De-escalation and stopping treatment of imatinib, nilotinib or sprycel in chronic myeloid leukaemia
| ISRCTN | ISRCTN74084226 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN74084226 |
| EudraCT/CTIS number | 2012-004025-24 |
| ClinicalTrials.gov number | NCT01804985 |
| Secondary identifying numbers | 14492 |
- Submission date
- 12/06/2013
- Registration date
- 12/06/2013
- Last edited
- 06/06/2017
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Cancer
Plain English Summary
Background and study aims
The aim of this study is to investigate whether some patients, with excellent responses to treatment of white blood cell cancer [chronic myeloid leukaemia (CML)], are being over-treated and can remain well on either a lower dose of treatment or without treatment at all. The dose of drugs, imatinib (Glivec), nilotinib (Tasigna) or dasatinib (Sprycel), will initially be cut to half the standard dose for 12 months and then treatment will be stopped completely for a further two years. This study will also help to develop a treatment decrease and stopping strategy for future patients.
Who can participate?
Patients who have been treated with imatinib, dasatinib or nilotinib for at least 3 years from original diagnosis and whose BCR-ABL1 levels (measure of a gene fusion product) have been at or below 0.1% on all tests for the past 12 months.
What does the study involve?
Two groups are studied: those in whom BCR-ABL1 has been undetectable for at least 12 months in at least three samples (molecular remission at the 4-log level, abbreviated as the MR4 group) and those in whom BCR-ABL1 is detectable on some or all tests in the past 12 months, but always below a level of 0.1% (major molecular response, abbreviated to the MMR group). Both groups are treated identically though analysed separately, by initially decreasing treatment to half of the standard dose for 12 months. If the BCR-ABL1 level remains at or below 0.1%, treatment is then completely stopped and observation continues for a further 24 months.
What are the possible benefits and risks of participating?
It is estimated that DESTINY will bring substantial savings to the NHS. Dose decrease or discontinuation of treatment might improve quality of life. Imatinib has several mild but persistent side effects such as rash, oedema and stomach upset. Similarly, dasatinib may cause fluid accumulation in lungs and hypertension and nilotinib may be associated with an increased late risk heart diseases.
Where is the study run from?
1. The Royal Liverpool University Hospital (UK) (lead centre)
2. Cancer Research UK Liverpool Cancer Trials Unit (UK) (coordinating centre)
When is study starting and how long is it expected to run for?
August 2013 to August 2014
Who is funding the study?
Leukaemia & Lymphoma Research (UK)
Who is the main contact?
Tony Coffey
tony.coffey@liverpool.ac.uk
Contact information
Scientific
University of Liverpool Cancer Research Centre
200 London Road
Liverpool
L3 9TA
United Kingdom
| tony.coffey@liverpool.ac.uk |
Study information
| Study design | Non-randomised; Interventional; Design type: Treatment |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Non randomised study |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| Scientific title | A trial of de-escalation and stopping treatment in chronic myeloid leukaemia patients with excellent responses to tyrosine kinase inhibitor therapy (De-Escalation and Stopping Treatment of Imatinib, Nilotinib or sprYcel in chronic myeloid leukaemia) (DESTINY) |
| Study acronym | DESTINY |
| Study hypothesis | The DESTINY trial will evaluate the feasibility of de-escalation and then stopping treatment in chronic myeloid leukaemia patients with excellent responses to prior treatment. DESTINY is conceived as a pilot for including this strategy in the next phase III study for the UK (to be known as SPIRIT3). Patients are eligible if in first chronic phase; have been treated with imatinib, dasatinib or nilotinib for at least 3 years from original diagnosis; and whose BCR-ABL1 levels have been at or below 0.1% on all tests for the past 12 months. Two groups will be studied; those in whom BCR-ABL1 has been undetectable for at least 12 months in at least 3 samples, all of which have at least 104 control transcripts (molecular remission at the 4-log level, abbreviated as the MR4 group), and those in whom BCR-ABL1 is detectable on some or all tests in the past 12 months, but always below a level of 0.1% (major molecular response, abbreviated to the MMR group). Both MR4 and MMR groups will be treated identically though analysed separately, by initially de-escalating treatment to 50% of the standard dose for 12 months. If the BCR-ABL1 level remains at or below 0.1%, treatment is then completely stopped, and observation continues for a further 24 months. The objective of DESTINY is to determine the safety and efficacy of initially de-escalating and then stopping tyrosine-kinase inhibitor (TKI) treatment, in CML patients with either undetectable disease or with stable MMR. |
| Ethics approval(s) | 13/NW/0265; First MREC approval date 20/05/2013 |
| Condition | Topic: National Cancer Research Network; Subtopic: Haematological Oncology; Disease: Leukaemia (chronic) |
| Intervention | Dasatinib, imatinib or nilotinib; de-escalated to half the standard dose for 12 months. If on imatinib, the dose should be decreased to 200mg daily, if on nilotinib, to 200mg twice daily (which is half the standard dose for second line use, since it is anticipated that the vast majority of nilotinib entrants will be receiving 400mg twice daily because of prior imatinib intolerance) and if on dasatinib then to 50 mg daily. Follow Up Length: 37 month(s). |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | Imatinib, nilotinib, dasatinib |
