Please note the ANZCTR will be unattended from Friday 20 December 2019 for the holidays. The Registry will re-open on Tuesday 07 January 2020. Submissions and updates will not be processed during that time.

Please be advised that as the ANZCTR is funded by Australia and New Zealand, we must prioritise submissions from these countries first. International submissions should allow additional time for registration. Apologies for any inconvenience caused.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12616000738426
Ethics application status
Approved
Date submitted
28/01/2016
Date registered
6/06/2016
Date last updated
12/08/2019
Date data sharing statement initially provided
17/06/2019
Date results information initially provided
12/08/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
The DIRECT Study: Individualised dasatinib dosing for patients with chronic myelogenous leukaemia.
Scientific title
A single arm phase II study to individualize dasatinib dosing based on trough levels and molecular response to maintain efficacy whilst minimising toxicity
Secondary ID [1] 288439 0
ALLG CML12
Universal Trial Number (UTN)
Trial acronym
DIRECT (Dasatinib Intensity Regulation to Eliminate Cumulative Toxicities).
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Myelogenous Leukaemia in Chronic Phase 297461 0
Condition category
Condition code
Cancer 297651 297651 0 0
Leukaemia - Chronic leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients will be treated with Oral Dasatinib at one of 4 dose levels: Dose level 0 = 100mg daily; Dose level -1 = 70mg daily; and Dose level -2 = 50mg daily. Dose level -3 = 50mg alternate daily (exists in this protocol only for treatment re-introduction in the event of treatment cessation for toxicity).
All patients will commence treatment with dasatinib at 100mg once daily. Dose adjustments may occur at day 7, 28 and 56. In general, a therapeutic drug monitoring (TDM) result should be available from the central lab within 5 days of sample receipt.
At day 7, plasma dasatinib trough level will be performed for all patients.
1. Patients with trough level greater than or equal to 3nM will decrease their dose
from 100mg once daily to 70mg once daily (i.e. dose level 1).
2. Patients with trough level less than 3nM will continue with 100mg once daily
At day 28, all patients will have a further dasatinib trough level performed
1. Patients with trough level less than 3nM will continue with their assigned dose at day 7
2. Patients with trough level greater than or equal to 3nM will decrease their dose by 1 dose level
-Patients on 70mg once daily will take 50mg once daily
-Patients on 100mg once daily will take 70mg once daily
At day 56, all patients will have a further dasatinib trough level performed.
1. Patients on 70mg at this time point with a plasma trough level of greater than or equal to 3nM will dose decrease to 50mg daily. No dose adjustment will occur for other patients for pharmacokinetic reasons.
In addition to TDM directed dose reductions, patients may have dose reductions for toxicity management at any time during their treatment.
Further trough levels will be performed at 3, 6, 9, 12, 18 and 24 months. Dose adjustments at these time points will only occur for toxicity management and will not be determined by trough drug level.
Molecular monitoring for disease response will be performed on all patients, specified as a series of time dependent molecular targets: BCR-ABL1 = 10%, 1% and 0.1% at 3, 6 and 12 months respectively. Patients on reduced dose dasatinib will automatically dose escalate for failing to meet any of these targets:
i) Failing to achieve BCR-ABL1 =10% at 3 months or beyond OR BCR-ABL1 =1% at 12 months – resume 100mg daily;
ii) Failing to achieve BCR-ABL1 =1% at 6 months OR BCR-ABL1 =0.1% at 12 months
– patients to dose increase by one level every 3 months up to 100mg once daily, until target response is achieved.
The treatment period of this study will be 2 years. If clinically appropriate, patients will remain on their assigned therapy beyond this point and receive active follow-up for a further 3 years. Drug accountability logs will be used.
Intervention code [1] 293762 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 297187 0
The primary objective of the DIRECT study is to assess the incidence of treatment related pleural effusion in CML-CP patients, treated with TDM dose optimised dasatinib. This will be assessed by the cumulative incidence of pleural effusions of all grades, at 24 months, in CML-CP patients, treated with TDM dose optimised dasatinib. A chest X-Ray will be performed at baseline, then at the 24 month time point, or for early trial withdrawal. Additional chest X-rays will be performed for investigations of clinically suspected pleural effusion. Pleural effusions could be detected on routine clinical examination or radiology.
Timepoint [1] 297187 0
Cumulative incidence (%) of patients with at least one event classified as pleural effusions of any grade, at 24 months.
Secondary outcome [1] 320273 0
To assess molecular response in patients treated with dasatinib when a dose reduction strategy based on therapeutic dose monitoring (TDM) is followed (the DIRECT strategy). This will be assessed as follows:

Molecular response - Blood samples will be evaluated at the central laboratory by QPCR testing for levels of BCR-ABL transcripts every month for the first 3 months, followed by every 3 months for the remainder of the first 24 months. During the Extension Phase, blood samples will be collected every 3 months and QPCR testing performed at the local laboratory, except for months 36, 48 and 60 which will be tested at the Central Laboratory.
Timepoint [1] 320273 0
Molecular response, assessed at 3, 6 and 12 months post commencement of intervention.
Secondary outcome [2] 320428 0
To assess OS, TFS and EFS in patients treated with the DIRECT strategy.

