A Trial of De-escalation and Stopping Treatment in Chronic Myeloid Leukaemia Patients With Excellent Responses to Tyrosine Kinase Inhibitor Therapy
Phase: PHASE2
Conditions: Chronic Myeloid Leukaemia
Sponsor: University of Liverpool

Protocol No: ISRCTN 74084226 
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DESTINY 
 
Version 7 Date 24 May 2018 
 
 
CONFIDENTIAL 
 
 
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) 
 
 
 
 
 
Co-sponsors: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The Royal Liverpool and Broadgreen 
University Hospitals NHS Trust, 
Prescot Street, 
Liverpool. 
L7 8XP 
 
The University of Liverpool, 
Research and Business Services, 
The Foresight Centre, 
3 Brownlow Street, 
Liverpool. 
L69 3GL 
 
EudraCT number: 
2012-004025-24 
ISRCTN number: 
74084226 
Protocol version:  
7 
Date:  
24 May 2018 

Protocol No: ISRCTN 74084226 
Page 2 of 69 
Trial Protocol Approval 
I, the undersigned, hereby approve this clinical trial protocol: 
Signature: ----'------7''''--->,----------
Professor Richard Cia k 
Chief Investigator 
University of Liverpool 
I~
. 
~! -
Signature: ____ 
~ __ 
~~-'--_______ _ 
Alex Astor 
Head of Research Support - Health and Life Sciences 
University of Liverpool, Sponsor 
Signature: ----~===:::::::::::::~=---4-=~=--
Professor Tom Walley 
Chair Research Governance Group 
Date: 
Date: 
Royal Liverpool and Broadgreen University Hos itals NHS Trust, Sponsor 
DESTINY 
Version 7 Date 24 May 2018 

Protocol No: ISRCTN 74084226 
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DESTINY 
 
Version 7 Date 24 May 2018 
General Information 
This document describes the DESTINY trial and provides information about procedures for 
entering patients into it. The protocol should not be used as an aide-memoire or guide for 
the treatment of other patients. Every care was taken in its drafting, but corrections or 
amendments may be necessary. These will be circulated to the registered investigators in 
the trial, but centres entering patients for the first time are advised to contact the 
coordinating centre (Cancer Research UK Liverpool Cancer Trials Unit (LCTU)) to 
confirm they have the most up to date version. Clinical problems relating to this trial should 
be referred to the relevant Chief Investigator via LCTU. 
 
 
Statement of Compliance 
This trial is designed to comply with the guideline developed by the International 
Conference on Harmonisation (ICH) for Good Clinical Practice (GCP) and will be 
conducted in compliance with the protocol, LCTU Standard Operating Procedures and 
EU Directive 2001/20/EC, transposed into UK law as the UK Statutory Instrument 2004 
No 1031: Medicines for Human Use (Clinical Trials) Regulations 2004 
 
 
UK Registration 
This trial has National Research Ethics Service (NRES) approval and holds a Clinical 
Trials Authorisation issued by the Medicines and Healthcare Products Regulatory 
Agency (MHRA). Each centre must also undergo Site Specific Assessment by the 
relevant Trust Research and Development department (or Local Research Ethics 
Committee for Non-NHS Sites) and NHS sites must be granted Research and 
Development Approval from each Trust where the trial will be carried out. 
 
 
 
Registration 
 
Tel: 0151 794 8186 
Fax: 0151 794 8931 
(Monday – Friday, 09:00 – 17:00) 

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DESTINY 
 
Version 7 Date 24 May 2018 
Contact Details: Institutions 
Co-sponsors: 
 
Trial Management and 
Monitoring: 
 
Clinical Laboratory (Liverpool): 
 
The Royal Liverpool and 
Broadgreen University 
Hospitals NHS Trust, 
Prescot Street, 
Liverpool. 
L7 8XP 
 
The University of Liverpool, 
Research and Business 
Services, 
The Foresight Centre, 
3 Brownlow Street, 
Liverpool. 
L69 3GL 
 
Liverpool Cancer Trials Unit 
 
University of Liverpool 
1st Floor, Block C, 
Waterhouse Building 
3 Brownlow Street 
Liverpool 
L69 3GL  
 
Tel: +44 (0)151 795 5479 
Fax: +44 (0)151 794 8931 
 
Mrs Gemma Austin 
Department of Haematology 
Royal Liverpool University 
Hospital 
Prescot Street 
Liverpool 
L7 8XP 
 
Tel: +44 (0)151 706 4326 
E: 
gemmajon@liverpool.ac.uk 
 
 
Clinical Laboratory 
(Hammersmith): 
 
Clinical Laboratory (Glasgow) 
 
Imperial Molecular 
Pathology Department 
G Block, Level 2, Room 313 
North Corridor 
Hammersmith Hospital 
Du Cane Road 
London 
W12 0HS 
 
Tel: +44 (0)20 8383 2179 
Office: +44 (0)20 8383 
2167/2177 
Fax:+44 (0)20 3313 1507 
E: l.foroni@imperial.ac.uk 
 
Heather Morrison 
Paul O’Gorman Leukaemia 
Research Centre 
Gartnavel General Hospital 
1053 Great Western Road 
Glasgow 
G12 0ZD 
 
Tel: +44 (0)141 301 7880 
Fax: +44 (0)141 301 7898 
E: 
Heather.morrison@gla.ac.uk  
 
 
 
 
 
 

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DESTINY 
 
Version 7 Date 24 May 2018 
Contact Details: Individuals 
Individual Authorised to Sign the 
Protocol and Protocol 
Amendments on behalf of the 
Sponsor: 
Chief Investigator (CI): 
Co-Investigator 
Prof Richard E Clark 
Department of Haematology 
Royal Liverpool University 
Hospital  
Prescot Street 
Liverpool 
L7 8XP 
 
Tel: +44 (0)151 706 4344 
Fax:+44 (0)151 706 5810  
E: clarkre@liverpool.ac.uk 
 
 
Prof Richard E Clark 
Department of 
Haematology 
Royal Liverpool University 
Hospital  
Prescot Street 
Liverpool 
L7 8XP 
 
Tel: +44 (0)151 706 4344 
Fax:+44 (0)151 706 5810  
E: clarkre@liverpool.ac.uk 
 
Prof Mhairi Copland 
Paul O’Gorman Leukaemia 
Research Centre 
Gartnavel General Hospital 
1053 Great Western Road 
Glasgow 
G12 0ZD 
 
Tel: +44 (0)141 301 7872 
Fax: +44 (0)141 301 7898  
E: 
mhairi.copland@glasgow.ac.
uk 
 
Co-Investigator 
Co-Investigator (molecular 
data) 
Trial Coordinator: 
Prof Stephen G O’Brien 
Northern Institute for Cancer 
Research 
Newcastle University Medical 
School 
Newcastle 
NE2 4HH 
 
Tel: +44 (0)191 282 0904 
Tel: +44 (0)191 213 8482 
E: 
stephen.o’brien@newcastle.a
c.uk 
 
 
 
Prof Letizia Foroni 
Consultant Clinical 
Scientist 
Haematology Department 
G Block, Level 2, Room 
313 
Hammersmith Hospital 
DuCane Road 
London 
W12 0HS 
 
Tel: +44 (0)20 8383 2167 / 
2177 / 2179 
Fax: +44 (0)20 3313 1507 
E: l.foroni@imperial.ac.uk 
 
Lucy Read 
Cancer Research UK 
Liverpool Cancer Trials Unit 
Department of Molecular and 
Clinical Cancer Medicine 
University of Liverpool 
1st Floor, Block C, 
Waterhouse Building 
3 Brownlow Street 
Liverpool 
L69 3GL  
 
Tel: +44 (0)151 794 8186 
Fax: +44 (0)151 794 8931 
Email: 
lucy.read@liverpool.ac.uk 
 
Trial Statistician: 
Health Economist 
Medical Expert who will Evaluate 
SAE Reports (If other than CI) 
Dr Richard Jackson 
Liverpool Cancer Trials Unit 
Department of Molecular and 
Clinical Cancer Medicine 
University of Liverpool 
1st Floor, Block C, Waterhouse 
Building 
3 Brownlow Street 
Liverpool 
L69 3GL  
 
Tel: +44 (0)151 794 8335 
Fax: +44(0)151 794 8931 
Email: 
Richard.Jackson@liverpool.ac.
uk   
Dr Alan Haycox 
Director, Health 
Economics Unit 
University of Liverpool 
Management School 
Chatham Street 
Liverpool 
L69 7ZH 
 
Tel: +44 (0)151 795 3612 
E: ahay@liverpool.ac.uk 
 
Dr Rahuman Salim 
Consultant Haematologist 
Department of Haematology 
Royal Liverpool University 
Hospital 
Prescot Street 
Liverpool 
L7 8XP 
 
Tel: +44 (0)151 4027 
 
 
Email: 
raksalim@liverpool.ac.uk  

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DESTINY 
 
Version 7 Date 24 May 2018 
Contact Details: Individuals 
Medical Expert who will Evaluate 
SAE Reports (If other than CI) 
Medical Expert who will 
Advise on Protocol Related 
Clinical Queries  
Medical Expert who will Advise 
on Protocol Related Clinical 
Queries 
Prof Stephen G O’Brien 
Northern Institute for Cancer 
Research 
Newcastle University Medical 
School 
Newcastle 
NE2 4HH 
Tel: +44 (0)191 282 0904 
Tel: +44 (0)191 213 8482 
E: 
stephen.o’brien@newcastle.a
c.uk 
 
Prof Stephen G O’Brien 
Northern Institute for 
Cancer Research 
Newcastle University 
Medical School 
Newcastle 
NE2 4HH 
Tel: +44 (0)191 282 0904 
Tel: +44 (0)191 213 8482 
E: 
stephen.o’brien@newcast
le.ac.uk 
 
Prof Mhairi Copland 
Paul O’Gorman Leukaemia 
Research Centre 
Gartnavel General Hospital 
1053 Great Western Road 
Glasgow 
G12 0ZD 
 
Tel: +44 (0)141 301 7872 
Fax: +44 (0)141 301 7898  
E: 
mhairi.copland@glasgow.ac.
uk 
 
 

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DESTINY 
 
Version 7 Date 24 May 2018 
  
Table of Contents 
 
1 
Protocol Summary ................................................................................ 10 
2 
Background Information ....................................................................... 14 
2.1 
Introduction .............................................................................................. 14 
2.2 
Rationale ................................................................................................. 14 
2.3 
Objectives ................................................................................................ 15 
2.4 
Potential Risks and Benefits .................................................................... 16 
3 
Selection of Centres/Clinicians ............................................................ 18 
3.1 
Centre/Clinician Inclusion Criteria ............................................................ 18 
3.2 
Centre/Clinician Exclusion Criteria ........................................................... 18 
4 
Trial design ............................................................................................ 19 
4.1 
Overall Design ......................................................................................... 19 
4.2 
Primary Endpoint ..................................................................................... 19 
4.3 
Secondary Endpoint(s) ............................................................................ 19 
5 
Trial Population ..................................................................................... 21 
5.1 
Eligibility Criteria ...................................................................................... 21 
5.2 
Patient Transfer and Withdrawal .............................................................. 21 
6 
Enrolment and Registration ................................................................. 23 
6.1 
Screening ................................................................................................ 23 
6.2 
Enrolment/ Baseline ................................................................................. 23 
6.3 
Samples ................................................................................................... 24 
7 
Trial Treatment/s ................................................................................... 28 
7.1 
De-escalation phase (12 months) ............................................................ 28 
7.2 
Accountability Procedures for Trial Treatment .......................................... 29 
7.3 
Assessment of Compliance with Trial Treatment/s ................................... 29 
7.4 
Concomitant Medications/Treatments ...................................................... 29 
7.5 
Co-enrolment Guidelines ......................................................................... 30 
8 
Assessments and Procedures ............................................................. 31 
8.1 
Schedule of Trial Procedures ................................................................... 31 
8.2 
Procedures for assessing Efficacy ........................................................... 35 
8.3 
Procedures for Assessing Safety ............................................................. 37 
8.4 
Quality of Life and Health Economics....................................................... 37 
8.5 
Substudies ............................................................................................... 37 
8.6 
Loss to Follow-up ..................................................................................... 37 
8.7 
Trial Closure ............................................................................................ 38 
9 
Statistical Considerations .................................................................... 39 
9.1 
Introduction .............................................................................................. 39 
9.2 
Outcome Measures .................................................................................. 39 
9.3 
Sample Size............................................................................................. 40 
9.4 
Interim Monitoring and Analyses .............................................................. 40 
9.5 
Analysis Plan ........................................................................................... 41 
10 Pharmacovigilance ................................................................................ 42 
10.1 
Terms and Definitions .............................................................................. 42 
10.2 
Notes Severity / Grading of Serious Adverse Events ............................... 43 
10.3 
Relationship to Trial Treatment ................................................................ 44 
10.4 
Expectedness .......................................................................................... 44 

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DESTINY 
 
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10.5 
Reference Safety Information .................................................................. 44 
10.6 
Follow-up After Serious Adverse Events .................................................. 45 
10.7 
Reporting Procedures .............................................................................. 45 
10.8 
Responsibilities – CR:UK LCTU ............................................................... 47 
11 Ethical Considerations.......................................................................... 49 
11.1 
Ethical Considerations ............................................................................. 49 
11.2 
Ethical Approval ....................................................................................... 49 
11.3 
Informed Consent Process ....................................................................... 49 
11.4 
Trial Discontinuation ................................................................................ 50 
12 Regulatory Approval ............................................................................. 51 
13 Trial Monitoring ..................................................................................... 52 
13.1 
Risk Assessment ..................................................................................... 52 
13.2 
Source Documents .................................................................................. 52 
13.3 
Data Capture Methods ............................................................................. 53 
13.4 
Monitoring at LCTU .................................................................................. 53 
13.5 
Clinical Site Monitoring ............................................................................ 56 
13.6 
Records Retention ................................................................................... 57 
14 Indemnity ............................................................................................... 59 
15 Financial Arrangements ........................................................................ 60 
16 Trial OVERSIGHT Committees ............................................................. 61 
16.1 
Trial Management Group (TMG) .............................................................. 61 
16.2 
Trial Steering Committee (TSC) ............................................................... 61 
16.3 
Independent Data and Safety Monitoring Committee (IDSMC) ................ 61 
17 Publication ............................................................................................. 62 
18 Protocol Amendments .......................................................................... 63 
18.1 
Version 1 (21 March 2013) ....................................................................... 63 
18.2 
Version 2 (03 February 2014) .................................................................. 63 
18.3 
Version 3 (18 December 2014) ................................................................ 65 
18.4 
Version 4 (16 January 2015) .................................................................... 65 
19 References ............................................................................................. 69 

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DESTINY 
 
Version 7 Date 24 May 2018 
Glossary 
 
 
AE 
Adverse Event 
AR 
Adverse Reaction 
BCR-ABL1 
The fusion oncogene that causes CML. Its level correlates with disease burden 
CI 
Chief Investigator 
CML 
Chronic myeloid leukaemia 
CRF 
Case Report Form 
CTU 
Clinical Trials Unit 
GP 
General Practitioner 
IB 
Investigator’s Brochure 
IDSMC 
Independent Data and Safety and Monitoring Committee 
IEC 
Independent Ethical Committee 
IMP 
Investigational Medicinal Product 
IS 
International Standard (for reporting molecular blood tests results) 
LREC 
Local Research Ethics Committee 
MREC 
Multi-centre Research Ethics Committee 
Ph 
Philadelphia chromosome 
PI 
Principal Investigator 
(q) PCR 
(quantitative) Polymerase chain reaction 
R&D 
Research & Development 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SPC 
Summary of product characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TKI 
Tyrosine kinase inhibitor (imatinib, nilotinib or dasatinib) 
TSC 
Trial Steering Committee 
UAR 
Unexpected Adverse Reaction 
 

Protocol No: ISRCTN 74084226 
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DESTINY 
 
Version 7 Date 24 May 2018 
1 
PROTOCOL SUMMARY 
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) 
 
Phase: 
II 
 
Sample Size: 
168 patients from approximately 22 sites across the UK will be 
recruited from two groups; those with molecularly undetectable 
disease (the ‘MR4’ group); and those with stable low level but 
still detectable BCR-ABL1 (where BCR-ABL1 is consistently 
below 0.1%; the 'MMR' group).    
 
