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Trial registered on ANZCTR


Registration number
ACTRN12616001022459
Ethics application status
Approved
Date submitted
10/06/2016
Date registered
2/08/2016
Date last updated
1/06/2020
Date data sharing statement initially provided
19/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A phase I pharmacokinetic evaluation of oral arsenic trioxide in previously untreated patients with acute promyelocytic leukaemia
Scientific title
A phase I pharmacokinetic evaluation of oral arsenic trioxide in previously untreated patients with acute promyelocytic leukaemia
Secondary ID [1] 289333 0
ALLG APML5
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Promyelocytic Leukaemia 298941 0
Condition category
Condition code
Cancer 299018 299018 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a phase 1 study that looks at the bioavailability of an oral arsenic trioxide (ATO) in consolidation therapy for APML.

Following standard induction therapy of All-Trans Retinoic Acid (ATRA, tretinoin) + IV ATO (+ idarubucin for high-risk patient), patients will be registered into the trial after documentation of haemotological complete remission.

The study consists of two parts:
(i) A 1-sequence, 4 ATO period single arm study over 28 weeks in total. Patients will be given 7 cycles of All-Trans Retinoic Acid (ATRA, tretinoin) (45mg/m^2, in 2 divided doses) + 4 cycles of IV ATO (0.15mg/kg/day) with the exception of week one of ATO cycle #2, and week one of ATO cycle # 4, when oral tablet ATO (0.15mg/kg/day) will be used. The pharmacokinetic data will be used to adjust each patient's oral dose for week 1 of cycle #4.
(ii) A 2-sequence, 4 ATO period, randomised cross-over study over 28 weeks in total. Patients will be given 7 cycles of ATRA (45mg/m^2, in 2 divided doses) + 4 cycles of IV ATO, with the exception of week one of either ATO cycle #1 or ATO cycle #2, and week one of either ATO cycle #3 or ATO cycle #4, when oral tablet ATO will be used (sequence will be determined by randomisation).
*ATO cycle= 5 days/week for 4 weeks; 4 weeks between cycles;
*ATRA cycle= 7 days/week for 2 weeks; 2 weeks between cycles.

ATRA is administered in oral capsule form; IV ATO is administered IV by infusion pump over 2 hours.

Part (i) - There is an effective ATO washout period of 30 days between each cycle of consolidation (the weekend of week 4 followed by the 4-week interval before the subsequent cycle). The oral ATO capsule formulation will be used at a dose of 0.15mg/kg/d in week 1 of cycle #2. The oral ATO dose that will be administered in week 1 of cycle #4 will be determined on an individual patient basis by the trial management committee, based on the results of the PK data obtained in week 1 of cycles #1, #2 and #3.

All ATO in part (ii) will be given IV at a dose of 0.15mg/kg/day, with the exception of week 1 of either cycle #1 or cycle #2 (determined by randomisation), when ATO will be given orally at a dose of 0.15mg/kg/day as determined by the TMC based on the aggregate PK data that was generated in part (i). Oral ATO will also be used at the same dose (0.15mg/kg/day) in week 1 of either cycle #3 or #4. Oral arsenic capsules should be taken 1 hour before food on an empty stomach. PK studies will again be performed in week 1 of each ATO cycle.

Regardless of the PK data, the maximum oral dose of ATO will be 0.3mg/kg/day, and the minimum will be 0.08mg/kg/day.

Maintenance therapy, typically involving ATRA + methotrexate + 6-mercaptopurine, will not be used for either part (i) or part (ii) of this study, regardless of initial risk category.

The investigator, or a responsible party designated by the investigator such as the Pharmacy Department at participating institutions, must maintain a careful record of the inventory and disposition of the investigative agent. A pharmacy file will be provided for the purpose and will collect information such as drug name, batch number, expiry date, amount dispensed and disposal of supplies via approved procedures at the end of the study.
Intervention code [1] 294893 0
Treatment: Drugs
Comparator / control treatment
The IV ATO is the control formulation for the oral ATO with each patient in this cross over study.
Control group
Active

Outcomes
Primary outcome [1] 298479 0
Composite outcomes:
(a) To determine the absorption and PK characteristics of an oral capsule formulation of ATO (intrasubject comparison of peak serum level and AUC0-24);
(b) To determine the recommended phase 2 dose (RP2D) or oral ATO for use in a subsequent phase 2 study to examine efficacy.


