Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12606000118505
Ethics application status
Approved
Date submitted
3/04/2006
Date registered
3/04/2006
Date last updated
31/08/2023
Date data sharing statement initially provided
31/08/2023
Date results information initially provided
31/08/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A phase II study of withdrawal of imatinib therapy in adult patients with chronic phase chronic myeloid leukaemia in stable molecular remission
Scientific title
A phase II study to determine relapse-free interval after withdrawal of imatinib therapy in adult patients with chronic phase chronic myeloid leukaemia in stable complete molecular remission
Secondary ID [1] 254 0
Australasian Leukaemia and Lymphoma Group (ALLG): ALLG CML8
Universal Trial Number (UTN)
Trial acronym
TWISTER
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic phase chronic myeloid leukaemia in stable molecular remission 1083 0
Condition category
Condition code
Cancer 1163 1163 0 0
Leukaemia - Chronic leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a non-randomised Phase 2 clinical study. Patients who have achieved a stable complete molecular response on imatinib mesylate treatment (i.e. undetectable BCR-ABL mRNA for at least 2 years) will stop imatinib treatment and be monitored closely for molecular evidence of early relapse. Monitoring off treatment will continue until relapse or for a maximum of 2 years. Patients who relapse will resume imatinib treatment and close monitoring will continue to assess the molecular response to re-treatment. Monitoring in the re-treatment phase will continue until complete molecular response is confirmed or for a maximum of 12 months.
Intervention code [1] 965 0
Treatment: Drugs
Comparator / control treatment
No comparator.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 1568 0
To assess what proportion of CML patients with stable complete molecular response (CMR) on imatinib for at least 2 years remain in complete molecular response (without recurrence of RQ-PCR-detectable BCR-ABL in blood)
Timepoint [1] 1568 0
For 2 years after ceasing imatinib therapy
Secondary outcome [1] 2822 0
1. To assess the proportion of patients who, after ceasing imatinib for up to 2 years, have recurrence of detectable BCR-ABL that is NOT eradicated within 12 months of re-starting imatinib.
Timepoint [1] 2822 0
Secondary outcome [2] 2823 0
2.To assess the proportion of patients who, after ceasing imatinib for up to 2 years, have recurrence of detectable BCR-ABL but maintain a major molecular response, or regain a major molecular response or complete molecular response within 12 months of restarting imatinib.
Timepoint [2] 2823 0
Secondary outcome [3] 2824 0
3.To assess the proportion of patients who develop cytogenetic or haematological relapse in the two years after cessation of imatinib
Timepoint [3] 2824 0
Secondary outcome [4] 2825 0
4.To establish the rate of molecular relapse-free survival after cessation of imatinib treatment (MRFS).
Timepoint [4] 2825 0
Secondary outcome [5] 2826 0
5.To assess quality of life and resolution of any identified imatinib toxicity during the period of drug withdrawal.
Timepoint [5] 2826 0

Eligibility
Key inclusion criteria
1. Diagnosis of chronic myeloid leukaemia associated with BCR-ABL quantifiable by RQ-PCR at the time of commencing imatinib therapy 2. Treatment with imatinib for at least 3 years 3. No other current or planned anti-leukaemia therapies 4. Sustained complete molecular response of leukaemia (assessed by undetectable levels of BCR-ABL by RQ-PCR in blood or marrow, for 2 years or longer, tested on at least 2 occasions per year and confirmed by the central PCR laboratory at IMVS using a technique with sensitivity of at least 4 logs) 5. No signs of extramedullary leukaemia 6. ECOG Performance status 0, 1, or 2 (see Section 6.1.2) 7. Female patients must have a negative pregnancy test within one week before starting imatinib OR have been amenorrhoeic for at least two years. All patients of reproductive potential must agree to birth control for the duration of the study monitoring and re-treatment phases. 8. Life expectancy of more than 12 months in the absence of any intervention 9. Patient has given written, informed consent to participate in the study (which includes consent to obtain samples for the correlative study) and has been given the option to participate in tissue banking.
Minimum age
18 Years
Maximum age
Not stated
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patient has received another investigational agent within last 2 years.2. Currently receiving imatinib treatment as part of a clinical trial (including Extension Phase of IRIS trial)3. Administration of cytokine therapy (e.g. G-CSF, GM-CSF or SCF) within 4 weeks prior to study entry.4. Atypical BCR-ABL transcript not quantifiable by standard RQ-PCR.5. Another primary malignant disease, except those which do not currently require treatment (adequately treated conditions, such as excised skin cancer or cervical intra-epithelial neoplasia would not be considered exclusion criteria. If in doubt, please refer to the Principal Investigator). 6. Another severe and/or life-threatening medical disease. 7. Active liver disease (e.g., chronic active hepatitis, cirrhosis).8. Known diagnosis of human immunodeficiency virus (HIV) infection. 9. History of non-compliance or inability to grant informed consent.10. Prior allogeneic stem cell transplantation11. Interruption of imatinib therapy for a cumulative period in excess of 14 days in the preceding 3 months.

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
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/04/2006
Actual
1/08/2006
Date of last participant enrolment
Anticipated
Actual
28/07/2011
Date of last data collection
Anticipated
Actual
23/10/2013
Sample size
Target
25
Accrual to date
Final
40
Recruitment in Australia
Recruitment state(s)
NSW,NT,QLD,WA,VIC

Funding & Sponsors
Funding source category [1] 1271 0
Commercial sector/Industry
Name [1] 1271 0
Novartis Australia
Country [1] 1271 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group
Address
35 Elizabeth street VIC 3121
Country
Australia
Secondary sponsor category [1] 1126 0
None
Name [1] 1126 0
none
Address [1] 1126 0
Country [1] 1126 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313723 0
Southern Adelaide Clinical Human Research Ethics Committee
Ethics committee address [1] 313723 0
Flinders Dr, Bedford Park SA 5042
Ethics committee country [1] 313723 0
Australia
Date submitted for ethics approval [1] 313723 0
Approval date [1] 313723 0
28/06/2006
Ethics approval number [1] 313723 0

Summary
Brief summary
Following the achievement of deep molecular response on tyrosine kinase inhibitors (TKIs)
54 around half of patients with chronic myeloid leukemia (CML) can discontinue TKI and remain in
55 treatment-free remission (TFR). The ALLG CML8 study commenced in July 2006 and enrolled 40
patients with undetectable BCR-ABL1 mRNA (approximately MR4.5 56 ). Molecular relapse was
57 defined as detectable BCR-ABL1 at any level on two consecutive tests or a single value >0.1%.
58 With a median follow-up of 8.6 years (range 5.7-11.2 years) 18 patients remain alive and in TFR
59 (45.0%; 95% confidence interval 31.9% - 63.4%). The latest relapse that occurred was at 27
60 months after stopping imatinib. No patient progressed to advanced phase CML. Twenty-two
61 patients met the criteria for imatinib re-treatment and all regained undetectable molecular
62 response. Twelve of these patients attempted TFR a second time after a median 5.9 years re63 treatment, and 5/12 patients had restarted TKI at last follow-up. Nine patients in long-term TFR
64 were additionally monitored by highly-sensitive BCR-ABL1 DNA PCR in a sufficient number of
65 samples to enable more precise quantification of residual leukemia. The level of BCR-ABL1 DNA
decreased from a median of MR5.5
in the first year of TFR to MR6.2 66 in the latest 3 years of TFR.
67 Our results support the long-term safety and remarkable stability of response after imatinib
68 discontinuation in appropriately selected CML patients. Furthermore, serial high sensitivity testing
69 provides a new and unexpected finding: that the level of residual leukemia steadily declines in
70 patients in prolonged TFR
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 35311 0
Prof Prof Tim Hughes
Address 35311 0
IMVS, Frome Road, Adelaide SA 5000
Country 35311 0
Australia
Phone 35311 0
+61 8 8222 3330
Fax 35311 0
+61 8 8222 3139
Email 35311 0
[email protected]
Contact person for public queries
Name 10154 0
Dr Dr David Ross
Address 10154 0
Division of Haematology
Institute of Medical and Veterinary Science
PO Box 14
Rundle Mall SA 5000
Country 10154 0
Australia
Phone 10154 0
+61 8 82223566
Fax 10154 0
+61 8 82223162
Email 10154 0
[email protected]
Contact person for scientific queries
Name 1082 0
Dr Dr David Ross
Address 1082 0
Division of Haematology
Institute of Medical and Veterinary Science
PO Box 14
Rundle Mall SA 5000
Country 1082 0
Australia
Phone 1082 0
+61 8 82223566
Fax 1082 0
+61 8 82223162
Email 1082 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified IPD data for all data collected during the trial
When will data be available (start and end dates)?
Data available 3 months following publication, for an indefinite period
Available to whom?
Data are potentially available to:
• Researchers from not-for-profit organisations
• Commercial organisations
• Other
Based in:
• Any location
Further information:
All data requests will be considered by the sponsor ALLG on a case by case basis. Requests must include a methodologically sound proposal. Specific conditions of use may apply and will be specified in a data sharing agreement (or similar) that the requester must agree to before access is granted.
Available for what types of analyses?
Any type of analysis. Proposals will be assessed on a case-by-case basis
How or where can data be obtained?
Access can be requested via the Health Data Australia catalogue (https://researchdata.edu.au/health/). Search for the ACTRN number in the catalogue to find datasets associated with this trial or email enquiries to [email protected]


What supporting documents are/will be available?




Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Study results articleYes 2013 122: 515-522 Blood Prepublished online May ... [More Details] 1198-(Uploaded-02-12-2020-12-04-01)-Journal results publication.pdf

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseDifferentiating factors in treatment-free remission trials: impact of study design on results and clinical applications.2019https://dx.doi.org/10.1080/10428194.2018.1535114
EmbaseImproving Outcomes in Chronic Myeloid Leukemia Over Time in the Era of Tyrosine Kinase Inhibitors.2018https://dx.doi.org/10.1016/j.clml.2018.06.029
EmbaseFirst-line therapy for chronic phase CML: selecting the optimal BCR-ABL1-targeted TKI.2018https://dx.doi.org/10.1080/10428194.2017.1379074
Dimensions AISuccessful treatment-free remission in chronic myeloid leukaemia and its association with reduced immune suppressors and increased natural killer cells2020https://doi.org/10.1111/bjh.16718
N.B. These documents automatically identified may not have been verified by the study sponsor.