Main Criteria for 
Inclusion: 
 
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):  
o (MR4 group) all the available BCR-ABL1 
molecular results over the preceding 12 
months are in MR4 (MR4 is defined as a 
BCR-ABL1/ABL1 ratio of zero, (reported to 
international 
standard 
(IS) 
where 
possible); with at least 10,000 ABL1 control 
transcripts). 
o (MMR group) some or all BCR-ABL1 
molecular results are in MMR (BCR-
ABL1/ABL1 ratio of 0.1% or less, (reported 
to International Standard (IS) where 
possible), 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) may be eligible, but 

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DESTINY 
 
Version 7 Date 24 May 2018 
before screening the patient, contact should be made with Prof Foroni at Hammersmith 
Hospital (see contacts) since specialised quantitative molecular assessment will be 
required. 
Main Criteria for 
Exclusion: 
 
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 
trial 
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. Patients who switched previous licensed TKI 
treatment (imatinib, nilotinib or dasatinib) twice or 
more because of intolerance.  
7. Treatment with higher than standard TKI doses 
(‘standard’ is defined as imatinib 400mg daily, 
nilotinib 400mg twice daily or dasatinib 100mg 
daily).  However, an exception is made for 
patients who at original diagnosis commenced 
on either 800mg of imatinib on the SPIRIT1 
study, or 140mg (or 70mg b.d.) of dasatinib in 
the Bristol-Myers Squibb 034 study.  In each 
case these latter patients ARE eligible provided 
they fulfil other molecular criteria, since they do 
not demonstrate resistant disease. 
8. Patients who switched previous licensed TKI 
treatment (imatinib, nilotinib or dasatinib) because 
of resistance. Patients treated with lower (but at 
least 50%) than standard TKI doses (as defined 
in the previous criterion) 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. 
9. 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 and the use of interferon 
ceased at least 12 months prior to study entry. 
10. Pregnant or lactating women 
11. 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 trial 
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.  
 
 

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DESTINY 
 
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Number of Sites: 
Approximately 22, all in the UK  
 
Trial Duration: 
A maximum of 37 months follow-up per patient 
 
 
 
 
 
Description of 
Agent/ Intervention: 
 
Imatinib, nilotinib or dasatinib; 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. 
 
 
Outcomes: 
Primary: 
 
The proportion of patients who can first de-escalate their 
treatment (to half the standard dose of their TKI) for 12 
months, and then stop treatment completely for a further 
2 years, without losing MMR. 
 
 
Secondary 
 
Proportion of patients who can successfully de-escalate 
their treatment (to half the standard dose of their TKI), but 
who then lose MMR on complete TKI cessation. 
 
Proportion of patients who lose their MMR on de-
escalation/stopping and regain MMR on resumption of 
their TKI. 
 
Molecular relapse-free survival (RFS) 
 
Progression-free survival (PFS) 
 
Overall survival (OS) 
 
Event-free survival (EFS) 
 
Time to MMR recovery (TTR) 
 
Proportion of registered MMR and MR4 patients in 
confirmed MR4.5 prior to being enrolled in the study. 
 
Quality of Life 
 
Health Economic Assessment 
 
Lab studies to define subsets of patients who are more 
likely to relapse on de-escalation / cessation.  
 

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DESTINY 
 
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Protocol Summary - continued 
 
Figure 1: Schematic of Trial Design: 
 
 
Total 168 Recruited
Screen Subjects by 
inclusion criteria.  
Obtain Written 
Informed Consent
MONTHS 1-12
DE-ESCALATE
CURRENT THERAPY 
BY HALF
MR4 GROUP
MMR GROUP
Baseline samples 
(section 6)
Baseline samples 
(section 6)
MONTHS 1-12
SEND PCR TO HAMMERSMITH HOSPITAL 
EVERY MONTH
IF PCR RISES, YOU WILL BE NOTIFIED BY THE 
CENTRAL LABORATOY.  A REPEAT SAMPLES 
WILL BE REQUESTED.  IF REPEAT PCR REMAILS 
AOVE 0.1% FOR EITHER GROUP, COMPLETE END 
OF STUDY VISIT (RELAPSE) AND RESUME TKI AT 
STANDARD (FULL) DOSE.
Note:  A PCR sample must still eb sent monthy 
until it returns to either MMR or MR4
MR4 group:  if PCR remains 
0.1% or below following
month 12, proceed to 
stopping phase
MMR group: if PCR remains 
0.1% or below following
month 12, proceed to 
stopping phase
MONTHS 12-25
SEND PCR TO HAMMERSMITH 
HOSPITAL EVERY MONTH
MR4 group:  if PCR remains 
0.1% or below following
month 25, proceed to 
month 27 visit
MMR group: if PCR remains 
0.1% or below following
month 25, proceed to 
month 27 visit
IF PCR RISES, YOU WILL BE NOTIFIED BY THE 
CENTRAL LABORATOY.  A REPEAT SAMPLES 
WILL BE REQUESTED.  IF REPEAT PCR REMAILS 
AOVE 0.1% FOR EITHER GROUP, COMPLETE END 
OF STUDY VISIT (RELAPSE) AND RESUME TKI AT 
STANDARD (FULL) DOSE.
Note:  A PCR sample must still be sent monthy 
until it returns to either MMR or MR4
MONTHS 27-37
SEND PCR TO HAMMERSMITH HOSPITAL 
EVERY 2 MONTHS
MR4 group: if PCR remains 0.1% or below 
followingmonth 37 the patient has completed 
the study.  Further treatment is at the local 
investigators discretion, but should be recorded 
in the CRF
MR4 group:  if PCR remains 0.1% or below 
followingmonth 37 the patient has completed 
the study.  Further treatment is at the local 
investigators discretion, but should be recorded 
in the CRF

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DESTINY 
 
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2 
BACKGROUND INFORMATION 
2.1 
Introduction 
 
About 800 new patients are diagnosed with CML annually in the UK. The vast majority 
are in the chronic phase at diagnosis, but the disease has a propensity to transform to 
an acute leukaemia, which is usually fatal. CML treatment was revolutionised about a 
decade ago by the tyrosine kinase inhibitor (TKI) imatinib. Dasatinib and nilotinib are 
licensed second generation TKI that are widely used as second line agents for imatinib 
failure or intolerance, and ongoing trial data suggest that as first line agents they may 
give more rapid and deeper molecular responses than imatinib1,2. Together, these 3 
drugs have transformed the outlook for CML from a median survival of about 5 years 
to one where perhaps 90% of patients are well at 9 years of therapy, and it is predicted 
that some of these may have a normal life expectancy. Despite its rarity, CML is 
therefore becoming a common chronic disease in outpatient clinics, since few patients 
now progress to acute leukaemia. 
 
Response to imatinib and other TKI treatment in CML is assessed according to a series 
of arbitrary response levels. Within a few weeks of treatment, almost all patients will 
achieve the first of these, complete haematological response, whereby the blood count 
and splenomegaly return to normal. The second is clearance of Philadelphia (Ph) 
chromosome positive cells from the bone marrow, called complete cytogenetic 
remission, and this typically takes 12-18 months. Patients who do not achieve these 
two target milestones need treatment modifications, and are not eligible for DESTINY. 
 
Once in complete cytogenetic remission, treatment response is routinely assessed by 
molecularly measuring BCR-ABL1. BCR-ABL1 is the fusion oncogene that drives CML, 
and is produced by the Ph chromosomal translocation. The blood BCR-ABL1 transcript 
level, expressed as a % ratio to normal ABL1 transcripts, reflects the disease burden. 
In about 50% of patients, the BCR-ABL1/ABL1 ratio remains detectable but very low 
(0.1% or less). This is termed major molecular response (MMR), and this is 
internationally used as a response milestone3. Once in MMR, the acute leukaemic 
progression rate is very low; in the IRIS trial of long-term imatinib outcome, in 164 
patients achieving MMR at 18 months the subsequent progression rate to acute 
leukaemia was under 1% at 84 months4. 
 
After some years of imatinib treatment, BCR-ABL1 transcripts may become 
undetectable in about 20% of patients, suggesting that some of these may be 
functionally cured. Since apparent BCR-ABL1 negativity is relative to the volume of the 
tested sample, it is preferable to describe undetectable transcripts in relation to the 
number of control (almost always ABL1) transcripts in the sample. Undetectable BCR-
ABL1 amongst at least 10,000 control ABL1 transcripts is increasingly used as a more 
stringent molecular milestone than MMR, and is known as 'molecular response at the 
4 log level’ or ‘MR4' (since 10,000 is equivalent to 4 logs). MR4 is preferable to the 
term 'complete molecular responders' and is used here. It is therefore possible that 
after some years of TKI treatment, CML patients in stable MR4 and MMR are being 
unnecessarily over-treated.  
 
 
2.2 
Rationale 
 

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DESTINY 
 
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The French STop IMatinib (STIM) trial stopped imatinib in patients treated at any dose 
for at least 3 years, who had been in sustained MR4 for at least 2 years (confirmed 
with five BCR–ABL1 analyses during this time). Data on 69 patients with at least 12 
months follow up have been published5. Updated data on 100 cases presented in 
September 2012 show that 43% remain free of molecular relapse ('relapse' defined as 
reappearance of BCR-ABL1) at 18 months and 39% at 24 months. A total of 61 (of 
100) cases have had a molecular relapse, of which 59 occurred within the first 7 
months off treatment, and one relapse each at 19 and 21 months. Similar data on 35 
Australian cases have been presented6 but not yet published. In a separate 
retrospective Korean trial7 stopping imatinib in patients at various response states 
(some not even in complete cytogenetic remission), all but 2 relapsed. The frequency 
of molecular monitoring was variable in this trial. Of those in MR4, 3 had cytogenetic 
relapse and had not returned to MMR by the end of the trial. In a separate ongoing trial 
in France, 7 of 12 patients in MR4 after first line dasatinib or nilotinib remain in MR4 
after at least 6 months off treatment (Réa D, personal communication). 
 
In STIM, the probability of relapse is higher in female patients (though this is less clear 
on later follow up) and in those with shorter duration of prior imatinib (especially under 
48 months). All 61 relapses were advised to recommence imatinib, and 51 of 56 
assessable cases were restored to MR4 with a median of 4 months, with the remaining 
5 cases all in MMR but with occasionally undetectable BCR-ABL1 (the 5 non-
assessable cases opted to delay their recommencement of imatinib; all have also 
returned to MMR with occasional undetectable BCR-ABL1). 
 
The European LeukaemiaNet is setting up a trial called EUROSKI for excellent CML 
responders, which is a repeat of the French STIM trial in several hundred patients in 
MR4 across Europe. Each country will run their own version and results will then be 
collated centrally.  
 
DESTINY is a pilot for SPIRIT3, the UK national phase III trial in newly diagnosed CML 
opening during 2013. It is also of pharmaco-economic relevance as the prevalence of 
CML continues to rise. 
 
2.3 
Objectives 
 
The next definitive UK phase III trial in chronic myeloid leukaemia (CML) will be 
SPIRIT3, which will open in the second half of 2013. This will incorporate a de-
escalation and stopping strategy for patients who achieve excellent responses after at 
least 3 years of treatment with a tyrosine kinase inhibitor (TKI). 
 
DESTINY is to act as a pilot for this strategy in SPIRIT3, by defining the proportion of 
patients that relapse during 12 months of TKI de-escalation followed by 24 months of 
cessation. DESTINY also includes scientific bolt-on studies (sections 6.3 and 8.), 
quality of life assessments and health economic evaluation (sections 4.1 and 8.2.4).  
 
Patients are eligible for DESTINY 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% (reported to IS where possible) 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 

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the past 12 months, but always below a level of 0.1% (reported to IS where possible) 
(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% IS, 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 TKI treatment, in CML patients with either undetectable 
disease or with stable MMR. 
 
 
2.4 
Potential Risks and Benefits 
2.4.1 Potential Risks 
The UK NCRI CML subgroup has extensively discussed its strategy for stopping, and 
has also consulted with patients at the national CML patient day in 2011 and 2012, 
where a poll suggested that at least 75% of patients wish to decrease or stop their 
treatment if thought to be clinically safe. The issue is also of interest to the wider NHS, 
especially as the prevalence of CML continues to rise. Whilst confirmation of French 
STIM and other studies is important, in view of their high relapse rate we would prefer 
a more cautious approach, whereby patients first de-escalate TKI treatment for 12 
months, to identify patients in whom outright cessation of TKI might rapidly produce 
molecular relapse. In addition, pilot/anecdotal experience in MMR patients who stop 
TKI (because of pregnancy or personal preference) suggest that on stopping imatinib, 
BCR-ABL1 transcripts may remain unchanged for prolonged periods in some patients, 
and treatment resumption in patients who lose MMR almost always restores molecular 
response. Some MMR patients may therefore behave similarly to MR4 patients, and 
they are therefore included in this conservative strategy of initial de-escalation prior to 
cessation. DESTINY therefore includes not only MR4 patients but also those in 
enduring MMR, and is designed to harmonise with EUROSKI wherever possible, but 
to accommodate these aims. 
2.4.2 Known Potential Benefits 
 
Imatinib has several mild but persistent side effects such as rash, oedema and GI 
upsets. Patients differ in their tolerance of these, and their improvement on dose 
decrease or discontinuation might improve quality of life. Similarly, dasatinib may 
produce pleural effusions in about 14% of patients, and there are also recent 
suggestions that dasatinib may produce pulmonary hypertension, and that nilotinib 
may be associated with an increased late risk of peripheral vascular and ischaemic 
heart disease. Treatment cessation and de-escalation therefore merit further trial in 
CML patients with excellent responses to TKI; data are also required on which patients 
may benefit most. 
 
As the prevalence of CML continues to rise, there is a financial cost of giving 
unnecessary treatment, since the annual cost of imatinib 400mg daily is £20,980, 
dasatinib 100mg daily £30,477 and nilotinib 400mg twice daily £20,980 (via the UK 
patient access scheme) (all prices exclusive of VAT). 
 