Timepoint [1] 298479 0
In part (ii), there are two co-primary endpoints.
AUC: 0-24. The area under the curve of arsenic concentrations in the blood (micromol/l), from time zero (immediately before the first dose on a cycle day) until the sample at 24 hours that precedes the dose on the following day.
Cmax- The maximum observed arsenic concentration in the blood (micromol/l) in the 24 hours following administration of the dose, and prior to the next administration of the dose.

The endpoints are assessed on days 1 and 4 of the first week in each cycle of ATO consolidation. 10ml of whole blood will be collected immediately prior to dosing (time 0), and at 0.5, 1, 2, 4, 6-8, and 24 hours after the start of dosing.

Samples will be analysed for concentrations of ATO and other arsenical species by liquid chromatography coupled to ICPMS.

A calculation of the bioavailability will be made based on the ratio of AUC 0-24 for the oral administration (day 1 of week 1, cycle #2), divided by the AUC0-24 for IV administration in the same patient (day 1 of week 1, cycle #1).

In part (i), the oral dose that is used in week 1 of cycle #2 will be 0.15mg/kg/day, the same as used for IV ATO. The PK data will then be used to adjust each patient’s oral dose for week 1 of cycle #4. If necessary, part (i) will be extended to include more than 8 patients to ensure confidence in the oral dose selected for part (ii).

The aggregate PK data for all patients in part (i) will be used to determine the oral ATO dose that will be used in part (ii) of the study, which will involve a randomisation to oral or IV ATO in the first week of cycle #1 to eliminate unanticipated bias. The alternative route will then be used in week 1 of cycle #2. The same schedule will be repeated for week 1 of cycle #3 and #4 to assess intrapatient PK variability. When all the PK data are available (from all patients in both part (i) and part (ii)), a further adjustment in the oral dose that is selected for the subsequent phase II study will be made, if necessary.

Patients will be on 4 cycles of ATO (cycle = 5 days/week for 4 weeks; 4 weeks between cycles).
Secondary outcome [1] 324288 0
To assess the safety of oral ATO relative to IV ATO.
Timepoint [1] 324288 0
From beginning of consolidation therapy until the end of the study.

Safety analyses will be performed on all patients who received at least one dose of ATO in consolidation. Five mutually exclusive observation periods will be used-
* Pre-ATO treatment in consolidation: The interval between registration on the study and the time of the first dose of ATO in cycle 1 of consolidation therapy.
* Periods corresponding to consolidation cycles: from the time of the first dose of ATO in a cycle of consolidation therapy until the earlier of the commencement of the next cycle or 28 days after the last dose of ATO on study. There will be up to 4 such periods.

Summary tables for worst grades of adverse events (AEs) will include only AEs that started or worsened during an observation period. The incidence of these emergent events will be summarised by system organ class and/or preferred term, severity (based on Common Terminology Criteria for Adverse Events; CTCAE grades), type of adverse event and relationship to study drug.

Possible toxicities associated with ATRA and IV ATO include QTc prolongation and other conduction abnormalities, hepatotoxicity, pseudotumour cerebri, peripheral neuropathy, myelosuppression, hyperlipidaemia, hyperglycaemia, and APL differentiation syndrome with/without hyperleukocytosis.
Secondary outcome [2] 324289 0
To evaluate the Relapse-Free Survival (RFS) and Overall Survival (OS). These are composite outcomes.
Timepoint [2] 324289 0
Two non-key secondary efficacy endpoints will be evaluated,
(i) relapse-free survival (RFS), measured from the date of commencement of consolidation to the earlier of the date of documented relapse or the date of death, and
(ii) overall survival (OS) measured from the date of commencement of consolidation to the date of death.
These are composite outcomes.

Relapse is defined as either: (1) the reappearance of abnormal blast cells and/or promyelocytes or the development of extramedullary disease (haematologic relapse) or (2) reversion to PML-RARA positivity confirmed on serial samples after previously documented negativity (molecular relapse), whichever occurs first.

Relapse is assessed by bone marrow aspirate for morphology, cytogenetics and quantitative reverse transcript polymerase chain reaction of PML-RARA transcripts.