This will be assessed from patient visits – physical examinations and disease assessments which include bone marrow and/or peripheral blood tests.
Timepoint [2] 320428 0
Survival over the course of the study and in particular with point estimates at 24 and 60 months.
Secondary outcome [3] 320429 0
To assess the proportion of patients eligible for TFR. The number (and proportion) of patients eligible for treatment free remission studies, defined as greater than or equal to 24 months of continuous MR4.5 in a patient who has had greater than or equal to 36 months of TKI therapy.
Timepoint [3] 320429 0
within 5 years post commencement of intervention.
Secondary outcome [4] 320430 0
Composite outcome exploring the correlation between dasatinib trough levels (by blood sample), dose intensity (by review of study records) and incidence of molecular response (by review of medical records) and toxicity (by review of incidence of pleural effusion, infection, pulmonary hypertension, bleeding, proteinuria, cardiovascular and haematological toxicities).
Timepoint [4] 320430 0
at 3 months, 12 months and 24 months
Secondary outcome [5] 320437 0
To assess QOL. Assessed using QOL survey (FACT-BRM)
Timepoint [5] 320437 0
at screening, 6 months, 12 months, 18 months,24 months and end of study or withdrawal.
Secondary outcome [6] 320438 0
To assess the number (and proportion) of patients who acquired kinase domain mutations and other related mechanisms of treatment failure. Blood samples assessed in the laboratory for mutations; gene microarrays, kinase inhibition assays, expression and function of drug transporters, pharmacokinetics, and primitive hematopoietic cells.
Timepoint [6] 320438 0
at 24 months, and 60 months.
Secondary outcome [7] 322167 0
Overall tolerability of dasatinib in patients treated with the DIRECT strategy.
Timepoint [7] 322167 0
Incidence of Adverse events assessed 3 monthly over 5 years.
-Incidence of pleural effusion (assessed by review of medical records, chest X ray report)
-Incidence of other adverse events of special interest namely infection (by review of medical records and lab reports),
-pulmonary hypertension (assessed by review of medical records),
- bleeding, proteinuria, cardiovascular and haematological toxicities (by review of lab reports)
-Incidence of all other grade III/IV adverse events (by review of medical records and relevant reports).
-Number of SAEs
-Number (%) of patients discontinuing treatment due to intolerance