It is estimated that DESTINY will bring a substantial saving to the NHS. Routine care 
typically requires 3-monthly molecular monitoring, whereas in DESTINY this will be 

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carried out monthly for 2 years and then 2-monthly. This means an additional 18 extra 
visits for molecular tests in DESTINY patients who complete the 37-months of follow-
up. However, the hypothesis is that the cost of the extra visits and tests is more than 
offset by the saving in TKI drug costs. To take a worst case scenario with results worse 
than the French STIM, whereby 50% relapse at a median of 6 months de-escalation, 
50% of the remainder relapse at a median of 6 months of cessation, and the remaining 
25% (42 cases) have not relapsed by 37 months, then the strategy will save 
approximately £4.26 Million. The saving will be increased if the relapse rate is less 
dramatic than this, or if some entrants are receiving dasatinib rather than imatinib or 
nilotinib. 
 

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3 
SELECTION OF CENTRES/CLINICIANS 
Each participating Centre (and investigator) has been identified on the basis of: 
 
Having at least one lead clinician with a specific interest in, and responsibility 
for, supervising and managing patients with CML.  
 
Showing enthusiasm to participate in the trial. 
 
Ensuring that sufficient time, staff and adequate facilities are available for the 
trial. 
 
Providing information to all supporting staff members involved with the trial or 
with other elements of the patient’s management. 
 
Acknowledging and agreeing to conform to the administrative and ethical 
requirements and responsibilities of the trial, including signing up to Good 
Clinical Practice (GCP) and other regulatory documentation. 
3.1 
Centre/Clinician Inclusion Criteria 
a. Positive Site Specific Assessment (SSA) by Local  NHS R&D offices 
b. Local Research and Development (R&D) approval 
c. Signed Research Site Agreement  
d. Receipt of evidence of completion of (a) & (b) by LCTU  
e. Completion and return of ‘Signature and Delegation Log’ to LCTU  
f. Curriculum Vitae (CV) including a record of International Conference 
for Harmonisation (ICH) of GCP training  – Principal Investigator (PI) 
g. CV including a record of ICH GCP training – Other personnel on the 
delegation log 
h. Clinical Trial Protocol Receipt Form 
i. 
Investigator Brochure’s Receipt Form 
j. 
Local laboratory accreditation/Quality Check 
k. Local laboratory reference ranges 
l. 
Patient information sheet (PIS), consent form and GP letter on local Trust 
headed paper 
3.2 
Centre/Clinician Exclusion Criteria 
 
a. Not meeting the inclusion criteria listed above. 

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4 
TRIAL DESIGN 
4.1 
Overall Design 
 
This is a phase IIb feasibility trial of TKI de-escalation followed by cessation, in CML in 
either stable MR4 or MMR. If this strategy has a lower relapse rate than simple 
cessation (as studied in the French STIM trial and to be expanded in EUROSKI), it will 
then become part of the ‘cessation module’ in the next UK phase III trial, known as 
SPIRIT3. It is anticipated that SPIRIT3 will open in the second half of 2013, though its 
de-escalation/stopping module does not need to be finalised until 2016/17. The present 
trial will inform the safety of de-escalation/stopping in MMR patients, the frequency of 
molecular monitoring, the optimal duration of prior TKI, and whether particular risk 
groups or laboratory features predict relapse. 
 
The trial consists of 2 groups of CML patients who have had excellent responses to at 
least 3 years of TKI treatment; firstly those with molecularly undetectable disease (MR4 
group) and secondly those with disease at a low and stable level (the MMR group), in 
each case for at least the preceding 12 months. 
 
168 MR4 and MMR will be recruited in total.  MR4 and MMR entrants will be treated 
identically though will be analysed separately. All will first de-escalate to half the 
standard first line dose (i.e. imatinib 200mg daily, nilotinib 200mg twice daily or 
dasatinib 50mg daily) for 12 months. Molecular monitoring will be carried out monthly. 
'If that at 12 months remains in MMR (either MR4 or MMR group), then TKI is stopped 
at the end of month 13 (this allows a month for the 12 month result to be done and 
reported, and the patient to be seen). Monitoring continues monthly until the end of 
month 25, then 2-monthly until the end of month 37. See flow chart in Section 1. 
 
At molecular relapse (defined as the loss of MMR on 2 consecutive occasions), TKI 
should be re-escalated/resumed at standard dose and the patient is off trial, except 
that samples should still be sent centrally until MMR (or MR4), i.e. BCR-ABL ≤ 0.1% 
IS, is regained, and the patient should be followed indefinitely for outcome. Although 
the primary endpoint is the proportion who lose MMR by the end of month 37 (i.e. 2 
years of cessation), follow-up continues indefinitely. See flow chart in Section 1. 
 
Quality of life assessment will be assessed at entry and after 1, 2, 3, 6, 9, 12/13, 14, 
15, 16, 19, 22, 25, 29, 33 and 37 months. Standard EQ-5D and FACT-BRM 
questionnaires will be used at each assessment point.  
 
4.2 
Primary Endpoint 
The primary end-point for both the MR4 and the MMR groups is the proportion of 
patients who can first de-escalate their treatment (to half the standard dose of their 
TKI) for 12 months, and then stop treatment completely for a further 2 years, without 
losing MMR. This will be calculated separately for each of the two groups (MR4 and 
MMR). BCR-ABL1 will be assessed by standard PCR based molecular monitoring on 
blood, carried out more frequently than usual. It is not expected that any patient will 
undergo more serious relapse than loss of MMR. 
4.3 
Secondary Endpoint(s) 
 

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 
Proportion of patients who can successfully de-escalate their treatment (to half the 
standard dose of their TKI), but who then lose MMR on complete TKI cessation. 
 
Proportion of patients who lose their MMR on de-escalation/stopping and regain 
MMR on resumption of their TKI. 
 
Molecular relapse-free survival (RFS). RFS is defined as the time from the first 
day of de-escalation to the date of confirmed loss of MMR (two consecutive BCR-
ABL >0.1% IS). 
 
Progression-free survival (PFS). PFS is defined as the time from the first day of 
de-escalation to the date of progression to accelerated phase/ blast crisis or death 
from any cause (earliest occurrence). 
 
Overall survival (OS). OS is defined as the time from the first day of de-escalation 
to the date of death from any cause. 
 
Event-free survival (EFS). EFS is defined as the time from the first day of de-
escalation to the date of confirmed loss of MMR, progression to AP/BC or death 
from any cause. 
 
Time to MMR recovery (TTR). TTR is defined as the time from the date of 
confirmed loss of MMR to the date of MMR recovery. 
 
Proportion of registered MMR and MR4 patients in confirmed MR4.5 (BCR-ABL ≤ 
0.0032% IS with at least 31,623 ABL1 control transcripts) prior to being enrolled 
in the study (screening phase).   
 
Quality of Life 
 
Health Economic Assessment 
 
Lab studies to define subsets of patient who are more likely to relapse on de-
escalation / cessation.  
 

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5 
TRIAL POPULATION 
5.1 
Eligibility Criteria 
Please refer to section 1, protocol summary, for eligibility criteria. 
 
5.2 
Patient Transfer and Withdrawal 
In consenting to the trial, patients are consented to trial treatment, sample collection, 
follow-up and data collection. If voluntary withdrawal occurs, the patient should be 
asked to allow continuation of scheduled evaluations, complete an end-of-trial 
evaluation, and be given appropriate care under medical supervision until the 
symptoms of any adverse event resolve or the subject’s condition becomes stable.  
 
Final assessments will be performed (if possible) and should include laboratory 
samples, and recording concomitant medication. All the results of the evaluations and 
observations, together with a description of the reasons for trial withdrawal, must be 
recorded in the CRF. 
 
Patients who are removed from the trial due to adverse experiences (clinical or 
laboratory) will be treated and followed-up according to accepted medical practice.  All 
pertinent information concerning the outcome of such treatment must be recorded in 
the CRF. 
 
The following are justifiable reasons for the Investigator to withdraw a patient from the 
trial: 
 
 
unacceptable toxicity 
 
 
unforeseen events (any event which in the judgement of the Investigator makes 
further TKI de-escalation/cessation inadvisable) 
 
 
SAE requiring recommencement of TKI treatment 
 
 
withdrawal of consent (where the patient is not evaluable, additional patients will 
be recruited to replace them) 
 
 
serious violation of the trial protocol (including persistent patient attendance failure 
and persistent non-compliance with the de-escalation/stopping strategy) 
 
 
withdrawal by the Investigator for clinical reasons not related to the trial strategy 
 
 
evidence of disease relapse 
 
If patients withdraw from the trial, all efforts should be made to continue follow-up for 
outcome, especially relapse.  
5.2.1 Patient Transfers 
For patients moving from the area, every effort should be made for the patient to be 
followed-up at another participating trial centre and for this trial centre to take over 
responsibility for the patient or for follow-up via GP. 

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A copy of the patient CRFs should be provided to the new site. The patient will have 
to sign a new consent form at the new site, and until this occurs, the patient remains 
the responsibility of the original centre. The LCTU should be notified in writing of patient 
transfers. 
5.2.2 Withdrawal from Trial Intervention 
Patients may be withdrawn from treatment for any of the following reasons: 
a. Patient (or, where applicable, the parent/ legal representative) withdraws 
consent. 
b. Unacceptable toxicity. 
c. Intercurrent illness preventing further treatment. 
d. Any change in the patient’s condition that justifies the discontinuation of 
treatment in the clinician’s opinion. 
If a patient wishes to withdraw from trial treatment, centres should nevertheless explain 
the importance of remaining on trial follow-up, or failing this, of allowing routine follow-
up data to be used for trial purposes. Generally, follow-up will continue unless the 
patient explicitly also withdraws consent for follow-up (see section 5.3.3). 
5.2.3 Withdrawal from Trial Completely 
Patients who withdraw from the trial for other reasons have previously consented to 
follow-up in the trial. Data up to this time can be included in the trial if anonymised. 
They may need to reaffirm that they consent to follow-up through usual NHS 
mechanisms. If the patient explicitly states their wish not to contribute further data to 
the trial, an End of Trial form should be completed in the CRF.  

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6 
ENROLMENT AND REGISTRATION 
6.1 
Screening 
A log of all potential patients will be kept, including individuals who decide not to 
participate in or who are found to be unsuitable for the trial. 
 
Screening will be performed for potential trial patients after they have consented to trial 
participation and signed the informed consent form. 
 
If a patient is screened - regardless of whether or not they are entered to the trial – 
their details should be entered onto the on-line screening form at the LCTU website: 
 
http://www.lctu.org.uk/home/index.asp 
 
Prior to trial entry the following assessments are required: 
 
 
The history of the patient’s CML and its treatment are required, together with 
all the available cytogenetic and molecular PCR (BCR-ABL1) results since 
diagnosis. These must include: 
o A minimum of 3 BCR-ABL1 molecular results in the 12 months prior to 
trial entry* (since these define whether the patient is in the MR4 or the 
MMR group). Please see sections 1 and 5.1 for details.  
 
Details of other clinical conditions and concomitant medications are also 
required, together with an appropriate physical examination.  
 
Pre-registration assessments must be performed within 28 days prior to the start of 
de-escalation. 
 
* Local molecular results from any UK laboratory will define entry 
 
6.2 
Enrolment/ Baseline 
 
Patients who have given informed consent and have been found to comply with all 
inclusion and exclusion criteria will be enrolled on the trial by the LCTU. 
To ensure essential entry criteria are fulfilled, enrolment can only occur following the 
completion and forwarding of the trial registration documents by the investigators: 
 
 
Inclusion and Exclusion Criteria 
 
Registration and screening forms 
 
Signed Consent form 
 
The registration documents should be faxed or emailed to the LCTU on Monday - 
Friday from 09:00 to 17:00, fax number: 0151 794 8931. Prior to sending 
documents, site staff should telephone 0151 795 5479 to inform the LCTU staff of 
the incoming registration fax or to ascertain the email address. 
 
Registration – Tel: 0151 795 5479 Fax: 0151 794 8931 
(Note that the LCTU is open from 09:00 – 17:00, Monday – Friday, excluding public 
holidays) 
 

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6.3 
Samples 
 
Laboratory studies to monitor disease response to de-escalation and stopping 
treatment are an integral and essential part of DESTINY. Additional scientific studies 
aim to identify factors that predict successful de-escalation/stopping.  
 
Local molecular results from any UK laboratory will define entry, but baseline and all 
prospective molecular monitoring will be done centrally at Imperial College London, 
Hammersmith Hospital (Hammersmith), supervised by Prof Foroni (see section 6.3.1 
and 3 and Contact Details: Individuals). 
 
All samples should be sent on Monday –Wednesday only. 
 
 
6.3.1 Samples required 
 
The samples required for external despatch are summarised in Table 1, below. All 
patients require bone marrow sending to Glasgow Clinical Laboratory and blood to 
Hammersmith Hospital Clinical Laboratory. 
 
Patients recruited and treated at the Royal Liverpool University Hospital ONLY also 
require a blood sample to be sent to the Liverpool laboratories. 
 
 

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Table 1: Summary of external sample requirements, timing and destinations 
 
Laboratory 
Diagnosis 
Screening 
Subsequent scheduled 
visits (monthly until month 
25, then 2-monthly until 
month 37) 
At relapse or month 37 
(whichever is the sooner) 
GLASGOW 
Not needed 
1-2ml Bone MARROW in 
green (heparinised) tube 
or mauve/purple (EDTA) 
tubes 
Not needed 
1-2ml Bone MARROW in 
green (heparinised) tube 
or mauve/purple (EDTA) 
tubes (Relapse ONLY) 
HAMMERSMITH 
Sample of original 
diagnostic blood, can 
be sent after de-
escalation has 
commenced.  Site to 
provide kit/postage. 
3 x 6ml (i.e. 18ml) 
BLOOD into 
mauve/purple (EDTA) 
tubes 
3 x 6ml (i.e. 18ml) BLOOD 
into mauve/purple (EDTA) 
tubes 
3 x 6ml (i.e. 18ml) 
BLOOD into 
mauve/purple (EDTA) 
tubes. 
In relapsing patients 
resuming full standard 
dose treatment, please 
continue to send 
samples at monthly 
intervals until MMR (or 
MR4), i.e. BCR-ABL ≤ 
0.1% IS, is regained. 
LIVERPOOL (only 
required for patients 
recruited at Royal 
Liverpool University 
Hospital) 
Not needed 
30ml blood collected in a 
Universal Container with 
preservative free heparin  
Not needed 
Not needed 

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Glasgow (all patients) 
At trial entry and molecular relapse bone marrow samples are requested to examine 
the proportion of leukaemic colonies. RNA will also be stored at entry and relapse for 
later microarray analysis to identify a gene signature associated with relapse.  
Molecular relapse bone marrow samples should still be requested even if a sample at 
trial entry was not available. 
 