Follow-up beyond 4th cycle of consolidation (7 months of treatment, 4 cycles of ATO during consolidation treatment) is at the investigator’s discretion. A follow-up schedule of every 3 months for at least 2 years after completion of consolidation cycle #4 is recommended.
The Trial Coordinating Centre will request the survival and relapse status of each patient annually for a minimum of 3 years following the 4th cycle of ATO consolidation.

NB: ATO cycle = 5 days/week for 4 weeks; 4 weeks between cycles.

Eligibility
Key inclusion criteria
1. Patient has consented to and registered with the National Blood Cancer Registry (NBCR).
2. Morphological diagnosis of APL, either classical FAB-M3 or variant FAB-M3v.
3. Diagnosis of APL has been confirmed by the presence of PML-RARA fusion transcripts in pre-treatment blood or bone marrow.
4. Age greater than or equal to 18 years
5. In haematological complete remission (hCR or hCRi) following induction with ATRA + ATO (standard-risk as per APL0406) or ATRA + ATO + idarubicin (high-risk as per APML4).
6. An ECOG performance status score of 3 or less.
7. Absence of previous history of serious cardiac, pulmonary, hepatic or renal disease.
8. Serum creatinine less than or equal to 200µmol/L (unless medically correctable).
9. Serum bilirubin less than or equal to 50µmol/L (unless medically correctable).
10. ECG showing sinus rhythm and QTc interval (Framingham) < 450msec. Prolongation of QTc due to medication or electrolyte disturbance must be corrected before registration.
11. No contra-indication to use of any of the study drugs.
12. Has provided written informed consent.
13. Females of childbearing potential must have a negative pregnancy test at registration for APML5.
14. Females of childbearing potential and males must use an effective method of contraception or practice absolute abstinence during treatment and for 2 months after treatment discontinuation.
15. Participants must agree not to donate blood, semen or sperm whilst on study treatment and for 2 months after treatment discontinuation.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Failure to meet the inclusion criteria, or the presence of any of the following, will exclude the participant from enrolment in the study:
1. Participants aged < 18 years.
2. Women who are pregnant or lactating.
3. Has any other clinically important abnormalities or conditions as determined by the investigator that may interfere with his or her participation in the trial or compliance with the trial protocol.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled 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
Crossover
Other design features
Phase
Phase 1
Type of endpoint(s)
Pharmacokinetics
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
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)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 10752 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 10753 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [3] 10754 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [4] 10755 0
The Alfred - Prahran
Recruitment hospital [5] 10756 0
Westmead Hospital - Westmead
Recruitment hospital [6] 10757 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [7] 10758 0
Concord Repatriation Hospital - Concord
Recruitment hospital [8] 10759 0
Royal Hobart Hospital - Hobart
Recruitment hospital [9] 10760 0
Gosford Hospital - Gosford
Recruitment hospital [10] 16786 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [11] 16787 0
Wollongong Hospital - Wollongong
Recruitment hospital [12] 16788 0
Royal Perth Hospital - Perth
Recruitment hospital [13] 16789 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [14] 16790 0
Liverpool Hospital - Liverpool
Recruitment hospital [15] 16791 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment postcode(s) [1] 22480 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 22478 0
2050 - Camperdown
Recruitment postcode(s) [3] 30409 0
2065 - St Leonards
Recruitment postcode(s) [4] 22484 0
2139 - Concord
Recruitment postcode(s) [5] 22482 0
2145 - Westmead
Recruitment postcode(s) [6] 30413 0
2170 - Liverpool
Recruitment postcode(s) [7] 22486 0
2250 - Gosford
Recruitment postcode(s) [8] 22479 0
2298 - Waratah
Recruitment postcode(s) [9] 30410 0
2500 - Wollongong
Recruitment postcode(s) [10] 22481 0
3004 - Prahran
Recruitment postcode(s) [11] 30412 0
3050 - Parkville
Recruitment postcode(s) [12] 30414 0
3065 - Fitzroy
Recruitment postcode(s) [13] 22483 0
4029 - Herston
Recruitment postcode(s) [14] 30411 0
6000 - Perth
Recruitment postcode(s) [15] 22485 0
7000 - Hobart
Recruitment outside Australia
Country [1] 7927 0
New Zealand
State/province [1] 7927 0