Eligibility
Key inclusion criteria
1. Newly diagnosed CML-CP who have had either no prior exposure or less than 1 month of exposure to alternative TKI therapy
a) Must demonstrate a quantifiable BCR-ABL1 fusion transcript on molecular studies, reported on the international scale; and
b) Must have morphological appearance consistent with CML-CP, as defined by the European Leukaemia Net criteria.1 Additional cytogenetic abnormalities at baseline or diagnosis do not classify a patient as accelerated phase for the purpose of this study. Extramedullary leukaemia would automatically classify a patient as having blastic phase disease; and
c) Must be less than or equal to 3 months from diagnosis to screening
2. Aged 18 years or older
3. Willingly provide informed consent and agree to comply with study protocol
4. ECOG performance status 0-2.
5. No prior anti-CML therapy, except for short term (less than 12 weeks) treatment with hydroxyurea, anagrelide or leukapheresis. Less than 1 month of prior non-dasatinib TKI therapy permitted prior to screening.
6. Adequate liver and renal function.
a) ALP, ALT and AST less than or equal to 2.5 x ULN; or = 5.0 if tumour related; and
b) Bilirubin less than or equal to 2 x ULN unless secondary to Gilbert’s syndrome; and
c) Creatinine Clearance of greater than or qqual to 20mL/min, calculated using the Cockroft-Gault formula. Idealised body weight should be used for patients at the extremes of body weight.
7. Serum Na, K, Mg, and total serum Ca or ionized Ca levels must be greater than or equal to the institutional lower limit of normal. Subjects with low K or Mg levels, total serum Ca and/or ionized Ca must be replete for protocol entry.
8. Subjects are expected to have a life expectancy of greater than or equal to 12 months in the opinion of the investigator, in the context of the patient’s general condition and comorbidities.
9. Eligible for a reimbursed treatment with dasatinib under the PBS complex drug program in Australia, the Pharmac system in New Zealand, or through other arrangements with regulatory and funding authorities.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patients who have undergone major surgery within the 4 weeks prior to study entry or have not recovered from earlier surgery.
2. Impaired cardiac function, uncontrolled or significant cardiovascular disease, including any of the following:
a) A myocardial infarction within 6 months
b) Uncontrolled angina within 3 months
c) Congestive heart failure within 3 months
d) Diagnosed or suspected congenital long QT syndrome
e) Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de Pointe, or third degree heart block without pace maker insertion)
f) Prolonged QTcF interval greater than 450 msec on baseline ECG (rescreening allowed after correction of rectifiable factors, eg electrolytes management, or rationalisation of medications)
g) Patient receiving medications associated with QT interval prolongation
3. Impaired pulmonary function including any of the following:
a) Previously diagnosed with pulmonary hypertension
b) Severe pre-existing pulmonary disease that
i) Imposes limits on activities of daily living
ii) FEV1, FVC or DLCO less than or equal to 50% of the predicted value (formal pulmonary function testing is not required for patients without antecedent diagnosis of pulmonary disease) or
iii) Impaired pulmonary function as defined using any other relevant clinical measure by the investigator
c) Current and unresolved pleural effusion(s), or previous history of pleural effusions (excluding those infective in aetiology)
4. Treatment with agents that prolong QT interval or inhibit CYP3A4, as listed under prohibited concomitant medications (Consult Appendix 1 for CYP3A4 inducers, inhibitors and substrates, as well as prohibited medications).
5. Another primary malignant disease, except for such conditions that do not currently require treatment, lesions that can be or had been completely excised (e.g. Skin Cancers) and neoplasms that does not significantly affect long term survival of the patient
6. Other concurrent uncontrolled medical conditions (e.g. uncontrolled diabetes, active or uncontrolled infections, acute or chronic liver and renal disease) that could cause unacceptable safety risks or compromise compliance with the protocol.
7. Cytopathologically confirmed CNS infiltration. [In the absence of suspicion of CNS involvement, lumbar puncture is not required.]
8. Patients unwilling or unable to comply with protocol and patients with a history of noncompliance or inability to grant informed consent.
9. Prior stem cell transplantation.
10. Reproductive status
h) Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug.
i) Women must not be breastfeeding.
j) WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug, plus 30 days (duration of ovulatory cycle) for a total of 30 days post-treatment completion.
k) Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug plus 90 days (duration of sperm turnover) for a total of 90 days post-treatment completion.
l) Azoospermic males and WOCBP, who are not heterosexually active, are exempt from contraceptive requirements. However, WOCBP must still under pregnancy testing as described in this section.
m) Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of unexpected pregnancy. Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective contraception. Highly effective methods of contraception have a failure rate of <1% when used consistently and correctly.
n) At a minimum, subjects must agree to the use of two methods of contraception, with one method being highly effective and the other method being either highly effective or less effective as listed below.11. Current participation in another therapeutic clinical trial (participation in clinical trials that do not involve active interventions is not an exclusion for the study).
12. Congenital or acquired platelet disorders with increased risk of clinically significant bleeding.
c) Diagnosed congenital bleeding disorders (e.g. von Willebrand’s disease)
d) Diagnosed acquired bleeding disorder within one year (e.g. acquired anti-factor VIII antibodies)

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
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not 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)
NSW,QLD,SA,TAS,VIC
Recruitment hospital [1] 10723 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [2] 10724 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [3] 10725 0
Toowoomba Hospital - Toowoomba
Recruitment hospital [4] 10726 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [5] 10727 0
Gosford Hospital - Gosford
Recruitment hospital [6] 10728 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [7] 10729 0
Royal Hobart Hospital - Hobart
Recruitment hospital [8] 10730 0
Concord Repatriation Hospital - Concord
Recruitment hospital [9] 10731 0
Westmead Hospital - Westmead
Recruitment hospital [10] 10732 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [11] 10733 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [12] 10734 0
Liverpool Hospital - Liverpool
Recruitment hospital [13] 10735 0
Border Medical Oncology - Albury
Recruitment postcode(s) [1] 22444 0
5000 - Adelaide
Recruitment postcode(s) [2] 22445 0
3220 - Geelong
Recruitment postcode(s) [3] 22446 0
4350 - Toowoomba
Recruitment postcode(s) [4] 22447 0
2298 - Waratah
Recruitment postcode(s) [5] 22448 0
2250 - Gosford
Recruitment postcode(s) [6] 22449 0
5042 - Bedford Park
Recruitment postcode(s) [7] 22450 0
7000 - Hobart
Recruitment postcode(s) [8] 22451 0
2139 - Concord
Recruitment postcode(s) [9] 22452 0
2145 - Westmead
Recruitment postcode(s) [10] 22453 0
4102 - Woolloongabba
Recruitment postcode(s) [11] 22454 0
3084 - Heidelberg
Recruitment postcode(s) [12] 22455 0
2170 - Liverpool
Recruitment postcode(s) [13] 22456 0
2640 - Albury