A quantity of bone marrow should be taken according to local practice, with 1-2 ml 
collected in either the green topped, heparin-containing tube or the mauve/purple 
(EDTA) tube (whichever is provided in the kit) and sent overnight (morning delivery) 
directly to the analysis lab for immediate processing. It is imperative that the analysis 
lab receives adequate (at least one day’s) notice that clinical samples are being 
shipped, to ensure that the appropriate resources are available and ready upon sample 
delivery. Samples should therefore be despatched on Monday–Wednesday, so as to 
arrive at the analysis facility on a weekday (Tuesday-Friday). 
 
Hammersmith (all patients) 
An initial sample to this central laboratory for molecular monitoring is required to 
assess the level of BCR-ABL1 at trial entry.  
Samples to assess the level of BCR-ABL1 by conventional RT-PCR are then required 
at each scheduled visit. Three 6ml (i.e. 18ml) of blood into the mauve/purple (EDTA) 
tubes are required; these tubes are labelled ‘DESTINY’ and provided in the sample kits 
for the trial. These should be collected on a Monday, Tuesday or Wednesday only (to 
allow them time to arrive at the analysing laboratory before the weekend). Each tube 
should be clearly marked with the patient’s DESTINY trial number, initials, date of birth 
and the date and time of the sample. Each sample should be accompanied by a 
DESTINY PCR shipping form. 
These samples should continue to be sent at each scheduled visit until relapse and at 
monthly intervals thereafter until MMR (or MR4), i.e. BCR-ABL ≤ 0.1% IS, is regained. 
Note that there is no cost to the investigational site for these molecular analyses. 
 
For all patients, the level of BCR-ABL1 will also be assessed by more sensitive DNA-
based PCR. This requires an additional sample from original diagnosis, though this 
should not be sent at trial entry and should follow after the patient has commenced de-
escalation. Hammersmith Hospital is happy to liaise about sample details with the local 
molecular monitoring lab. The contact details are Prof Letizia Foroni, as in section 6.3.  
Sites will need to provide the kit components for this sample, in discussion with Prof 
Foroni’s team, and arrange postage themselves.  
 
 
Liverpool (for Royal Liverpool University Hospital patients ONLY) 
Samples for Liverpool studies are only required from patients recruited and treated at 
the Royal Liverpool University Hospital. At trial entry a blood sample is required to 
examine immune responses to CML (Liverpool). 30ml blood should be collected in a 
Universal Container with preservative free heparin and sent to Gemma Austin or Alison 
Holcroft in the Haematology 2nd floor lab.  Samples should be despatched on Monday–
Thursday, so as to arrive in the Liverpool laboratory on a weekday (Tuesday-Friday). 
 
 

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6.3.2 Sample Kits 
Sample boxes (postage pre-paid) will be provided by the LCTU, containing the 
necessary sample tubes and paperwork for both blood and bone marrow at trial entry, 
for blood at the subsequent scheduled visits, and for bone marrow at relapse. 
LCTU will not supply sample kits, paperwork or pre-paid postage boxes for the 
additional original diagnosis sample. 
 
 
6.3.3 Laboratory Contact Details 
 
LIVERPOOL (for patients recruited at the Royal Liverpool University Hospital only)  
Mrs Gemma Austin 
 
 
 
Tel  
+44(0)151-706-4326 
Dept of Haematology  
 
 
email:  gemmajon@liverpool.ac.uk 
Royal Liverpool University Hospital 
Prescot St 
LIVERPOOL  
L7 8XP 
 
GLASGOW 
 
Ms Heather Morrison  
 
 
  Tel: 0141 301 7880 
Paul O’Gorman Leukaemia Research Centre  e-mail: heather.morrison@gla.ac.uk   
Institute of Cancer Sciences 
University of Glasgow 
21 Shelley Road 
Gartnavel General Hospital 
Glasgow G12 0ZD 
 
 
HAMMERSMITH - the package should be clearly marked ‘DESTINY trial’, and send 
by 1st class post to  
 
Prof Letizia Foroni, MD PhD FRCPath 
Consultant Scientist 
Imperial Molecular Pathology Laboratory 
         Tel:      0208 383 2179 
G Block, Level 2, room 313  
 
         Office: 0208 383 2167/2177 
North Corridor  
 
 
 
         FAX     0203 313 1507 
Hammersmith Hospital 
 
 
         email: l.foroni@imperial.ac.uk 
Du Cane Road 
London W12 0HS 
 

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7 
TRIAL TREATMENT/S 
7.1 
De-escalation phase (12 months) 
 
Patients in both the MR4 and the MMR groups will be treated identically. During the 
de-escalation phase, all patients (irrespective of their dose at entry) will decrease to 
half the standard dose of their TKI. It is advised that drug should be dispensed monthly 
during the 12-month de-escalation phase. 
Table 2: Trial drug doses 
TKI 
De-escalated dose 
Frequency 
Imatinib 
200mg  
Once daily 
Nilotinib 
200mg* 
Twice daily 
Dasatinib 
50mg 
Once daily 
 
*This 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. Patients receiving nilotinib as first line therapy should also receive 
200mg twice daily in the de-escalation phase, regardless of dose prior to de-escalation. 
 
7.1.1 Formulation, Packaging, Labelling, Storage and Stability 
 
Please refer to the appropriate summary of product characteristics (SmPC): 
 
Glivec 100mg film-coated tablets (imatinib mesilate) 
 
Tasigna 200mg hard capsules (nilotinib hydrochloride monohydrate) 
 
Sprycel 100mg film coated tablets (dasatininb monohydrate) 
 
IMP will be supplied from local site supplies.  All IMP management will be conducted 
as per local site standard conditions  
7.1.2 Preparation, Dosage and Administration of Trial 
Treatment/s 
 
Please refer to the appropriate summary of product characteristics (SmPC) for each 
IMP 
.  
Doses are specified in section 7.1 (table 2) of the Protocol.   
 
The reduced study dose is managed by local PI’s for all patients on DESTINY.  The 
patient’s prescription will be reduced as per table 2. 
 
The local site pharmacy will manage all aspects of dispensing, returns and labelling.   
 

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7.1.3 Dose Modifications 
 
Because of the nature of the trial design, dose modifications are not appropriate. If 
during de-escalation phase a patient requires a different dose to that listed in Table 2, 
the local investigator should contact the DESTINY trial coordinator who will request 
further advice from the CI.  If the CI cannot make a definitive decision after discussion 
with the local PI, the matter can be taken to the TMG. 
 
Patients whose molecular monitoring has not changed by 12 months of de-escalation 
(i.e. remaining undetectable in the MR4 group, or remaining within MMR for the MMR 
group) will stop therapy. Since time is required to test the 12-month sample, relay the 
result to the clinical site and for the patient to be seen, the date at which the patient 
actually stops their treatment is deemed as the month 13 visit. 
 
7.2 
Accountability Procedures for Trial Treatment 
 
 
There is no requirement to maintain drug accountability logs for trial related purposes. 
 
IMPs are administered according to their licensed indication and form.  
 
If treatment is supplied through routine prescribing practices involving, for example 
community pharmacies or a Homecare provider, these organisations may continue to 
dispense IMPs once the patient begins de-escalation provided that the local PI 
approves. 
 
7.3 
Assessment of Compliance with Trial Treatment/s 
 
Data regarding dose of treatment prescribed and taken at home will be recorded on 
the CRF, thus allowing assessment of compliance with the treatment regimen. Data 
relating to any alteration in symptoms (which may be related to TKI de-
escalation/stopping) are also recorded in the drug diaries and the CRF.  At the start of 
each treatment cycle, patients will be issued with treatment diaries to record 
compliance with home treatment regimens and asked if they had any difficulties with 
the previous cycle of treatment. 
 
7.4 
Concomitant Medications/Treatments 
 
There are no restrictions on concurrent medications or treatments. 
7.4.1 Data on Concomitant Medication 
Dose and names of all concomitant medication should be documented on the CRF 
from screening. This will be reassessed by the PI throughout trial participation during 
clinical review. Any new medications introduced or changes to medications during the 
trial period should be documented on the CRF. 

Protocol No: ISRCTN 74084226 
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DESTINY 
 
Version 7 Date 24 May 2018 
7.5 
Co-enrolment Guidelines 
Patients in the DESTINY trial should not be recruited into other studies of anti-CML 
treatment prior to disease progression. Similarly, patients already participating in other 
trials of anti-CML therapy should not enter the DESTINY trial.  
 
Individuals already participating in a trial testing a medicinal product unrelated to CML 
will not be excluded from the DESTINY trial. However, patients in the DESTINY trial 
will not be allowed to enter other trials, even if these do not involve anti-CML therapy.  
 
Any queries should be addressed to the trial coordinator. 
 

Protocol No: ISRCTN 74084226 
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DESTINY 
 
Version 7 Date 24 May 2018 
8 
ASSESSMENTS AND PROCEDURES 
8.1 
Schedule of Trial Procedures 
Table 3: Schedule of Assessments and Trial Procedures 
Procedure 
Screening% 
Baseline% 
Hammersmith Alert∞ 
Month (i.e. 1 calendar month +/- 7 days, and not 4 weeks) 
At relapse 
After Relapse@ 
12 Months after study 
end (withdraw or relapse)
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12& 
13&  (0*) 
14  (1*) 
15 (2*) 
16 (3*) 
17 (4*) 
18 (5*) 
19 (6*) 
20 (7*) 
21 (8*) 
22 (9*) 
23 (10*) 
24 (11*) 
25 (12*) 
27 (14*) 
29 (16*) 
31 (18*) 
33 (20*) 
35 (22*) 
37 (24*) 
Written Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Confirmation of diagnosis 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Demographic Data 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Medical History 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Weight, Physical Examination 
and Vital Signs 
X 
  
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
X
∆ 
 
Prior Treatment for CML 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Past and present disease status 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Concomitant disease and 
treatment 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
X 
Pregnancy test (in women of 
child bearing potential only) 
X
^ 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Laboratory Tests (Haematology 
and Biochemistry) 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Additional original diagnostic 
blood sample to Hammersmith  
X# 
  
  
 
Blood Samples for BCR-ABL1 to 
Hammersmith 
  
X
$ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
 
Bone marrow samples to 
Glasgow 
  
X
€ 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
 

Protocol No: ISRCTN 74084226 
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DESTINY 
 
Version 7 Date 24 May 2018 
Blood samples to Liverpool 
(Liverpool patients only) 
  
X
$ 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
 
Quality of Life assessments 
(EQ-5D & FACT-BRM) 
  
X
$ 
X 
X 
X 
X 
  
  
X 
  
  
X 
  
  
X 
X 
X 
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
X 
  
X 
  
X 
  
  
 
Patient diary /symptoms 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
 
12 Month TKI stopping CRF 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
 
 
% Within 28 days prior to commencing de-escalation unless otherwise stated 
^ Within 14 days prior to commencing de-escalation 
# Can be sent after patient has commenced de-escalation, see section 6.3.1 
$ Within 7 days prior to commencing de-escalation 
€ Within 1 calendar month prior to commencing de-escalation 
∞ Will only occur if BCR-ABL elevates to >0.1% IS   
∆ Weight only 
&The BCR-ABL1 molecular result at 12 months will determine whether the patient proceeds to stop therapy. 1 month is allowed to perform this test, relay the result to the local team and then see the patient. Therefore the date on which the 
patient stops their TKI is taken as the month 13 visit, though this may not be exactly 13 months from trial entry.  
* Months after stopping treatment appear in brackets 
? Unless already relapsed 
@ At monthly intervals until MMR, i.e. BCR-ABL ≤ 0.1% IS, is regained.

Protocol No: ISRCTN 74084226 
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DESTINY 
 
Version 7 Date 24 May 2018 
8.1.1 Screening Assessments 
 
Screening assessments must be performed before a patient is registered for the trial. 
Please refer to Table 3 for a specific list of assessments. After patients have consented 
to trial participation and signed the informed consent form, they will be assessed for 
their eligibility for entry into the trial. Patients who fulfil the entry criteria will be 
registered. De-escalation must be commenced within 28 days of tests performed at 
screening (except for pregnancy test which must be within 14 days of de-escalation 
starting).  
 
At trial entry, the history of the patient’s CML and its treatment are required, together 
with all the available cytogenetic and molecular PCR (BCR-ABL1) results since 
diagnosis (reported to IS where possible). These must include a minimum of 3 BCR-
ABL1 molecular results in the 12 months prior to trial entry, since these define whether 
the patient is in the MR4 or the MMR group; please see inclusion criteria in sections 1 
and 5.1 for details. Details of other clinical conditions and concomitant medications are 
also required, together with an appropriate physical examination (including spleen size 
and ECOG status).  
 
8.1.2 Baseline Assessments 
 
Baseline assessments must be performed before a patient begins de-escalation. 
Please refer to Table 3 for a summary of baseline assessments. It is permissible for 
baseline assessments to be performed at the same time as the screening assessments 
if they are part of standard care. The following baseline assessments should be 
performed: 
 
 
Laboratory Tests (within 28 days prior to starting de-escalation): 
o Full Blood Count (Haemoglobin; White Blood Cells; Neutrophils; 
Lymphocytes; Monocytes; Eosinophils; Basophils; Platelets 
o Serum Biochemistry (Urea; Creatinine; Bilirubin; ALT or AST; γGT) 
 
Blood sample for PCR testing for BCR-ABL1 sent to Hammersmith Hospital 
(within 7 days prior to starting de-escalation). DESTINY aims to trial the effect 
of treatment de-escalation/stopping on the disease burden, as assessed by 
standard BCR-ABL1 monitoring by quantitative PCR. Local PCR results are 
adequate for defining trial entry, but all subsequent the testing for BCR-ABL1 
is centralised at Hammersmith Hospital (see section 6.3 for further details) 
 
Samples for scientific tests Blood sample to Liverpool (patients recruited at 
Royal Liverpool University Hospital only) and bone marrow sample to Glasgow 
(see section 6.3 for further details) 
 
Quality of life assessments 
 
8.1.3 Planned assessments during de-escalation follow-up 
phase (1-12 months) 
 
Please refer to Table 3. Once treatment de-escalation is begun, the cardinal 
investigation is the molecular monitoring of BCR-ABL1 (reported to IS). This is 
centralised at Hammersmith Hospital, supervised by Prof Foroni, and should be carried 
out monthly for the 12 months of the de-escalation. Note that for this purpose, 1 month 
= 1 calendar month and not 4 weeks; although an actual date within one week either 

Protocol No: ISRCTN 74084226 
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DESTINY 
 
Version 7 Date 24 May 2018 
side of the exact monthly calendar date is permissible. The actual monthly evaluation 
date should be recorded in the CRF.  
 
Once the sample after 12 months of de-escalation is taken, the trial clock pauses while 
this sample is analysed, the result is relayed to the clinician and the patient is seen. 
This pause is likely to be about 4 weeks and should not exceed 6 weeks for any reason. 
During this pause the patient should remain on their de-escalated dose. 
  
Assuming that this 12-month sample shows stable disease (i.e. the PCR result remains 
at or below 0.1% IS for both the MR4 and the MMR groups), the clock restarts as the 
‘month 13’ visit and the patient should discontinue treatment altogether. Centralised 
molecular monitoring of BCR-ABL1 (reported to IS) continues monthly for a further 12 
months (i.e. to month 25), then 2-monthly until month 37.  Section 6.3 summarises the 
details for the sending of all samples at all time points. 
 
In the particular case where BCR-ABL1 molecular monitoring from entry until month 
11 has remained at or below 0.1% IS, but the month 12 sample shows a level above 
0.1% IS, the clock remains paused and another sample should be sent for molecular 
monitoring (called ’Hammersmith ALERT’). If this is also above 0.1% IS then the patient 
fulfils the definition of relapse, and should resume their full dose of TKI treatment; they 
should not proceed to complete discontinuation. 
 
 
8.1.4 Planned assessments during ‘stopping’ follow-up phase 
(13-37 months) 
 
Please refer to Table 3. The duration of formal follow-up is 37 months. Patients should 
be seen monthly for the first 12 months of complete cessation, and thereafter 2-
monthly. It is assumed that one month is required to test the 12-month sample, relay 
this to the clinical site and for the patient to be seen. The date at which the patient 
actually stops their treatment is therefore deemed as the month 13 visit. 
 
Once the patient reaches the month 37 time point, formal monitoring can discontinue 
and no further trial-specific tests are required; the patient can then be followed 
according to local practice. Follow-up for outcome is however still required beyond 
month 37, until 5 years from trial entry; this should include all local PCR results and 
any requirement for further CML treatment. Details should be entered in the CRF. 
 
8.1.5 Planned assessment at relapse 
 
Please refer to Table 3. Relapse in this trial is defined as a BCR-ABL1/ABL1 ratio 
assessed by quantitative PCR (i.e. BCR-ABL1 level) measured centrally at the 
Hammersmith Hospital which rises above 0.1% IS on two consecutive occasions. 
Baseline samples are not included in the establishing of relapse.  It is stressed that this 
definition of relapse is actually the loss of molecular response, and quite different from 
more serious relapse such as loss of cytogenetic response, overt haematological 
relapse or disease progression. The likelihood of any of these latter serious events is 
seen as exceptionally unlikely (no such events have been observed in any of the 61 
relapsing cases in the French STIM trial). 
 

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DESTINY 
 
Version 7 Date 24 May 2018 
Given this conservative definition of relapse, it is envisaged that overall a substantial 
proportion of patients will relapse, and not complete trial treatment. 
 
Any sample showing a rise in BCR-ABL1 to > 0.1% IS will prompt an individual 
call/email to the local site, stressing the importance of the next sample for that patient. 
If this rise occurs during the final year of trial, where follow-up is normally alternate 
months, an additional visit (designated ’Hammersmith ALERT’) will become 
mandatory, timed at 1 month after the last visit. If the subsequent sample also shows 
a BCR-ABL1 level of > 0.1% IS, then the patient has relapsed. The patient should then 
be recalled promptly, and should resume the full dose of the TKI that they were 
receiving at trial entry. 
 
At this visit, samples should be sent as in Table 3 (and see Table 1 for sample 
destinations). This includes a repeat bone marrow, partly for repeat sampling to 
Glasgow (to monitor changes in primitive leukaemic colonies, as given in section 6.3; 
please note the requirement to notify Glasgow prior to shipment), and partly for routine 
standard investigations at local discretion (e.g. to confirm continuance of chronic phase 
morphologically and cytogenetic remission by G-banded cytogenetics). Details should 
be entered in the ‘relapse’ section in the CRF, including additional local bone marrow 
investigations for morphology and cytogenetics. The patient is then ‘off trial’ and further 
treatment decisions can be made according to local practice; however these should be 
recorded in the CRF under ‘after relapse’, and centralised monitoring at the 
Hammersmith Hospital continues at monthly intervals as required, until MMR (or MR4), 
i.e. BCR-ABL ≤ 0.1% IS, is regained. 
 
 
8.1.6 Scheduled collection of Samples 
 
Please refer to Tables 1 and 3 and section 6.3. 
 
8.2 
Procedures for assessing Efficacy 
8.2.1 Trends in molecular monitoring of BCR-ABL1 
 
Local molecular results for BCR-ABL1 (reported to IS where possible) are acceptable 
to define trial entry, though a sample should be sent at trial entry to Hammersmith 
Hospital, the site for centralised monitoring.  
 
All centralised Hammersmith Hospital results shall be entered directly onto the LCTU 
database by their staff.  Local results are recordable in the CRF for post month 37 only. 
  
A relapse date is defined as the first of 2 consecutive molecular monitoring tests in 
excess of 0.1% IS. This date together with the molecular monitoring data should be 
recorded in the CRF. 
 
8.2.2 Response to recommencing treatment after relapse 
 
Patients who relapse are ‘off protocol’ and can be treated according to their physician’s 
discretion, but it is strongly recommended that all patients will resume their previous 

Protocol No: ISRCTN 74084226 
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DESTINY 
 
Version 7 Date 24 May 2018 
TKI at the standard dose. After relapse, monthly monitoring samples should still be 
sent to Hammersmith Hospital for centralised molecular monitoring for BCR-ABL, until 
MMR (or MR4), i.e. BCR-ABL ≤ 0.1% IS, is regained. This is to document the kinetics 
of return to MMR/MR4. Details should be recorded in the ‘after relapse’ section of the 
CRF. 
 
8.2.3 Quality of Life Assessments and Patient Diaries 
 
All documents in this section are available for download from the LCTU website 
http://www.lctu.org.uk. To ensure current versions are used, please print directly from 
the LCTU website as and when they are needed. 
 
Quality of Life Assessments 
 
Either de-escalation or complete cessation of TKI therapy (or both) may alter the 
patient’s quality of life. This will be investigated using standard EQ-5D and FACT-BRM 
questionnaires at 1, 2, 3, 6, 9, 12 and 13, 14, 15, 16, 19, 22, 25, 29, 33 and 37 months 
after commencing de-escalation. These timings will coincide with planned 
attendances. At each of these visits, the patient should complete the questionnaires 
while at the hospital; they should not take them home. 
 
Note that questionnaires are required at both the 12 month and the ‘month 13’ visit. 
This is because the 12 month questionnaire will give the results of 12 months of de-
escalation, while the ‘month 13’ questionnaire will serve as the baseline for the 
stopping phase.  
 
Patient Diaries 
 
Patient diaries should be completed during the entire de-escalation and stopping 
phases and any alteration in symptoms (which may be related to TKI de-
escalation/stopping) recorded. 
 
8.2.4 Health Economic Assessment 
 
 
Patients suitable to enter DESTINY would normally typically attend outpatients 3-
monthly, for BCR-ABL1 molecular monitoring and repeat TKI prescription, plus maybe 
a blood count and biochemical profile including liver function testing. In DESTINY, 
attendance is required monthly for 2 years and then alternate months for a further year. 
This is an additional 18 visits and 18 BCR-ABL1 molecular monitoring tests over and 
above that delivered to the typical patient not contemplating de-escalation/stopping. 
However, this excess cost may be offset by the saving on TKI expenditure as the 
patient comes off treatment. 
 
DESTINY entrants are generally well, maybe asymptomatic, and do not require 
inpatient episodes. Resource utilisation analysis is therefore envisaged to be 
straightforward, and can be based on the data recorded in the CRFs as set out in 
sections 7 and 8.1. This aspect of the trial will be supervised by Dr Alan Haycox (see 
contact details at start of protocol).  
 

Protocol No: ISRCTN 74084226 
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DESTINY 
 
Version 7 Date 24 May 2018 
8.2.5 Laboratory based studies 
 
Laboratory studies should be carried out at trial entry and at relapse (where this 
occurs). RNA will be stored at entry and relapse, to identify a gene signature 
associated with relapse, and the immune response to CML will also be examined.  
 
Whether the more sensitive DNA-based BCR-ABL1 assessment predicts relapse will 
be investigated for MR4 patients where genomic DNA from original diagnosis is 
available. This will be led by Prof Letizia Foroni, Imperial College London, 
Hammersmith Hospital. This technique may be more sensitive than conventional RT-
PCR.  
 
Finally, the bone marrow sample at entry (and relapse) will be used to examine the 
proportion of leukaemic colonies by BCR-ABL1 FISH on replate assays from bone 
marrow colony forming assays (led by Prof Mhairi Copland, Glasgow). 
 
 
8.3 
Procedures for Assessing Safety 
Safety will be assessed through the reporting of serious adverse events as described 
in Section 10. 
8.4 
Quality of Life and Health Economics 
 
Quality of life assessment will be assessed at entry and after 1, 2, 3, 6, 9, 12/13, 14, 
15, 16, 19, 22, 25, 29, 33 and 37 months. Standard EQ-5D and FACT-BRM 
questionnaires will be used at monthly intervals initially, decreasing subsequently.  
 
Amelioration of symptoms during the de-escalation and/or stopping phases will be 
captured in the patient drug diaries, which ask patients to record any alteration to 
symptoms experienced at baseline. 
8.5 
Substudies  
 
No sub-studies are planned. 
 
 
8.6 
Loss to Follow-up 
If any of the trial patients are lost to follow up, contact will initially be attempted through 
the PI at each centre. If the PI at the trial centre is not the patient’s usual clinician 
responsible for their speciality care then follow-up will also be attempted through this 
clinician. Where all of these attempts are unsuccessful, the patient’s GP will be asked 
to provide follow-up information to the recruiting centre. 
 

Protocol No: ISRCTN 74084226 
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DESTINY 
 
Version 7 Date 24 May 2018 
8.7 
Trial Closure 
Investigators will be informed when patient recruitment is to cease. 
 
Trial enrolment may be stopped at a site when the total requested number of subjects 
for the trial has been obtained. 
 
The Independent Safety and Data Monitoring Committee (ISDMC) may recommend to 
the Trial Steering Committee (TSC) that the trial be stopped prematurely. Such 
premature termination/suspension of the trial will be notified to the MHRA and MREC 
as required. 
 
The trial will be considered formally “closed” when the database is locked. 

Protocol No: ISRCTN 74084226 
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DESTINY 
 
Version 7 Date 24 May 2018 
9 
STATISTICAL CONSIDERATIONS 
9.1 
Introduction 
An overview of the statistical considerations relevant for the trial is included. A single 
analysis plan will be developed prior to the first planned interim analysis. This analysis 
plan will contain all information required for all interim analyses and the final analysis 
of the data. This document will be approved by the trial steering committee and an 
Independent Safety and Data Monitoring Committee (ISDMC).  
 
For any statistical analysis MR4 patients will be re-classified to either MMR or MR4 
group based on the following criterion: 
 
 
MR4: At least complete molecular remission MR4 (either (i) detectable disease 
≤0.01% BCR-ABL IS or (ii) undetectable disease in cDNA with ≥ 10,000 ABL or ≥ 
24,000 GUS transcripts) for at least one year; at least three PCR-results with MR4 
within the last year (+- 2 months) before study entry and no PCR-results > 0.01% 
during the same period. 
 
This is required because: 
 
The MR4 group definition described in the eligibility criteria is not up-to-date with 
technological advances in PCR methods; new methods can detect very low levels 
of residual disease (<0.01%). 
 
We want to provide comparable results with other major similar trials, and thus we 
decided to harmonise the MR4 group definition with EUROSKI trial. 
 
To avoid causing any unnecessary confusion to the sites we decided to keep the 
initial definition in the eligibility criteria.   
9.2 
Outcome Measures 
9.2.1 Primary 
The primary end-point for both the MR4 and the MMR groups is the proportion of 
patients who can first de-escalate their treatment (to half the standard dose of their 
TKI) for 12 months, and then stop treatment completely for a further 2 years, without 
losing MMR. This will be calculated separately for each of the two groups (MR4 and 
MMR). 
 
9.2.2 Secondary 
 
Secondary endpoints are: 
 
 
Proportion of patients who can successfully de-escalate their treatment (to half the 
standard dose of their TKI), but who then lose MMR on complete TKI cessation. 
 
Proportion of patients who lose their MMR on de-escalation/stopping and regain 
MMR on resumption of their TKI. 
 
Molecular relapse-free survival (RFS). RFS is defined as the time from the first 
day of de-escalation to the date of confirmed loss of MMR (two consecutive BCR-
ABL >0.1% IS). 

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DESTINY 
 
Version 7 Date 24 May 2018 
 
Progression-free survival (PFS). PFS is defined as the time from the first day of 
de-escalation to the date of progression to accelerated phase/ blast crisis or death 
from any cause (earliest occurrence). 
 
Overall survival (OS). OS is defined as the time from the first day of de-escalation 
to the date of death from any cause. 
 
Event-free survival (EFS). EFS is defined as the time from the first day of de-
escalation to the date of confirmed loss of MMR, progression to AP/BC or death 
from any cause. 
 
Time to MMR recovery (TTR). TTR is defined as the time from the date of 
confirmed loss of MMR to the date of MMR recovery. 
 
Proportion of registered MMR and MR4 patients in confirmed MR4.5 (BCR-ABL ≤ 
0.0032% IS with at least 31,623 ABL1 control transcripts) prior to being enrolled 
in the study (screening phase).   
 
Quality of Life. 
 
Health Economic Assessment. 
 
Lab studies to define subsets of patients who are more likely to relapse on de-
escalation / cessation.  
 
All secondary endpoints will be calculated separately for each of the two groups (MR4 
and MMR). Safety variables will be summarised by descriptive statistics. SAEs 
occurring during the 37-month de-escalation and stopping phases will be reported, 
summarised by incidence rates and classified by the worst observed severity grade. 
Laboratory data will be presented by day from commencement of de-escalation or 
stopping. For biochemical investigations, values outside normal limits will be identified 
and summarised by frequency distribution.  
 
9.3 
Sample Size 
Seventy cases will give a 90% confidence interval of maximum width 0.2, for a wide 
range (0.3 to 0.7) of values of the proportion, p, of relapsing patients. The width will be 
smaller the closer the estimate is to 0 (or 1). Assuming a dropout rate of 17% and an 
anticipated equal group allocation, 168 patients are needed.  
 
The accrual of patients within each group largely depends on factors that cannot be 
controlled or specified a-priori. Hence, to avoid early closing of recruitment in one group 
which could potentially have a negative effect in overall recruitment and would require 
substantial extension in the recruitment period we are willing to allow for unequal group 
allocation and some variation in the maximum confidence interval width. Assuming that 
we recruit 168 patients in total, under the worst case scenario (p=0.5, group allocation 
1:3) the 90% confidence intervals for the two groups (“larger” and “smaller”) will have 
a maximum width of 0.16 and 0.28 respectively. 
 
9.4 
Interim Monitoring and Analyses 
The proportion of relapsing patients will be assessed at 3 planned interim analyses: 
when 60 patients relapse or complete 12 months de-escalation, when 60 relapse or 
complete 12 months of cessation, and when 60 relapse or complete 24 months 
cessation. There are no formal stopping rules but the Independent Data Monitoring 

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DESTINY 
 
Version 7 Date 24 May 2018 
and Safety Committee (ISDMC) will review the interim analyses and give advice on 
whether the accumulated data from the trial, together with results from other relevant 
trials, justifies continuing recruitment of further patients or further follow-up. A decision 
to discontinue recruitment will be made only if the result is likely to convince a broad 
range of clinicians including participants in the trial and the general clinical community. 
The entire trial (or the MMR or MR4 elements alone) may be stopped if de-escalation 
or stopping are producing an unacceptable rate of molecular relapse. For this purpose, 
the MMR and MR4 groups will be treated separately, since the former may well have 
a higher relapse rate. Unacceptable relapse for this purpose is at the discretion of the 
Data Monitoring Committee, bearing in mind that the relapse rate in the STIM trial was 
61% overall and 59% (48% - 71%) after 12 months of cessation.  
 
Regardless of the reason(s) for termination, all data available for the patient at the time 
of discontinuation of follow-up must be recorded in the CRF.  All reasons for 
discontinuation of treatment must be documented. In terminating the trial, the sponsor 
and the Investigators will ensure that adequate consideration is given to the protection 
of the patient’s interest. 
 
All interim analysis results of the primary and secondary outcome measures will be 
confidential to the ISDMC members and will not be for review by the trial management 
group (except the trial statistician preparing the ISDMC report), Trial Steering 
Committee, investigators or collaborators. 
 
9.5 
Analysis Plan 
The trial will be analysed and reported following the ‘Consolidated Standards of 
Reporting Trials (CONSORT)’ guidelines. 
 
All statistical analyses will be on an intention to treat basis. Missing data, which are 
anticipated to mainly affect the quality of life outcome measure, will be handled by 
considering the robustness of the complete case analysis to sensitivity analyses using 
different imputation assumptions informed by data collected on reasons for missing 
data. Continuous variables will be summarised by descriptive statistics (mean, 
standard deviation, minimum, median and maximum) and frequency tables will be 
provided for categorical data. 
 
Proportions of patients relapsing, under the various primary and secondary outcomes 
will be estimated together with 90% confidence intervals. RFS, PFS, OS, EFS will be 
estimated by the method of Kaplan and Meier.  Cumulative incidence analysis 
adjusting for the competing risk of death/progression to BC will be used to estimate the 
cumulative incidence function of TTR. 
 
Quality of life measurements will be assessed over time and comparisons made 
between relapsing and non-relapsing patients, using longitudinal analysis with 
appropriate recognition for informative dropout.  

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10 
PHARMACOVIGILANCE 
10.1 Terms and Definitions 
The Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031) 
definitions: 
 
Serious Adverse Event (SAE), Serious Adverse Reaction (SAR) or Suspected 
Unexpected Serious Adverse Reaction (SUSAR) 
Any adverse event, adverse reaction or unexpected adverse reaction, respectively, 
that: 
 
Results in death. 
 
Is life-threatening* (subject at immediate risk of death). 
 
Requires in-patient hospitalisation or prolongation of existing hospitalisation**. 
 
Results in persistent or significant disability or incapacity. 
 
Consists of a congenital anomaly or birth defect. 
 
Observations of ‘Blasts’, Blast crisis’, ‘Acute leukaemia’ or ‘Transformation’. 
 
Other important medical events***. 
 
*Life-threatening’ in the definition of ‘serious’ refers to an event in which the patient 
was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
**Hospitalisation is defined as an inpatient admission, regardless of length of stay, 
even if the hospitalisation is a precautionary measure for continued observation. 
Hospitalisations for a pre-existing condition, including elective procedures that have 
not worsened, do not constitute an SAE. 
***Other important medical events that may not result in death, be life-threatening, or 
require hospitalisation may be considered a serious adverse event/experience when, 
based upon appropriate medical judgment, they may jeopardise the subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
 
Notes on Serious Adverse Event Inclusions and Exclusions 
10.1.1 Include 
 
An exacerbation of a pre-existing illness 
 
An increase in frequency or intensity of a pre-existing episodic event/condition 
 
A condition (even though it may have been present prior to the start of the trial) 
detected after trial drug administration 
 
Continuous persistent disease or symptoms present at baseline that worsen 
following the de-escalation of the trial/trial treatment 
 
Laboratory anomalies that require clinical intervention or further investigation 
(unless they are associated with an already reported clinical event) 
 
Abnormalities in physiological testing or physical examination that require 
further investigation or clinical intervention 
 
Injury or accidents 
10.1.2 Do Not Include 
 
Medical or surgical procedures- the condition which leads to the procedure is 
the adverse event 
 
Pre-existing disease or conditions present before de-escalation of treatment 
that do not worsen 

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 
Situations where an untoward medical occurrence has occurred e.g. cosmetic 
elective surgery 
 
Overdose of medication without signs or symptoms 
 
The disease being treated or associated symptoms/signs unless more severe 
than expected for the patient’s condition 
10.1.3 Reporting of Pregnancy 
If a patient or their partner becomes pregnant during trial treatment or within 28 days 
following treatment, a completed Pregnancy Report Form must be faxed to the LCTU 
within 24 hours of learning of its occurrence. (Should you need a copy of the Pregnancy 
Report Form please contact the Trial Coordinator). On pregnancy outcome, the final 
Pregnancy Report Form should be faxed to the LCTU 28 days after the outcome. The 
final Pregnancy Report Form is used to determine outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth 
defects, congenital abnormalities, or maternal and/or newborn complications. 
Pregnancy follow-up information on this form also includes an assessment of the 
possible relationship to the trial medication of any pregnancy outcome. Pregnancy 
outcomes should also be collected for the female partners of male patients 
participating in the trial. Consent to report information regarding these pregnancy 
outcomes should be obtained from the mother prior to completion and faxing of the 
final Pregnancy Report Form. Any SAE experienced during pregnancy must be 
reported on the SAE form.  
 
The LCTU will report all pregnancies to the trial Sponsor(s), MHRA and MREC. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.2 Notes Severity / Grading of Serious Adverse Events 
The assignment of the severity/grading should be made by the investigator responsible 
for the care of the participant.  Severity of any SAE will be graded according to the 
National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) 
version 4. 
 
 
The SAE severity must be assessed according to medical criteria alone using the 
values in CTCAE or, should the SAE not be listed, by following corresponding 
categories: 
 
Grade 1 (Mild): does not interfere with routine activities 
Grade 2 (Moderate): interferes with routine activities 
Pregnancies must be reported by faxing a completed Pregnancy Report 
Form sent within 24 hours of becoming aware of the event to the 
Liverpool Cancer Trials Unit 
Fax. No. 0151 794 8931 
 
Pregnancy outcomes must be reported by faxing a completed final 
Pregnancy Report Form 28 days following the outcome to the 
Liverpool Cancer Trials Unit 
Fax No. 0151 794 8931  
 

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Grade 3 (Severe): impossible to perform routine activities 
Grade 4 (Life threatening) 
Grade 5 (Death) 
 
A distinction is drawn between serious and severe AEs. Severity is a measure of 
intensity (see above) whereas seriousness is defined using the criteria in section 10.1, 
hence, a severe AE does not need reporting, whereas a serious AE would be 
reportable as a Serious Adverse Event. 
10.3 Relationship to Trial Treatment 
The assignment of the causality should be made by the investigator responsible for the 
care of the participant using the definitions in Table 4. 
 
If any doubt about the causality exists the local investigator should inform the trial 
coordination centre who will notify the Chief Investigator.  In the case of discrepant 
views on causality between the investigator and others, the MHRA will be informed of 
both points of view. 
 
Table 4: Definitions of Causality 
Relationship 
Description 
None 
There is no evidence of any causal relationship. N.B. An alternative 
cause for the SAE should be given 
Unlikely 
There is little evidence to suggest there is a causal relationship (e.g. 
the event did not occur within a reasonable time after administration 
of the trial medication).  There is another reasonable explanation 
for the event (e.g. the participant’s clinical condition, other 
concomitant treatment). 
Possibly 
There is some evidence to suggest a causal relationship (e.g. 
because the event occurs within a reasonable time after 
administration of the trial medication).  However, the influence of 
other factors may have contributed to the event (e.g. the 
participant’s clinical condition, other concomitant treatments). 
Probably 
There is evidence to suggest a causal relationship and the influence 
of other factors is unlikely. 
Highly Probable 
There is clear evidence to suggest a causal relationship and other 
possible contributing factors can be ruled out. 
10.4 Expectedness 
An SAE whose causal relationship to the trial drug is assessed by the investigator as 
“possible”, “probable”, or “highly probable” is an Adverse Drug Reaction. 
 
All events judged by the investigator to be possibly, probably, or highly probably related 
to the IMP, graded as serious and unexpected for list of Expected Adverse Events 
(see Reference Safely Information section 10.6) should be reported as a SUSAR. 
10.5 Reference Safety Information  
The Reference Safety Information (RSI) to be used for this trial is as follows: 
 
GLIVEC film coated tablets – Summary of Product Characteristics – imatinib mesilate 
– Section 4.8 
 

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TASIGNIA 200mg hard capsules – Summary of Product Characteristic – nilotinib 
hydrochloride monohydrate – Section 4.8 
 
SPRYCEL 20mg 50mg 80mg 100mg and 140mg film coated tablets – Summary of 
Product Characteristics – dasatinib monohydrate – Section 4.8 
 
10.6 Follow-up After Serious Adverse Events 
All SAEs should be followed until satisfactory resolution or until the investigator 
responsible for the care of the participant deems the event to be chronic or the patient 
to be stable. 
 
When reporting SAEs and SUSARs the investigator responsible for the care of the 
participant should apply the following criteria to provide information relating to event 
outcomes: resolved; resolved with sequelae (specifying with additional narrative); not 
resolved/ongoing; ongoing at final follow-up; fatal or unknown. 
10.7 Reporting Procedures 
All SAEs should be reported from the date of informed consent until 28 days after the 
last dose of treatment received in the de-escalation phase (or longer if felt to be a long-
term side effect of trial treatment). Any questions concerning SAE reporting should be 
directed to the LCTU in the first instance.   
10.7.1 
Serious ARs/AEs/SUSARs 
 
SARs, SAEs and SUSARs should be reported within 24 hours of the local site 
becoming aware of the event by faxing an SAE form to the Liverpool Cancer Trials Unit 
on 0151 795 8931.  This form is downloadable from the CRF section of the DESTINY 
eTMF here http://www.lctu.org.uk.  If this website is also unavailable the site should 
contact the DESTINY Trial team on 0151 795 5479 and a copy of the form can either 
be emailed or faxed as required.  In the unlikely event that all electronic systems are 
unavailable the SAE can be reported verbally and documentation completed when it 
later becomes available. 
 
The person reporting the event should also phone the Trial Co-ordinator on 0151 795 
5479 to alert that an SAE is being reported. On reporting an SAE to the LCTU, research 
sites will receive an acknowledgement. This will either be in as an email or a fax. If a 
receipt has not been received within two hours of submitting the SAE please ring the 
Trial Co-Ordinator for confirmation. 
 
The completed SAE form should be assessed and each page signed by the 
responsible investigator i.e. the consultant named on the ‘signature list and delegation 
of responsibilities log’ that is responsible for the patient’s care. The investigator should 
assess the SAE for the likelihood that that it is a response to an investigational 
medicine. In the absence of the responsible investigator the form should be completed 
and signed by a designated member of the site trial team. The responsible investigator 
should check the SAE form, make changes as appropriate and sign as soon as 
possible. The initial report shall be followed by detailed, written reports.  
 
i. 
The responsible investigator must notify their R&D department of the 
event (as per standard local procedure). 

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ii. In the case of an SAE the subject must be followed-up until clinical 
recovery is complete and laboratory results have returned to normal, or 
until the event has stabilised. Follow-up may continue after completion 
of protocol treatment if necessary. 
iii. Follow-up information is noted on the same SAE form.  Extra, 
annotated information and/or copies of test results may be provided 
separately. 
iv. The patient must be identified by trial number, date of birth and initials 
only. The patient’s name should not be used on any correspondence. 
 
The Investigator must institute appropriate therapeutic action and follow-up measures 
in accordance with Good Medical Practice and should notify the trial co-ordinator of 
such actions. 
 
Follow-up information should be provided within 5 days if the reaction/event had not 
resolved at the time of initial reporting. 
 
 
The minimum dataset required for a preliminary report should include the 
following. 
Page 1 
 
Patient trial number and initials. 
 
Days since last dose of trial treatment 
 
Date of onset of event. 
 
Outcome (i.e. current status). 
 
Overall diagnosis of event, with CTCAE grade. 
 
Relevant medical history or concurrent medical conditions 
Page 2 
 
Any changes in drug treatment 
 
Serious criteria 
 
Causality (investigator completes) 
Page 3 onwards 
 
Trial Medication and concurrent drug information, including causalities 
 
 
The LCTU will notify the MHRA, MREC and co-sponsors of all SUSARs occurring 
during the trial according to the following timelines; fatal and life-threatening within 7 
days of notification and non-life threatening within 15 days. All investigators will be 
informed of all SUSARs occurring throughout the trial. Local investigators should report 
any SUSARs and/or SAEs as required by their Local Research Ethics Committee 
and/or Research & and Development Office. 
 
 

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10.8 Responsibilities – CR:UK LCTU 
 
The LCTU is undertaking duties delegated by the trial co-sponsor/s, Royal Liverpool & 
Broadgreen University Hospital NHS Trust and the University of Liverpool, and is 
responsible for the reporting of SUSARs and other SARs to the regulatory authorities 
(MHRA, competent authorities of other European member states in which the trial is 
taking place and, if required, the research ethics committees) as follows: 
 
 
SUSARs which are fatal or life-threatening must be reported not later than 7 days 
after the LCTU is first aware of the reaction. Any additional relevant information 
must be reported within a further 8 days. 
 
SUSARs that are not fatal or life-threatening must be reported within 15 days of the 
LCTU first becoming aware of the reaction. 
 
A list of all SARs (expected and unexpected) must be reported annually. 
 
It is recommended that the following safety issues should also be reported in an 
expedited fashion  
 
An increase in the rate of occurrence or a qualitative change of an expected serious 
adverse reaction, which is judged to be clinically important; 
 
Post-trial SUSARs that occur after the patient has completed a clinical trial and are 
notified by the investigator to the sponsor; 
 
New events related to the conduct of the trial or the development of the IMPs and 
likely to affect the safety of the subjects, such as: 
a.  A serious adverse event which could be associated with the trial 
procedures and which could modify the conduct of the trial; 
b. A significant hazard to the subject population, such as lack of efficacy 
of an IMP used for the treatment of a life-threatening disease; 
c. A major safety finding from a newly completed animal trial (such as 
carcinogenicity). 
d. Any anticipated end or temporary halt of a trial for safety reasons and 
conducted with the same IMP in another country by the same sponsor; 
 
Recommendations of the Data Monitoring Committee, if any, where relevant for the 
safety of the subjects. 
 
Staff at the LCTU will liaise with the designated Clinical Co-ordinator who will evaluate 
all SAEs received for seriousness, expectedness and causality. Investigator reports of 
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and reported to regulatory authorities and MREC. The causality assessment given by 
the Local Investigator at the hospital cannot be overruled and in the case of 
disagreement, both opinions will be provided with the report. 
 
The LCTU will also send an annual safety report containing a list of all SARs (including 
SUSARs) to the regulatory authorities.   
 
From September 2011 the sponsor will submit a Development Safety Update Report 
(DSUR).  
 
The DSUR will present a comprehensive annual review and evaluation of pertinent 
safety information collected during the reporting period relating to the Investigational 
Medicinal Product it will cover the following 4 areas:   
 
(1)  
Examine whether the information obtained by the sponsor during the reporting 
period is in accord with  
previous knowledge of the investigational drug’s safety 
(2)  
Describe new safety issues that could have an impact on the protection of 
clinical trial subjects 
(3)  
A summary of the current understanding and management of identified and 
potential risks 
(4)  
Provide an update on the status of the clinical investigation/development 
programme and trial results. 
 
Patient safety incidents that take place in the course of research should be reported to 
the National Patient Safety Agency (NPSA) by each participating NHS Trust in 
accordance with local reporting procedures. 
 
 
 
 
 
 

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11 
ETHICAL CONSIDERATIONS 
11.1 Ethical Considerations 
The trial will be conducted to conform to the principles of the Declaration of Helsinki as 
adopted by the 18th World Medical Assembly, 1964, and subsequent amendments 
(Tokyo (1975), Venice (1983), Hong Kong (1989) and South Africa (1996). 
The trial will be conducted in accordance with the EU Directive 2001/20/EC, the 
Medicines for Human Use (Clinical Trials) Regulations 2004 and the principles of Good 
Clinical Practice. 
Patients will be asked to consent that data are recorded, collected, stored and 
processed and may be transferred to other countries, in accordance with any national 
legislation implementing the EU Data Protection Directive (95/46/EC). 
This trial may be terminated at the request of the Chief Investigator, Independent 
Safety and Data Monitoring Committee, Independent Ethics Committee or the MHRA 
if, during the course of the trial, concerns about the safety of further dosing emerge. 
The Chief Investigator will update the ethics committee of any new information related 
to the trial drug when appropriate. 
11.2 Ethical Approval 
The trial protocol has received the favourable opinion of the Multi-centre Research 
Ethics Committee (MREC) but must undergo site specific assessment (SSA) by 
completing section C of the REC application form and submitting all sections of this 
form to the NHS R&D offices). A copy of local Research & Development (R&D) 
approval and of the PIS and CF on local Trust headed paper should be forwarded to 
LCTU before patients are entered.  
 
Consent should be obtained prior to each patient participating in the trial, after a full 
explanation has been given of the treatment options, including the conventional and 
generally accepted methods of treatment. The right of patients to refuse their consent 
to participate in the trial without giving reasons must be respected.  
 
After the patient has entered the trial, the clinician must remain free to give alternative 
treatment to that specified in the protocol, at any stage, if he/she feels it to be in the 
best interest of the patient. However, the reason for doing so should be recorded and 
the patient will remain within the trial for the purpose of follow-up and data analysis. 
Similarly, the patient remains free to withdraw at any time from the protocol treatment 
and trial follow-up without giving reasons and without prejudicing his/her further 
treatment. 
 
11.3 Informed Consent Process 
Informed consent is a process initiated prior to an individual agreeing to participate in 
a trial and continues throughout the individual’s participation. Informed consent is 
required for all patients participating in LCTU coordinated trials. In obtaining and 
documenting informed consent, the investigator should comply with applicable 
regulatory requirements and should adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki. 
 

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Discussion of objectives, risks and inconveniences of the trial and the conditions under 
which it is to be conducted are to be provided to patients by staff with appropriate 
experience. Appropriate Patient Information and Consent forms, describing in detail 
the trial interventions/products, trial procedures and risks will be approved by an 
independent ethical committee (IEC) and the patient will be asked to read and review 
the document. Upon reviewing the document, the investigator will explain the research 
trial to the patient and answer any questions that may arise. A contact point where 
further information about the trial may be obtained will be provided. 
 
After being given adequate time to consider the information, the patient will be asked 
to sign the informed consent document. A copy of the informed consent document will 
be given to the patient representative for their records and a copy placed in the medical 
records, with the original retained in the Investigator Site File. 
 
The patient may withdraw from the trial at any time by revoking the informed consent. 
The rights and welfare of the patients will be protected by emphasising to them that 
the quality of medical care will not be adversely affected if they decline to participate 
in this trial. 
11.4 Trial Discontinuation 
 
The reason for discontinuation of trial treatment/trial should be clearly documented and 
the End of Trial Treatment form completed. 
 

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12 
REGULATORY APPROVAL 
This trial has been registered with the MHRA and has been granted a Clinical Trial 
Authorisation (CTA). The CTA reference is its EudraCT number: 2012-004025-24. . 
 

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13 
TRIAL MONITORING 
13.1 Risk Assessment 
In accordance with the LCTU Standard Operating Procedure a risk assessment has 
been completed in partnership with: 
 
Representatives of the Trial Sponsors (University of Liverpool and Royal 
Liverpool and Broadgreen University Hospital NHS Trust) 
 
Chief Investigator 
 
Trial Coordinator 
 
Trial Statistician  
 
 LCTU Operational Director 
 
In conducting this risk assessment, the contributors considered potential patient, 
organisational and trial hazards, the likelihood of their occurrence and resulting impact 
should they occur. 
 
The outcome of the risk assessment is assigned according to the following categories: 
 
 
Type A: no higher than that of standard medical care 
 
Type B: somewhat higher than that of standard medical care 
 
Type C: markedly higher than that of standard medical care 
 
Following risk assessment this trial is considered to be Type A.  
 
13.2 Source Documents 
Source Data  
Source data are all information, original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of the 
trial. Source data are contained in source documents (original records or certified 
copies). (ICH E6, 1.51).  
 
Source Documents  
Original documents and data records include: hospital records, clinical and office 
charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records 
kept at the pharmacy and laboratory departments involved in the clinical trial (ICH E6, 
1.52). 
 
In order to resolve possible discrepancies between information appearing in the CRF 
and any other patient related documents, it is important to know what constitutes the 
source document and therefore the source data for all information in the CRF. Data 
recorded in the CRF should be consistent and verifiable with source data in source 
documents other than the CRF (e.g. medical record, laboratory reports and nurses’ 
notes). Each participating site should maintain appropriate medical and research 
records for this trial, in compliance with ICH E6 GCP, Section 4.9 and regulatory and 
institutional requirements for the protection of confidentiality of subjects.  
 

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For data where no prior record exists and which are recorded directly in the CRF (e.g. 
inclusion/exclusion criteria, adverse events and Quality of life questionnaires), the CRF 
will be considered the source document, unless otherwise indicated by the 
investigator.  
 
In addition to the above, date(s) of conducting informed consent including date of 
provision of patient information, registration number, trial treatment and the fact that 
the patient is participating in a clinical trial should be added to the patient’s medical 
record contemporaneously.  
13.3 Data Capture Methods 
Trial data will be captured using paper case report forms (CRFs). 
13.3.1 Case Report Forms 
The trial CRF is the primary data collection instrument for the trial.  All data requested 
on the CRF must be recorded.  All missing data must be explained.  If a space on the 
CRF is left blank because the procedure was not done or the question was not asked, 
write “N/D”.  If the item is not applicable to the individual case, write “N/A”.  All entries 
should be printed legibly in black ink.  If any entry error has been made, to correct such 
an error, draw a single straight line through the incorrect entry and enter the correct 
data above it.  All such changes must be initialled and dated.  DO NOT ERASE OR 
WHITE OUT ERRORS.  For clarification of illegible or uncertain entries, print the 
clarification above the item, then initial and date it. 
 
CRFs will be available for download from the LCTU website http://www.lctu.org.uk.    
To ensure current versions of CRFs are used, please print pages directly from the 
LCTU website as and when they are needed. 
13.4 Monitoring at LCTU 
13.4.1 Green Light Process 
 
The Green Light Process in place at the LCTU means that no patients can be 
registered at a particular site without the green light having been given. It ensures that 
all approvals must be in place, all contracts/agreements signed and all trial-specific 
and ICH GCP training received by site research staff before patients can enter the trial.  
 
13.4.2 Site Research Staff 
 
All site research staff involved in the trial must be included on the delegation log. The 
PI at each site signs off on the delegation log only those staff members he/she feels 
are able and competent to complete the assigned tasks. The delegation log provides 
clearly defined delegation of responsibility thus ensuring site research staff are aware 
of their responsibilities, and is continuously checked (as part of the data management 
plan) against staff named on CRFs, SAE reports and registration forms.  
 
The TC ensures that as a minimum the PI, a research nurse, and a member of 
pharmacy staff at site have trial-specific training (on the protocol, SAE reporting and 
consent process) all of which is provided at site initiation (either on site or by 
teleconference) by the TC. The PI is responsible for ensuring site staff named on the 

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delegation log but not present at site initiation receive trial-specific training (on the 
protocol, SAE reporting and consent process). Sites are supplied with copies of training 
aids presented at site initiation to provide a constant reminder of key trial issues. 
Delegated site research staff must also submit their CV and provide the date of their 
last ICH GCP training. In order to ensure that site research staff maintain up to date 
ICH GCP training (to be renewed every 2 years as suggested by ICH GCP), an 
automated email reminder is sent to site research staff when their next ICH GCP 
training is due. Non-NHS staff must have honorary NHS contracts.  
 
Automated 6-monthly email reminders (from site opening) are sent to sites requesting 
that an updated delegation log is faxed to LCTU. On receipt of updated delegation 
logs, the TC ensures that new staff members have submitted their CVs and date of 
last ICH GCP training.  
 
 
13.4.3 Oversight Committees 
 
The ISDMC is an independent multidisciplinary group that, collectively, have 
experience in haematological oncology and in the conduct of clinical trials. It is 
responsible for safeguarding the interests of trial participants, assessing the safety and 
efficacy of the interventions during the trial and for monitoring the overall progress and 
conduct of the clinical trial.  See section 16 for further details. 
 
The TSC includes an independent Chairman and others, plus members of the Trial 
Management Group (TMG). Among other things, the TSC takes responsibility for 
monitoring and supervising the progress of the trial, considering recommendations 
from the ISDMC and advising the TMG on all aspects of the trial.  See section 16 for 
further details. 
 
13.4.4 Safety Reports 
 
Monthly safety reports are generated by the TC which allows monitoring of SAE 
reporting rates across sites. The ISDMC also regularly review adverse event reporting, 
and the TC prepares Annual Safety Reports for submission to the MHRA and research 
ethics committee. Any concerns raised by the ISDMC or inconsistencies noted at a 
given site may prompt additional training at sites, with the potential for the TC to carry 
out site visits if there is suspicion of unreported SAEs in patient case notes. Additional 
training will also be provided if unacceptable delay in safety reporting timelines (as 
outlined in the pharmacovigilance plan) is noted at a given site. 
 
13.4.5 Registration 
 
The TC verifies that all site research staff attended trial-specific training relating to 
eligibility screening and the informed consent, and registration processes. Prior to 
registration, the TC/data manager (DM) carry out a check of all consent forms sent to 
the LCTU. This includes checking that the patient is eligible, the correct versions of the 
PIS and Patient Informed Consent (PIC) forms have been used and the patient and 
clinician signatures are present and dated on the same day.  
 

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When registering a new patient, the computerised program used for registration 
protects against errors by its inbuilt validation checks on site green light status, patient 
eligibility and informed consent. The trial statistician checks at intervals over the course 
of the recruitment period to confirm that the registration dates of consecutive 
registration numbers are in the correct order and that there are no missing 
registrations. The dates and outcome of these checks are specified on the registration 
checklist form to coincide with ISDMC meetings. 
 
LCTU staff members receive appropriate registration training and there is always office 
cover to ensure the registration procedures are carried out correctly. The TC maintains 
a record of registration errors and notifies the trial statistician as they occur. 
Registration problems are monitored by the ISDMC, and if it is noted that a particular 
site is making consistent errors in the consent or registration processes, additional 
training will be provided by the TC to rectify the problem. 
 
 
13.4.6 Patient Confidentiality 
 
All LCTU and site research staff members have received ICH GCP training and are 
thus aware of the importance of patient confidentiality. The TC/DM consistently check 
that the CRFs sent to LCTU are all anonymised and are identifiable only by registration 
number (except for signed consent forms, which are stored in a locked cabinet in the 
LCTU). The TC will monitor site performance on maintaining patient confidentiality and 
will provide additional training if a particular site sends any patient identifiers to LCTU 
(other than on the signed consent form). 
 
13.4.7 Recruitment 
 
The TC will produce monthly recruitment reports, to allow the ISDMC, TSC and TMG 
to regularly review recruitment across sites. Slow or inconsistent recruitment will trigger 
further action centrally.  The TC may liaise directly with site staff in order to query 
reasons for slow recruitment and try to resolve any problems that could impact 
recruitment. The TC will check that the trial is being actively promoted at sites, and site 
recruitment schedules will be reviewed during the course of the trial as necessary. 
 
13.4.8 Protocol violations/deviations 
 
All protocol violations and deviations are recorded by the TC in the trial site status 
database, and are included in the regular ISDMC reports. The TC sends details of all 
protocol violations and deviations to the CI as soon as the LCTU is made aware of 
such occurrences, and any that are considered to be a potential serious breach would 
be forwarded immediately to the Co-sponsors. If it is noted that a particular site is 
making consistent protocol violations or deviations, additional training will be provided 
by the TC. 
 
13.4.9 Withdrawals, losses to follow up and missing data 
 
The TC will produce reports on withdrawals, losses to follow-up and the quantity of 
missing CRFs/data across sites for review by the LCTU business meeting, TMG, TSC 

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and ISDMC. Identified problems will be discussed and remedial action taken as 
necessary. 
 
As outlined in the data management plan, the TC/DM will check that the withdrawal 
CRF is completed for all withdrawn patients (including the reasons for withdrawal). The 
TC will compare withdrawal rates and reasons for withdrawal across centres, paying 
particular attention to withdrawals close to dates of registration. If a certain site 
experiences an excessive rate of withdrawals, additional training on the informed 
consent procedure will be provided.  
 
13.4.10 
Data management plan 
 
CRF data entered into the MACRO database will be centrally monitored by the LCTU 
to ensure that data collected are consistent with adherence to the trial protocol. The 
MACRO database used for this trial includes validation features which will alert the 
user to certain inconsistent or missing data on data entry. If any problems are identified 
via automated validation or central monitoring, a query is raised within the MACRO 
database and emailed to site. A complete log of discrepancies and data amendments 
is automatically generated by MACRO, including the date of each change, the reason 
for the change and the person who made the change, thus providing a complete audit 
trail. Automated email reminders are generated by the database if follow up data from 
a scheduled patient visit is overdue. 
 
Additional site training will be carried out if recurring problems are noted with data from 
a certain site, such as consistently incorrect or incomplete data, a backlog of 
unresolved queries, or unacceptable time delays in submitting CRFs. 
 
