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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 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]

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

Condition category

Condition code

Cancer

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]

Treatment: Drugs

Comparator / control treatment

No comparator.

Control group

Uncontrolled

Outcomes

Primary outcome [1]

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]

For 2 years after ceasing imatinib therapy

Secondary outcome [1]

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]

Secondary outcome [2]

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]

Secondary outcome [3]

3.To assess the proportion of patients who develop cytogenetic or haematological relapse in the two years after cessation of imatinib

Timepoint [3]

Secondary outcome [4]

4.To establish the rate of molecular relapse-free survival after cessation of imatinib treatment (MRFS).

Timepoint [4]

Secondary outcome [5]

5.To assess quality of life and resolution of any identified imatinib toxicity during the period of drug withdrawal.

Timepoint [5]

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?

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

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW,NT,QLD,WA,VIC

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Novartis Australia

Address [1]

54 Waterloo Rd, Macquarie Park NSW 2113

Country [1]

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]

None

Name [1]

none

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Southern Adelaide Clinical Human Research Ethics Committee

Ethics committee address [1]

Flinders Dr, Bedford Park SA 5042

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

28/06/2006

Ethics approval number [1]

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

Prof Prof Tim Hughes

Address

IMVS, Frome Road, Adelaide SA 5000

Country

Australia

Phone

+61 8 8222 3330

Fax

+61 8 8222 3139

[email protected]

Contact person for public queries

Name

Dr David Ross

Address

Division of Haematology
Institute of Medical and Veterinary Science
PO Box 14
Rundle Mall SA 5000

Country

Australia

Phone

+61 8 82223566

Fax

+61 8 82223162

[email protected]

Contact person for scientific queries

Name

Dr David Ross

Address

Division of Haematology
Institute of Medical and Veterinary Science
PO Box 14
Rundle Mall SA 5000

Country

Australia

Phone

+61 8 82223566

Fax

+61 8 82223162

[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?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
20194	Other				Publication	1198-(Uploaded-02-12-2020-12-27-34)-Study-related document.pdf
20195	Study protocol			[email protected]	Access can be requested via the Health Data Austra... [More Details]

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	First-line therapy for chronic phase CML: selecting the optimal BCR-ABL1-targeted TKI.	2018	https://dx.doi.org/10.1080/10428194.2017.1379074
Embase	Improving Outcomes in Chronic Myeloid Leukemia Over Time in the Era of Tyrosine Kinase Inhibitors.	2018	https://dx.doi.org/10.1016/j.clml.2018.06.029
Embase	Differentiating factors in treatment-free remission trials: impact of study design on results and clinical applications.	2019	https://dx.doi.org/10.1080/10428194.2018.1535114
Dimensions AI	Successful treatment-free remission in chronic myeloid leukaemia and its association with reduced immune suppressors and increased natural killer cells	2020	https://doi.org/10.1111/bjh.16718

N.B. These documents automatically identified may not have been verified by the study sponsor.

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