Funding & Sponsors
Funding source category [1] 292784 0
Commercial sector/Industry
Name [1] 292784 0
Bristol Myers Squibb
Address [1] 292784 0
Level 2, 4 Nexus Court, Mulgrave, VIC, 3170, Australia.
Country [1] 292784 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group
Address
Ground floor, 35 Elizabeth street, Richmond, Vic 3121
Country
Australia
Secondary sponsor category [1] 291519 0
None
Name [1] 291519 0
None
Address [1] 291519 0
None
Country [1] 291519 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294277 0
Royal Adelaide Hospital
Ethics committee address [1] 294277 0
North Terrace
Adelaide, SA 5000
Australia
Ethics committee country [1] 294277 0
Australia
Date submitted for ethics approval [1] 294277 0
01/06/2016
Approval date [1] 294277 0
22/08/2016
Ethics approval number [1] 294277 0
Ethics committee name [2] 300158 0
Human Research Ethics Committee (Tasmania) Network
Ethics committee address [2] 300158 0
Office of Research Services
University of Tasmania
Private Bag 1
Hobart Tasmania 7001
Ethics committee country [2] 300158 0
Australia
Date submitted for ethics approval [2] 300158 0
03/10/2016
Approval date [2] 300158 0
04/10/2016
Ethics approval number [2] 300158 0
H0016052

Summary
Brief summary
The primary purpose of this study is to evaluate the efficacy and safety of individualised dosing of dasatinib for elderly patients with chronic myelogenous leukaemia. Who is it for? You may be eligible to participate in this study if you are aged 18 years or over, and have been diagnosed with chronic myelogenous leukaemia in the chronic phase (CML-CP) in the previous three months. Study details All participants in this study will start taking dasatinib at 100mg per day. At day 7, a blood sample will be taken to measure the levels of dasatinib in the blood just prior to taking that day's dose. If the blood dasatinib level is above a certain point, then the daily dose will be decreased to 70mg per day. If the blood dasatinib level is adequately low, then the participant will continue taking 100mg per day. This process will be repeated on days 28 and 56, with further lower dose levels of 50mg per day and 50mg every other day available if blood dasatinib levels are above the specific concentration. The dose level may also be dropped at any time if signs of drug toxicity are present. Participants may also be escalated back up a dose level (up to a maximum of 100mg per day), if further blood tests every 3-6 months show that the drug has not sufficiently decreased markers of the leukaemia, i.e. treatment has not been adequately effective. Participants will continue taking the drug for the two year study period, followed by a further three years if it has proven to be safe and effective in these patients. It is hoped that the findings of this study will provide information on whether an individualised dose of dasatinib can be used in elderly CML-CP patients to minimise toxicity whilst maintaining the therapeutic effect to treat the disease.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 63158 0
Dr David Yeung
Address 63158 0
SA Pathology (Royal Adelaide Hosptial Campus)
Haematology, IMVS
Frome Road
Adelaide SA 5000
Country 63158 0
Australia
Phone 63158 0
+61 8 8222 3942
Fax 63158 0
Email 63158 0
David.Yeung@sa.gov.au
Contact person for public queries
Name 63159 0
Dr David Yeung
Address 63159 0
SA Pathology (Royal Adelaide Hosptial Campus)
Haematology, IMVS
Frome Road
Adelaide SA 5000
Country 63159 0
Australia
Phone 63159 0
+61 8 8222 3942
Fax 63159 0
Email 63159 0
David.Yeung@sa.gov.au
Contact person for scientific queries
Name 63160 0
Dr David Yeung
Address 63160 0
SA Pathology (Royal Adelaide Hosptial Campus)
Haematology, IMVS
Frome Road
Adelaide SA 5000
Country 63160 0
Australia
Phone 63160 0
+61 8 8222 3942
Fax 63160 0
Email 63160 0
David.Yeung@sa.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
No individual participant data will be publicly available as it is the aggregate data that is under investigation.
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary