ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12607000325404

Ethics application status

Approved

Date submitted

15/06/2007

Date registered

18/06/2007

Date last updated

4/08/2023

Date data sharing statement initially provided

30/07/2019

Date results provided

30/07/2019

Type of registration

Prospectively registered

Titles & IDs

Public title

A Phase II study in adult patients with newly diagnosed chronic-phase chronic myeloid leukaemia of initial intensified imatinib therapy and sequential dose-escalation followed by treatment with nilotinib in suboptimal responders to determine the rate and duration of major molecular response

Scientific title

Secondary ID [1]

Australasian Leukaemia and Lymphoma Group (ALLG): ALLG CML9

Universal Trial Number (UTN)

Trial acronym

TIDEL II

Linked study record

Health condition

Health condition(s) or problem(s) studied:

newly-diagnosed chronic phase chronic myeloid leukaemia

Condition category

Condition code

Cancer

Leukaemia - Chronic leukaemia

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

All patients commence imatinib at 600 mg/day. Dose is escalated to 800 mg/day if the trough imatinib plasma level is less than 1000 ng/ml on day 22. Dose is increased to 800 mg/day if the Real-Time Quantitative Polymerase Chain Reaction (RQ-PCR) values of BCR-ABL are >10% at 3 months, >1% at 6 months or >0.1% at 12 months. Dose is switched to nilotinib 400 mg/day if a patient is unable to dose escalate to 800 mg after 1 month of trying or if the BCR-ABL value is >10% at 6 months, >1% at 9 months or >0.1% at 15 months.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Control group

Uncontrolled

Outcomes

Primary outcome [1]

To determine the rates of major molecular response (MMR), as determined by RQ-PCR

Timepoint [1]

At 12 and 24 months

Primary outcome [2]

To estimate the duration of MMR.

Timepoint [2]

At 12 and 24 months

Secondary outcome [1]

1. To determine rates and duration of major molecular response in patients who switch to nilotinib therapy on study.

Timepoint [1]

Secondary outcome [2]

2. To assess overall rates of complete molecular response (CMR).

Timepoint [2]

Achieved on study at 12 and 24 months.

Eligibility

Key inclusion criteria

1. Post-pubertal patients who weigh 40kg or over. 2. Newly diagnosed (within six months of study entry) chronic phase, Philadelphia chromosome-positive Chronic Myeloid Leukaemia (Ph+ CML-CP) involving a BCR-ABL transcript known to be quantifiable.3. No prior therapy for CML and no other current anti-leukaemic therapies (other than prior or current treatment with hydroxyurea or anagrelide).4. No signs of extramedullary leukaemia, except for hepatosplenomegaly.5. Documented chronic-phase CML as defined by:6. Eastern Cooperative Oncology Group Performance Status score <2 7. Patients must have the following laboratory values:a) Potassium level > lower limit of normalb) Calcium (corrected for serum albumin) > lower limit of normalc) Magnesium level > lower limit of normald) Phosphorus > lower limit of normale) ALT and AST < 2.5 × upper limit of normal or < 5.0 × upper limit of normal if considered due to tumourf) ALP < 2.5 × upper limit of normal unless considered due to tumourg) Bilirubin < 1.5 × upper limit of normalh) Creatinine < 1.5 × upper limit of normali) Amylase and lipase < 1.5 × upper limit of normal8. a) Female patients of childbearing potential must have a negative pregnancy test within one week prior to study entry OR have been amenorrhoeic for at least two years. b) All patients of reproductive potential must agree to use birth control for the duration of the study.9. Life expectancy of more than 12 months in the absence of any intervention10. Patient has given written, informed consent to participate in the study

