individualized.

CyA and short course methotrexate
This immunosuppression combination includes full dose CyA and methotrexate. The dose of methotrexate is 15 mg/sqm iv day 1, 10 mg/sqm day 3 and day 6. The use of folinic acid rescue on
days 4 and days 7 –10 is optional. A fourth dose (10 mg/sqm) of methotrexate Day +11 with optional use of folinic acid rescue on day +12, should be added after MUD-RICT, or otherwise if the risk of GvHD is considered high.

CyA and mycophenolate mofetil (MMF). This immunosuppression combination includes full dose CyA and MMF. For CyA-dosage and schedule, see above. The MMF dose, either orally or IV, is 15 mg/kg bid. Doses will be rounded to the
nearest 250 mg (capsules are 250 mg). Most patients will receive 1000 mg bid.

After MSD-RICT, and in the absence of GvHD, MMF will be given until day +50 post-Tx and then stopped without tapering.

After MUD-RICT MMF will be given 15mg/kg q 8 hrs to day +40, then tapered to day +96. If there is nausea and vomiting, preventing oral administration, MMF dose should be reduced
accordingly, or administered intravenously.
GvHD, treatment Acute GvHD, should be treated as per local routines with prednisone/prednisolone. In case of steroid-refractory GvHD, defined as progression after three days or no improvement after 7 days or incomplete response after 14 days of corticosteroid treatment, patients will be managed according to local practice or ongoing studies. Chronic GvHD will be treated according to local practice.

Chimerism analysis and immunological intervention
Most centers have developed routines for chimerism assessment and immunological intervention.
Therefore, only some principles are stated and centers are free to use their own routines as to the rest.
For the purpose of this protocol, chimerism analysis should be performed at least in PB at +1 month, at D +100 and at 1 year in PB or BM. Extra assessments may be needed in case of remaining MRD or administration of DLI. It is recommended to assess chimerism in T-cells and myeloid cells separately. Remaining or reappearing of host myeloid cells may be used as surrogate marker for MRD.
Immunological intervention such as CyA taper or DLI may be considered.
No recommendations could be given as to the use of MRD surveillance. Local or national routines for surveillance and intervention will be applied.
Some details on chimerism, DLIs (time point, indication, dose, clinical effect) will be captured in the CRF.
Intervention code [1] 288085 0
Treatment: Other
Comparator / control treatment
MSD(Matched Sibling Donor)/Control and MUD(Matched Unrelated Donor)/Control groups
After treatment assignment, patients assigned to Control group will receive conventional consolidation therapy according to institutional practice or within studies of post consolidation therapy. It is presumed that patients in the Control group will receive a total of 3-4 chemotherapy courses. Relapsed patient in the Control group will be treated at the discretion of the clinician, but the patient will be followed and reported within the study for survival. Relapsed patients may receive any salvage treatment.
Control group
Active

Outcomes
Primary outcome [1] 290695 0
The primary objective of this study is to determine in a group of elderly AML CR1 patients with a potential matched sibling donor (MSD) whether a reduced intensity conditioning transplantation
(RICT) leads to a superior overall survival compared to standard of care. Overall survival (OS) is defined as the time interval between the date of inclusion and the date of death from any cause.
Timepoint [1] 290695 0
Primary endpoint is Overall Survival-Patients in both groups will be followed for survival, relapse and quality of life for a minimum of two
years.
Secondary outcome [1] 305054 0
1. Objective: To determine in the group of elderly AML CR1 patients without a MSD whether a matched unrelated donor (MUD) RICT leads to a superior overall survival compared to standard of care. Endpoint is Overall Survival. Overall survival (OS) is defined as the time interval between the date of inclusion and the date of death from any cause.
Timepoint [1] 305054 0
Overall Survival-Patients in both groups will be followed for survival, relapse and quality of life for a minimum of two
years.
Secondary outcome [2] 307365 0
2. Objective: To determine whether RICT from any donor (MSD or MUD) leads to superior overall survival compared to standard of care. Endpoint is Overall Survival. Overall survival (OS) is defined as the time interval between the date of inclusion and the date of death from any cause.
Timepoint [2] 307365 0
Overall Survival-Patients in both groups will be followed for survival, relapse and quality of life for a minimum of two
years.
Secondary outcome [3] 307366 0
3. Objective: To determine differences in DFS, NRM and QoL in the groups defined above.
Endpoints are Disease-free survival, causes of death and Quality of life (as assessed by the
EORTC QLQ-C30 instrument).
Timepoint [3] 307366 0
Overall Survival-Patients in both groups will be followed for survival, relapse and quality of life for a minimum of two
years. QOL will be assessed at baseline, 12months, and 24 months.