| Primary outcome measure | Proportion of patients who can de-escalate and stop TKI without losing MMR. Timepoint(s): The proportion of patients who can first de-escalate their treatment (to half the standard dose) |
| Secondary outcome measures | 1. Lab studies to define subsets of patients who are more likely to relapse on de-escalation/cessation; Timepoint(s): End of follow-up 2. Proportion of patients who can de-escalate but lose MMR on TKI cessation; Timepoint(s) 3. Proportion of patients who can successfully de-escalate their treatment (to half the standard dose o; Proportion of patients who lose MMR on de-escalation/stopping TKI but regain MMR on TKI resumption; Timepoint(s): 4. Proportion of patients who lose their MMR on de-escalation/stopping and regain MMR on resumption of Quality of Life; Timepoint(s): Baseline 1, 2, 3, 6, 9, 12, 13, 14, 16, 19, 22, 25, 29, 33 and 37 months after trial entry |
| Overall study start date | 01/08/2013 |
| Overall study end date | 01/08/2014 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 168; UK Sample Size: 168; Description: 84 patients will be recruited from both the 'MR4' and 'MMR' groups of patients. |
| Participant inclusion criteria | 1. CML in first chronic phase 2. Demonstration of BCR-ABL1 positivity at or shortly after original diagnosis* 3. Written informed consent 4. Must have received TKI treatment for at least 3 years 5. At least 3 molecular results over the preceding 12 months, that fit either of the following groups (results from any UK lab are acceptable): 5.1. (MR4 group) all the available BCR-ABL1 molecular results over the preceding 12 months are in MR4 (MR4 is defined as a BCRABL1/ABL1 ratio of zero, with at least 10,000 ABL1 control transcripts) 5.2. (MMR group) some or all BCR-ABL1 molecular results are in MMR (BCRABL1/ ABL1 ratio of 0.1% or less, but not zero, with at least 10,000 ABL1 control transcripts). If the results over the preceding 12 months are a mix of MMR and undetectable BCR-ABL1, then the patient is eligible for the MMR but not the MR4 group. *Patients who are Philadelphia chromosome (Ph) negative (or whose Ph status is not known) are eligible. Patients who do not have a standard BCR-ABL1 fusion transcript (i.e. other than e13a2 or e14a2, also known as b2a2 and b3a2) are eligible, but before screening the patient, contact should be made with Prof Foroni at Imperial College (see contacts) since specialised quantitative molecular assessment will be required. Target Gender: Male & Female; Lower Age Limit 18 years |
| Participant exclusion criteria | 1. Age under 18 2. Life expectancy is predicted to be less than 37 months because of intercurrent illness 3. Presence of serious concomitant illness (e.g. heart, renal, respiratory or active malignant disease) that might preclude completion of the study 4. CML in accelerated phase or blast crisis at any time 5. Any molecular result during the preceding 12 months that is not in either MMR or MR4 6. Treatment with higher than standard TKI doses (standard is defined as imatinib 400mg daily, nilotinib 400mg twice daily or dasatinib 100mg daily) 7. Patients who switched previous licensed TKI treatment (imatinib, nilotinib or dasatinib) twice or more because of intolerance 8. Patients who switched previous licensed TKI treatment (imatinib, nilotinib or dasatinib) because of resistance 9. Patients treated with lower than standard TKI doses (imatinib 400mg daily, nilotinib 400mg twice daily or dasatinib 100mg daily) for tolerance reasons may be included, but will de-escalate to the same doses as for standard dose patients and will be analysed separately, as they could be seen as undertreated 10. Previous treatment with ponatinib or bosutinib. Patients who received interferon prior to commencing TKI (even if resistant to their interferon) are eligible, provided their response to TKI fits the entry criteria. 11. Pregnant or lactating women 12. Women of childbearing potential, including women whose last menstrual period was less than one year prior to screening, unable or unwilling to use adequate contraception from study start to one year after the last dose of protocol therapy. Adequate contraception is defined as hormonal birth control, intrauterine device, double barrier method or total abstinence |
| Recruitment start date | 01/08/2013 |
| Recruitment end date | 01/07/2014 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
L3 9TA
United Kingdom
Sponsor information
University/education
Research and Business Services
The Forsight Centre
3 Brownlow Street
Liverpool
L69 3GL
England
United Kingdom
| Website | http://www.liv.ac.uk |
|---|
Hospital/treatment centre
Prescot Street
Liverpool
L7 8XP
England
United Kingdom
| abc@email.com | |
| Website | www.rlbuht.nhs.uk |
Not defined
| Website | http://www.liv.ac.uk/ |
|---|---|
"ROR" |
https://ror.org/04xs57h96 |
Funders
Funder type
Charity
Private sector organisation / Other non-profit organizations
- Location
- United Kingdom
Results and Publications
| Intention to publish date | |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not provided at time of registration |
| Publication and dissemination plan | Not provided at time of registration |
| IPD sharing plan |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Results article | results | 01/07/2017 | Yes | No | |
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
06/06/2017: Publication reference added.