Minimum age

15 Years

Maximum age

Not stated

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1. Patients who have previously received radiotherapy to >25% of their bone marrow.2. Patients who have undergone major surgery within the 4 weeks prior to study entry or have not recovered from earlier surgery.4 Impaired cardiac function5 Treatment with agents (other than warfarin) that prolong QT interval or inhibit CYP3A4, unless judged to be clinically essential. 6 Patients with international normalized ratio (INR) or activated partial thromboplastin time (APTT) >1.5 x upper limit of normal, except for patients requiring anticoagulants. 7 Cytokine therapy within 4 weeks prior to study entry.8 Another primary malignant disease, except for such conditions that do not currently require treatment9 Impaired gastro-intestinal function or gastro-intestinal disease that may alter imatinib/nilotinib absorption.10 Acute or chronic hepatic or renal disease considered unrelated to cancer.11 Occurrence of pancreatitis within six months of study entry. 12 Other concurrent severe and/or uncontrolled medical conditions that could cause unacceptable safety risks or compromise compliance with the protocol.13 Cytopathologically confirmed central nervous system infiltration 14 Patients unwilling or unable to comply with protocol and patients with a history of non-compliance or inability to grant informed consent.15 Known diagnosis of human immunodeficiency virus (HIV) infection.16 Prior allogeneic stem cell transplantation. 17 Current participation in another therapeutic clinical trial.

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

Efficacy

Statistical methods / analysis

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

1/08/2007

Actual

15/11/2007

Date of last participant enrolment

Anticipated

Actual

25/03/2011

Date of last data collection

Anticipated

Actual

31/10/2016

Sample size

Target

150

Accrual to date

Final

210

Recruitment in Australia

Recruitment state(s)

ACT,NSW,QLD,SA,TAS,WA,VIC

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Novartis Australia

Address [1]

4 Waterloo
Road, North Ryde, NSW 2113

Country [1]

Australia

Primary sponsor type

Other Collaborative groups

Name

Australasian Leukaemia and Lymphoma Group

Address

Country

Australia

Secondary sponsor category [1]

None

Name [1]

none

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Royal Adelaide Hospital Research Ethics Committee

Ethics committee address [1]

Level 3, Roma Mitchell House
136 North Terrace, ADELAIDE SA 5000

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

12/07/2007

Approval date [1]

15/08/2007

Ethics approval number [1]

070718

Summary

Brief summary

This trial tests the hypothesis that molecular response can be maximised by a combined approach of higher dose imatinib for all de-novo CML patients plus a rapid switch to nilotinib in patients who are intolerant or have suboptimal response to imatinib.

Trial website

Trial related presentations / publications

None

Public notes

Contacts

Principal investigator

Name

Prof Timothy Hughes

Address

SA Pathology (RAH Campus)
Frome Road, Adelaide SA 5000

Country

Australia

Phone

+61 8 8222 3330

Fax

[email protected]

Contact person for public queries

Name

Timothy Hughes

Address

Division of Haematology, Institute of medical and Veterinary Science
Frome road
Adelaide 5000 SA

Country

Australia

Phone

08 82223330

Fax

08 82223855

[email protected]

Contact person for scientific queries

Name

Timothy Hughes

Address

Division of Haematology, Institute of medical and Veterinary Science
Frome road
Adelaide 5000 SA

Country

Australia

Phone

08 82223330

Fax

08 82223855

[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 primary sponsor 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
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
19914	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	Early molecular response and female sex strongly predict stable undetectable BCR-ABL1, the criteria for imatinib discontinuation in patients with CML.	2013	https://dx.doi.org/10.1182/blood-2012-10-462291
Embase	TIDEL-Ii: First-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets.	2015	https://dx.doi.org/10.1182/blood-2014-07-590315
Embase	TGF-alpha and IL-6 plasma levels selectively identify CML patients who fail to achieve an early molecular response or progress in the first year of therapy.	2016	https://dx.doi.org/10.1038/leu.2016.34
Embase	A Method for Next-Generation Sequencing of Paired Diagnostic and Remission Samples to Detect Mitochondrial DNA Mutations Associated with Leukemia.	2017	https://dx.doi.org/10.1016/j.jmoldx.2017.05.009
Dimensions AI	Modelling Predictors of Molecular Response to Frontline Imatinib for Patients with Chronic Myeloid Leukaemia	2017	https://doi.org/10.1371/journal.pone.0168947
Embase	Widespread aberrant alternative splicing despite molecular remission in chronic myeloid leukaemia patients.	2020	https://dx.doi.org/10.3390/cancers12123738
Embase	Adverse outcomes for chronic myeloid leukemia patients with splenomegaly and low in vivo kinase inhibition on imatinib.	2023	https://dx.doi.org/10.1038/s41408-023-00917-4

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

Trial Review

Documents added manually

Documents added automatically