Eligibility
Key inclusion criteria
1. AML of intermediate or poor prognosis
2. Age 51 – 70 years.
3. Achieved CR1 or CRi.
4. Indication for a RIC but not a myeloablative alloSCT.
5. Judged to be able to tolerate a RICT if a suitable donor (MSD and/or MUD) is found.
6. Judged to be able to tolerate further standard consolidation chemotherapy.
7. Willing to undergo a RICT if a suitable donor is found.
8. Signed informed consent.
9. Willing and able to comply with protocol requirements.
10. Registration Form filled in and sent before initiation of donor search.
Minimum age
51 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. AML with good risk features.
2. Planned to receive full dose conditioning.
3. Initiation of donor search performed before registration in the study.
4. Additional malignancy that might interact with the endpoints of the study.
5. Serum creatinine > 2 x the ULN, or abnormal liver function; ALT or AST > 3 x ULN.
6. Other severe concurrent illness.

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)
Registration. Patients are registered for the study when a registration form has been sent to, and is
approved by, one of the national PIs. The Registration Form is a document confirming that the
investigator and her/his patient have agreed to aim for a reduced intensity conditioning transplant
(RICT) performed in accordance with Amendment #2 of the TRALG-01 study protocol, applying the
routines for donor search and donor selection outlined. The registration form should be sent before any
donor search is initiated. Patients can be registered for the study before attained CR1.

Registration and Inclusion process
The inclusion procedures differ depending on whether or not there are potential sibling donor(s).
Patients with at least one potential sibling donor
- A potential sibling donor is a sibling without apparent contraindications to G-CSF mobilization and
stem cell harvest, who is willing to undergo HLA-typing. It is recommended to briefly inform siblings
about the study at an early stage, and ask if they are willing to be HLA-typed. Note that siblings with
evident contraindications to G-CSF and PBSC collection, or BM harvest, are not considered “Potential
Sibling Donors” and should not proceed to HLA-typing.
Note:
- HLA typing of the patient may be performed at any point, e g at diagnosis.
-Patients can be registered for the study before or after attained CR1.
-Registration of the patient must precede HLA typing of a potential sibling donor.
Procedures, see Registration Form
1. Check Inclusion & Exclusion Criteria.
2. Patient´s signed informed consent.
3. Fill in and send the RF to the NSO. Note the important paragraph 6b.
4. The NSO confirms eligibility, formally registers the patient and faxes the RF back.
5. HLA-typing of sibling(s). To avoid selection bias, all potential sibling donors should
preferably undergo HLA-typing. The date of drawing blood from the first sibling is defined as
the Inclusion point2.
6. If a sibling is HLA identical, she/he has to sign the Donor`s Informed Consent .
Thereafter, medical work-up of donor and patient should be performed as per local practice
and the transplantation undertaken as soon as possible.
7. If sibling(s) are not HLA identical (or if unavailable due to eg medical infirmity) – proceed in
line with previous decision at registration, see RF paragraph 6b.
- If the answer was No (“no MUD search planned if sib(s) unavailable”), the patients will be
treated as per local practice.
-If the answer was Yes (“MUD search planned if (sib(s) unavailable”), a (“secondary”)
MUD search should be initiated, see below (procedure 5 and onwards).
Patients without a potential sibling donor
Note:
- HLA typing of the patient may be performed at any point, e g at diagnosis.
- Patients can be registered for the study before or after attained CR1.
-Registration of the patient must precede the date of dispatching a request for a MUD search.
Procedure
1. Check Inclusion & Exclusion Criteria
2. Patient´s informed consent.
3. Fill in and send the RF to the NSO.
4. The NSO confirms eligibility, formally registers the patient, and sends the RF back.
5. Dispatch MUD search request.
7. If a MUD is identified, the patient should undergo RICT as soon as possible.
8. If a MUD is not identified, the patient is allocated to MUD/Control group and treated as per
local practice.
Treatment assignment
1. Treatment assignment is the allocation of patients to study groups and is based on the
results of HLA-typing of siblings and/or of MUD search. The MUD search could be
performed as a primary procedure for patients without a potential sibling donor, or as a
secondary procedure for patients with siblings not eligible as donors. Any patient with
an identified and medically approved donor will be allocated to the RICT group,
whereas patients without such a donor will be allocated to the Control group. This
approach has consequences also for treatment assignment of patients whose donor
search will be called off for reasons other than just failure to find a donor (see below).
2. If a MSD search is called off due to patient´s refusal, relapse, death or medical infirmity
before the identification of a HLA identical, medically approved sibling donor, the
patient is allocated to the Control group, whereas patients with an identified and
medically approved MSD will be assigned to the RICT group, also if the transplant was
not undertaken.
3. If a MUD search is called off due to patient´s refusal, relapse, death or medical
infirmity before the identification of a medically approved MUD, that patient will
assigned to the Control group, whereas patients with an identified medically approved
MUD will be allocated to the RICT group, also if the transplant was not undertaken.
To be able to accomplish the treatment assignment, i.e. strictly allocate patients to study groups and
perform statistical analyses, the following dates will be retrieved in the CRF.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
This is a multi-center phase III prospective study applying HLA-based allocation of patients to RICT,
or to standard of care. The study will be performed according to GCP guidelines. Study population
encompasses AML patients, 51-70 years, in CR1 with an indication for allo-SCT but for whom a full
myeloablative conditioning is not advisable due to age and/or medical impairment.
To prevent patient selection bias, HLA typing of siblings or initiating MUD search should not
be performed prior to patient registration and signed informed consent. The statistical analyses rely
on comparisons between patients with identified donors (MSDs or MUDs), and patients for whom the
donor search was not successful. There will be three defined groups of AML CR1 patients, each contributing to final analyses.
1. One group comprises patients with at least one potential sibling donor, for whom there
is no indication for MUD search in case the sibling(s) are not HLA identical - or
otherwise not eligible for HSC donation.
2. One group comprises patients with at least one potential sibling donor, and for whom
there is an indication and intention to proceed for a MUD search in case the sibling(s)
are not HLA-identical or otherwise not eligible.
3. One group comprises patients without potential sibling donor, but for whom there is an
indication to go for a MUD search.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
The primary analyses will be performed on the intent-to-treat (ITT) populations with treatment
allocation. The stochastic component of
the potential MSD RICT/Control assignment procedure comes from the chance that a sibling is HLAidentical.
The corresponding stochastic component of the MUD RICT/Control assignment procedure
emanates from the chance of finding a MUD within a reasonable time (as judged by the investigator).
To avoid bias, it is essential that any donor search has not been initiated at the time of registration.