Funding & Sponsors
Funding source category [1] 293709 0
Other Collaborative groups
Name [1] 293709 0
Australasian Leukaemia and Lymphoma Group
Address [1] 293709 0
35 Elizabeth Street Richmond VIC 3121
Country [1] 293709 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group (ALLG)
Address
Ground Floor, 35 Elizabeth Street
North Richmond
Melbourne VIC 3121
Country
Australia
Secondary sponsor category [1] 292543 0
None
Name [1] 292543 0
Address [1] 292543 0
Country [1] 292543 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295144 0
SLHD Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 295144 0
c/- Research Ethics and Governance Office (REGO)
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 295144 0
Australia
Date submitted for ethics approval [1] 295144 0
09/11/2016
Approval date [1] 295144 0
27/03/2017
Ethics approval number [1] 295144 0
Protocol No X16-0457 & HREC/16/RPAH/654

Summary
Brief summary
PURPOSE
This study will determine the safety and pharmacokinetics of oral arsenic trioxide (ATO) in consolidation therapy for Acute Promyelocytic Leukaemia (APML)

WHO IS IT FOR?
You may be eligible to join this study if you are aged 18 years or above, have been diagnosed with APML, and are in complete remission following induction with ATRA + ATO, or ATRA + ATO + idarubicin (high risk APML patients).

STUDY DETAILS
Enrolled participants will have achieved haematological remission following standard induction therapy with ATRA + ATO, or ATRA + ATO + Idarubucin. Patients will then undergo consolidation therapy, which will consist of two phases:
Phase (i)- Approximately 8 patients will receive 7 cycles of ATRA (cycle= 7 days/week for 2 weeks; 2 weeks between cycles) + 4 cycles of IV ATO (cycle= 5 days/week, for 4 weeks; 4 weeks between cycles) with the exception of week 1 of ATO cycle #2, and week 1 of ATO cycle #4, when oral ATO will be used. The total time of consolidation treatment will be 28 weeks (7 months). Patients may have their oral doses adjusted throughout phase (i), with adjustments based on blood and urine results. The treatment regimen is designed so that patients will still receive effective doses of ATO, even if the oral ATO is completely unabsorbed by the body.
Phase (ii)- The remaining 20 patients will receive 7 cycles of ATRA (cycle= 7 days/week for 2 weeks; 2 weeks between cycles) + 4 cycles of IV ATO (cycle= 5 days/week for 4 weeks; 4 weeks between cycles) with the exception of week one of either ATO cycle #1 or ATO cycle #2, and week one of either ATO cycle #3 or ATO cycle #4, when oral ATO will be used (the sequence will be determined by randomisation). The total time of consolidation treatment will be 28 weeks (7 months);

Pharmacokinetics will be assessed by blood samples collected on days 1 to 2 and days 4 to 5, and urine collected on days 4 to 5 of the first week of each cycle of ATO consolidation. Safety will be assessed using Common Terminology Criteria for Adverse Events. Participants will be followed-up annually for a minimum of 3 years following the 4th cycle of ATO consolidation.

OUTCOMES
This trial is primarily a bioavailability study; however the efficacy and safety will be also evaluated, with the aim to determine the recommended phase 2 dose of oral ATO for use in a subsequent phase 2 trial to study efficacy.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 66286 0
Prof Harry Iland
Address 66286 0
Institute of Haematology
Royal Prince Alfred Hospital
Missenden Road
Camperdown NSW 2050
Country 66286 0
Australia
Phone 66286 0
+612 9515 7655
Fax 66286 0
+612 9515 6698
Email 66286 0
harry@email.cs.nsw.gov.au
Contact person for public queries
Name 66287 0
Ms Delaine Smith
Address 66287 0
Australasian Leukaemia and Lymphoma Group
Ground Floor, 35 Elizabeth Street,
North Richmond, VIC, 3121
Country 66287 0
Australia
Phone 66287 0
+613 8373 9701
Fax 66287 0
+613 9429 8277
Email 66287 0
delaine.smith@allg.org.au
Contact person for scientific queries
Name 66288 0
Prof Harry Iland
Address 66288 0
Institute of Haematology
Royal Prince Alfred Hospital
Missenden Road
Camperdown NSW 2050
Country 66288 0
Australia
Phone 66288 0
+612 9515 7655
Fax 66288 0
+612 9515 6698
Email 66288 0
harry@email.cs.nsw.gov.au

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 shared publically. Aggregate patient data and final results will be presented in the final report
What supporting documents are/will be available?
No other documents available
Summary results
No Results