Statistical Analyses
The primary objective is to compare overall survival from the inclusion point between MSD/RICT and
Control treatment for patients with a potential MSD. In the latter stratum “Late failures” before MUD
search starts will be included in the control group. According to the argument in the
next paragraph patients who turn non-eligible for transplantation during the MUD search are allocated
to MUD/Control. Patients lost to follow-up or patients refusing further participation in the
study, will be censored the date they were last known to be alive. Log-rank tests and Cox regression
models will be used for analyses and Kaplan-Meier curves will be used for illustration. Disease-free
survival will be analyzed parallel to overall survival.
A secondary objective is to compare survival and disease-free survival for MUD/RICT and
MUD/Control. This is done by combining two strata: patients with a primary MUD
search and patients with a secondary MUD search. Patients who turn non-eligible
for transplantation (e.g. due to relapse or toxicity) during the MUD search before a MUD is found
constitute a group that is difficult to handle in a statistically correct way, since MUD search then will
be stopped before the MUD search period has ended. This will most probably occur late in the period
when there is a relatively small chance left to find a MUD for the patient. Hence, in the main analyses
these patients will be allocated to the MUD/Control group, provided non-eligibility occurs before the
identification and medical approval of a MUD. Patients with an identified and approved MUD will be
allocated to the MUD/RICT group.
Another secondary objective is to compare any donor/RICT vs. Control, and this is ascertained by
combining the results for MSD and MUD.
Non-relapse mortality and relapse incidence will be analyzed taking competing risks into account,
e.g. using the cumulative incidence function.
Biological allocation, as in the present study, is not equivalent to strict randomization. For instance, it
is more likely to find an HLA-compatible sibling if the patient has many siblings. Moreover, age
might affect a sibling´s suitability as donor. Such factors may in turn be related to a patient´s prognosis

(e.g. via social factors), and thus they are potential confounders that might introduce bias in the
treatment comparison. For this reason the survival analyses will also be performed adjusted for known
potential confounding and prognostic factors.
The main analyses, outlined above, are intended to mirror ITT analyses for truly randomized trials.
Then the intention to use a certain treatment is evaluated, albeit both groups (RICT and Control) will
be diluted by patients who receive other treatments than those planned. As a complement, Per Protocol
(as treated) analyses will also be performed. The time from inclusion to transplantation may be
relatively long and hence the analyses will be adjusted for time to transplant using a time dependent
transplant indicator in the Cox analyses. All events before transplantation will then be assigned to the
Control group. These analyses may potentially yield better power than the “ITT” analyses, but bias
may be introduced with advantage for transplantation if late transplantations generally are performed
on patients with relatively better prognosis.
Landmark analyses analyses will also be done comparing survival from the landmark for patients
who are and who are not transplanted at this time. The landmark will be chosen so that 90% of all
transplants have been done.
Since treatment policies vary, subgroup analyses will be performed by country. Adverse events
and Quality of Life data will be presented in descriptive tables. All hypothesis tests, and construction
of confidence intervals, where appropriate, will be performed using two-sided tests at the 0.05
significance level and 95% confidence level, respectively.
Dimensioning of the Study
The sample size calculation is based on the planned analysis of the primary endpoint, overall survival
in the MSD/RICT versus Control comparison. The basic hypothesis rests on an assumption of an
overall survival three years after inclusion of 30 % in the control group and 50 % in the RICT group,
and this corresponds to a relative hazard of about 1.75 assuming exponentially distributed survival
times. The Control group estimate, 30%, is based on data from the Swedish population-based AMLregistry
(Billström 2002), whereas the hypothetical outcome in the RICT group is based on presently
available data in the literature (see Background). We assume that there will be approximately as many
RICT as Control patients. With a univariate Cox regression analysis (asymptotocally equal to the
logrank test) and a two-sided significance level of 5%, one gets approximately power 80% with d=100
events (deaths) in the MSD part of the study and power 90% with d=134 events (Piantodosi S, 1997).
The number of patients needed depends on the true death rate and the follow-up time. Suppose that
40% of the patients will be dead at the end of of the trial. Then n=d/0.40 patients are needed in the
trial; e.g. n=250 if d=100. To detect a relative hazard of 1.50 corresponding to an increase in 3-year
survival from 0.30 to 0.45, one needs 192 events to reach 80% power and 256 events to reach 90%.
The dimensioning is necessarily based on quite simplified assumptions, and is thus approximate.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
26/05/2014
Actual
5/12/2014
Date of last participant enrolment
Anticipated
Actual
27/04/2016
Date of last data collection
Anticipated
31/05/2018
Actual
15/06/2018
Sample size
Target
40
Accrual to date
Final
14
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,SA,TAS,WA,VIC
Recruitment outside Australia
Country [1] 5898 0
New Zealand
State/province [1] 5898 0
Country [2] 5899 0
Sweden
State/province [2] 5899 0
Country [3] 5900 0
Canada
State/province [3] 5900 0

Funding & Sponsors
Funding source category [1] 288905 0
Government body
Name [1] 288905 0
Swedish Research Council
Country [1] 288905 0
Sweden
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia & Lymphoma Group (ALLG)
Address
Level 5/10 St Andrews Place, East Melbourne, Victoria 3002
Country
Australia
Secondary sponsor category [1] 287600 0
None
Name [1] 287600 0
Address [1] 287600 0
Country [1] 287600 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290735 0
The Royal Melbourne Hospital
Ethics committee address [1] 290735 0
Ethics committee country [1] 290735 0
Australia
Date submitted for ethics approval [1] 290735 0
30/05/2014
Approval date [1] 290735 0
09/06/2014
Ethics approval number [1] 290735 0
HREC/14/MH/101

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

Contacts
Principal investigator
Name 43470 0
Dr David Ritchie
Address 43470 0
Bone Marrow Transplant Unit
The Royal Melbourne Hospital
Grattan Street (Corner of Royal Parade)
Parkville, Victoria, 3052


Country 43470 0
Australia
Phone 43470 0
+61 3 9342 2519
Fax 43470 0
Email 43470 0
[email protected]
Contact person for public queries
Name 43471 0
Delaine Smith
Address 43471 0
CEO Australasian Leukaemia and Lymphoma Group, Ground Level, 35 Elizabeth street, Richmond, 3121, Victoria
Country 43471 0
Australia
Phone 43471 0
+61, 03, 8373 9701
Fax 43471 0
Email 43471 0
[email protected]
Contact person for scientific queries
Name 43472 0
Delaine Smith
Address 43472 0
CEO Australasian Leukaemia and Lymphoma Group, ground Level, 35 Elizabeth Street, Richmond, 3121, Victoria
Country 43472 0
Australia
Phone 43472 0
+61, 03, 8373 9701
Fax 43472 0
Email 43472 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 patient data will not be available for this trial. All results presented are aggregate data from all patients enrolled into the clinical trial.


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No Supporting Document Provided



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