13.4.11 
LCTU staff 
All LCTU staff will receive regular ICH GCP training, have in-house training records 
and undergo regular Individual Performance Review (IPR) sessions, all of which are 
used to ensure that appropriate training is received and any problems identified and 
resolved in a timely fashion. 
13.5 Clinical Site Monitoring 
13.5.1 Direct access to data 
Site monitoring may be deemed to be necessary as a result of central data checks. In 
order to perform their role effectively, monitors and persons involved in Quality 
Assurance and Inspection will need direct access to primary subject data, e.g. patient 
records, laboratory reports, appointment books, etc. Each PI therefore permits trial 
related monitoring, audits, ethics committee review and regulatory inspections by 
providing direct access to source data/documents. As this also affects the patient’s 
confidentiality, this fact is included on the Patient Information Sheet and Informed 
Consent Form 
13.5.2 Confidentiality 
Individual participant medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited. Case report forms will be 
labelled with patient initials and unique trial registration number. Samples will be 
transferred to the Universities of Glasgow and Imperial College London, Hammersmith 

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Hospital, and will be identifiable by unique trial registration number only. Consent forms 
sent to the LCTU as part of the registration process may contain patient identifiers for 
the purpose of monitoring as described in the trial risk assessment. Such information 
will be stored within the patient folders in secure, locked cabinets. 
 
 
13.5.3 Quality Assurance and Quality Control of Data 
Systems of quality assurance, including all elements described in this protocol have 
been/will be implemented within relevant institutions with responsibility for this trial. 
Quality control is applied to each stage of data handling to ensure that data are 
accurate, reliable and processed correctly. 
The DESTINY Investigational sites, facilities, laboratories and all data (including 
sources) and documentation must be available for GCP audit and inspection by 
competent authorities or IEC.  Such audits/inspections may take place at any site 
where trial related activity is taking place (the Sponsor’s site(s), the LCTU or at any 
investigator’s site including laboratories, pharmacies etc.) 
The site staff should assist in all aspects of audit/inspection and be fully cognisant of 
the LCTU communication strategy for multicentre trials. This includes management 
systems for the green light process prior to site opening, conforming to the total Quality 
Management System currently operating within the LCTU. 
13.6 Records Retention 
The investigator at each investigational site must make arrangements to store the 
essential trial documents, (as defined in Essential Documents for the Conduct of a 
Clinical Trial (ICH E6, Guideline for Good Clinical Practice)) including the Investigator 
Trial File, until the LCTU informs the investigator that the documents are no longer to 
be retained. 
 
In addition, the investigator is responsible for archiving of all relevant source 
documents so that the trial data can be compared against source data after completion 
of the trial (e.g. in case of inspection from authorities). The investigator is required to 
ensure the continued storage of the documents, even if the investigator, for example, 
leaves the clinic/practice or retires before the end of required storage period. 
Delegation must be documented in writing. 
 
The LCTU undertakes to store originally completed CRFs and separate copies of the 
above documents for the same period, except for source documents pertaining to the 
individual investigational site, which are kept by the investigator only. 
 
Essential documents should be retained until at least 2 years after last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the Investigational Product. These 
documents should be retained for a longer period however if required by applicable 
regulatory requirements or by an agreement with the Sponsor. It is the responsibility of 
the Sponsor to inform the investigator/institution as to when these documents no longer 
need to be retained. 
  
Verification of appropriate informed consent will be enabled by the provision of copies 
of participants’ signed informed consent/assent forms being supplied to the LCTU by 
recruiting centres.  This requires that name data will be transferred to the LCTU, which 

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is explained in the PISC. The LCTU will preserve the confidentiality of participants 
taking part in the trial and the University of Liverpool is a Data Controller registered 
with the Information Commissioners Office. 
 
 

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14 
INDEMNITY 
DESTINY is jointly sponsored by The Royal Liverpool & Broadgreen University 
Hospital NHS Trust and the University of Liverpool, and will be co-ordinated by the 
LCTU in the University of Liverpool. The Royal Liverpool & Broadgreen University 
Hospital NHS Trust and the University of Liverpool do not hold insurance against 
claims for compensation for injury caused by participation in a clinical trial and they 
cannot offer any indemnity. As this is an investigator-initiated trial, The Association of 
the British Pharmaceutical Industry (ABPI) guidelines for patient compensation by the 
pharmaceutical industry do not apply. However, in terms of liability: NHS Trust and 
Non-Trust Hospitals have a duty of care to patients treated, whether or not the patient 
is taking part in a clinical trial, and they are legally liable for the negligent acts and 
omission of their employees. Compensation is therefore available in the event of 
clinical negligence being proven. The Royal Liverpool & Broadgreen University 
Hospital NHS Trust and the University of Liverpool does not accept liability for any 
breach in any other hospital’s duty of care, or any negligence on the part of employees 
of hospitals. This applies whether the hospital is an NHS Trust or not. 
 
Clinical negligence is defined as: 
“A breach of duty of care by members of the health care professions employed by NHS 
bodies or by others consequent on decisions or judgments made by members of those 
professions acting in their professional capacity in the course of their employment, and 
which are admitted as negligent by the employer or are determined as such through 
the legal process”. 
 
The University of Liverpool has vicarious liability for the actions of its staff, when 
through the course of their employment they are involved in the design and initiation 
of a clinical trial, including but not limited to the authorship of the Clinical Trial Protocol. 
The University of Liverpool has appropriate insurance in place to cover this liability. 

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FINANCIAL ARRANGEMENTS 
This is a non-commercial trial, and no direct payments are available to cover the costs 
associated with patient recruitment, treatment administration, follow-up visits, data 
collection or travel expenses. The trial has been funded and approved by the 
Leukaemia and Lymphoma Research Clinical Trials Committee and is therefore 
automatically adopted by the National Cancer Research Network (NCRN) and UK 
Clinical Research Network (UKCRN). These organisations will be responsible for 
providing local investigators with the necessary research infrastructure 
 

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16 
TRIAL OVERSIGHT COMMITTEES 
16.1 Trial Management Group (TMG) 
The Trial Management Group (TMG) comprises the Chief Investigator, Co-
Investigators, Health Economist, Trial Statistician and the LCTU trial team; as well as 
representatives from both of the Co-Sponsors and LCTU Operational Director. 
 
The TMG will be responsible for the day-to-day running and management of the trial 
and will meet at least three times per year. 
16.2 Trial Steering Committee (TSC) 
The composition of the TSC is as follows.  Membership details are available from the 
Trial Coordinator. 
 
Chairman  
Chief Investigator 
Research Nurse with CML experience  
Consultant Haematologist (current or retired) with CML experience x 3 
Statistician  
Patient representatives x 2 
Trial Statistician 
Trial Coordinator 
 
The role of the TSC is to provide overall supervision for the trial and provide advice 
through its independent Chairman. The ultimate decision for the continuation of the 
trial lies with the TSC. 
16.3 Independent Data and Safety Monitoring Committee 
(IDSMC) 
The composition of the ISDMC is as follows.  Membership details are available from 
the Trial Coordinator. 
 
Chairman  
Statistician  
Clinician  
 
The Chief Investigator, Trial Statistician and Trial Co-ordinator will also be invited to 
attend ISDMC meetings. 
 
The ISDMC will be responsible for reviewing and assessing recruitment, interim 
monitoring of safety and effectiveness, trial conduct and external data.  The ISDMC 
will define frequency of subsequent meetings (at least annually). Details of the interim 
analysis and monitoring are provided in section 9. 
 
The ISDMC will provide a recommendation to the Trial Steering Committee concerning 
the continuation of the trial. 

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17 
PUBLICATION 
The results from different centres will be analysed together and published as soon as 
possible. Individual clinicians must undertake not to submit any part of their individual 
data for publication without the prior consent of the Trial Management Group. 
 
The Trial Management Group will form the basis of the Writing Committee and advise 
on the nature of publications. The Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals (http://www.icmje.org/) will be respected. All publications shall 
include a list of participants, and the named authors should include the trial’s Chief 
Investigator, Statistician(s) and Trial Manager(s) involved. The ISRCTN allocated to 
this trial should be attached to any publications resulting from this trial. 
 
The members of the TSC and IDSMC should be listed with their affiliations in the 
Acknowledgements/Appendix of the main publication. 
 

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18 
PROTOCOL AMENDMENTS 
18.1 Version 1 (21 March 2013) 
Original Approved version. 
 
 
18.2 Version 2 (03 February 2014) 
 
Changes from protocol version 1 
 
Main changes 
Inclusion Criteria (sections  1 & 5) 
 
Clarification that reporting of molecular results should be to International Standard 
where possible.  This clarification is also reflected throughout the protocol. 
 
Clarification that potential patients without a standard BCR-ABL1 fusion transcript 
only may be eligible to participate. 
Exclusion Criteria (sections 1 & 5) 
 
The criterion that excludes patients with previous higher than standard dose has 
been modified to include an exception to allow higher dose patients that 
participated in specific studies to be included as they do not demonstrate resistant 
disease. 
 
Clarification that patients who are already being treated with lower doses for 
tolerance reasons are allowed, providing their current dosage it at least 50% of the 
defined standard dose. 
 
Running order of exclusion criteria changed as result of the changes to allow a better 
reading ‘flow’.  
Overall Design (section 4.1) 
 
Clarification that samples should continue to be collected for relapsed patients until 
the molecular result at study entry is regained. 
Primary Endpoint (section 4.2) 
 
Rewording for clarity of the primary endpoint.   
 
The line on there being no routine marrow examinations removed. 
Samples (section 6.3) 
 
This section has been updated so only patients recruited and treated at the Royal 
Liverpool Hospital are requested to provide blood samples for sending to the 
Liverpool labs.  This is also reflected throughout the protocol. 
 
Sample collection time-points clarified and receptacles to be used, plus kits that are 
provided have been updated; contact details for the labs have also been added.   
 
Additional samples from diagnostic blood tests being sent to Hammersmith has been 
updated to include all patients, rather than just those from the MR4 group, and 
clarified in the samples table. 
Accountability Procedures for Trial Treatment (section 7.2) 

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 
This section has been re-written to confirm that the Trial is a ‘Type A’ and that no 
accountability is required. 
 
Confirmation that other treatment supply practices (e.g. community pharmacy, 
homecare provider) are allowed if the PI approves. 
Schedule of Trial Procedures (section 8.1) 
 
Updated so procedures are indicated by individual month, rather than grouping 
months together. 
 
Confirmation that ‘after relapse’ procedures only need to be undertaken until 
molecular status at original trial entry is restored. 
 
Inclusion of the previously omitted combined patient drug diary and disease 
symptom record (see section 8.2.3 also). 
Planned assessments during ‘stopping’ follow-up phase (13-37 months) (section 8.1.4) 
 
Post month 37 PCR results (i.e. local) also being required has been added to this 
section. 
Trial closure (section 8.7) 
 
Confirmation that enrolment to each molecular group will cease when its required 
number is reached added. 
Pharmacovigilance (section 10) 
 
Confirmation that CTCAE v4 is being used to grade SAEs and advice provided on how 
to grade should the event not be listed in said version. 
 
Elaboration on the difference between severe and serious events added. 
 
Location of downloadable SAE forms in case of database unavailability clarified 
(section 10.2). 
 
Minimum dataset for preliminary report updated (section 10.7.1). 
 
Minor/administrative changes 
 
Clarification that the patient diary will also be used to collect information on 
patients’ symptoms (section 7.3). 
 
Time-points on when screening and baseline assessments need to be performed 
have been added (sections 8.1.1 & 8.1.2). 
 
Composition of oversight committees deleted from section 13.4.3 as it’s covered in 
section 16 
 
References to ‘start of treatment’ (or similar) replaced with ‘commencement of de-
escalation’ (or similar). 
 
Clarification that eligibility procedures need to be completed within certain 
timeframes of the commencement of de-escalation and not entry to the trial. 
 
Terminology for an extra blood test to confirm molecular relapse changed to 
‘Hammersmith Alert’. 
 
Number of sites increased. 
 
Other miscellaneous admin changes 
 

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18.3 Version 3 (18 December 2014) 
 
Changes from protocol version 2  
 
Main changes  
 
Molecular Grouping  
 
Deletion of statement ‘Enrolment to each molecular group will cease once the 
required number of patients for that particular group has been reached.’ Deleted 
from section 8.7.  
 
Reference to 2 equal groups of 84 MMR and MR4 patients removed throughout and 
replaced with 1 group of 168 MMR and MR4.  
 
18.4 Version 4 (16 January 2015) 
 
Changes from protocol version 3 
 
Main changes 
Throughout 
 
Clarification that the central analysis definition of MMR is a BCR-ABL1/ABL1 ratio of 
≤0.1% to International Standards (IS) 
 
Clarification that samples should continue to be collected for relapsed patients until 
MMR is regained 
Contact details 
 
Addition of extra medical expert who will assess SAE reports 
Protocol summary (section 1) 
 
Exclusion criterion 9 expanded to cover prior use of interferon 
 
‘Objectives’ renamed ‘Outcomes’ and the secondary outcomes expanded 
Overall design (section 4.1) 
 
Clarification that the study is a phase IIb 
Secondary endpoints (section 4.3) 
 
List expanded 
Trial population (section 5) 
 
Duplicated inclusion and exclusion criteria replaced with instruction to refer to the 
same in the protocol summary.  Section numbering altered as a result. 
Enrolment/Baseline (section 6.2) 
 
Updated to allow emailed registrations.     
Samples required (section 6.3.1) 
 
Quantity of marrow tissue required updated to 1-2ml in table 1 to be consistent with 
rest of section 

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 
Clarification that month 37 or relapse marrow samples should still be requested 
even if a baseline one wasn’t available, and that the quantity of marrow should be 
taken according to local practice 
Accountability procedures for Trial Treatment (section 7.2) 
 
Section re-worded for clarity and reference to ‘Type A’ trial removed as this is 
covered in the risk assessment section of the protocol. 
Assessments and procedures (section 8) 
 
Clarified throughout that molecular monitoring is reported to international 
standards and not just where possible, and that samples should continue to be 
collected for relapsed patients until MMR is regained 
Schedule of trial procedures (section 8.1) 
 
Table 3 updated to include Hammersmith alert procedures and weight 
measurement requirement at all post screening visits 
 
Baseline marrow window extended to 1 calendar month prior to the 
commencement of de-escalation 
 
Table legend updated accordingly 
Planned assessment at relapse (section 8.1.5) 
 
Addition to clarify that baseline samples are not included in the establishing of 
relapse 
Statistical introduction (section 9.1) 
 
Updated to include the reclassification of MR4 patients for statistical analysis 
purposes, plus rationale of same 
Secondary endpoints (section 9.2.2) 
 
Secondary endpoints expanded and confirmation that they will be calculated 
separately for each molecular group added 
Sample size (section 9.3) 
 
Section completely updated to reflect the changes to the molecular grouping  
Interim monitoring analyses (section 9.4) 
 
Triggers for interim analyses updated and addition that such results are confidential 
to ISDMC members only 
Analysis plan (section 9.5) 
 
Reporting to ‘CONSORT’ guidelines added 
 
Use of Kaplan and Meier and cumulative incidence analysis methods for stipulated 
estimations added  
Pharmacovigilance (section 10) 
 
Definitions of SAE expanded 
 
Erroneous use of grading to WHO toxicity criteria removed 
 
Online reporting instructions replaced with those for paper reporting 
Risk assessment (section 13.1) 
 
Low/moderate/high risk categories replaced with Type A/B/C. 
 
Minor/administrative changes 

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Throughout 
 
Updates to contact details and grammatical errors 
 
18.5 Version 5 (04 July 2016) 
 
Changes from Protocol V4 
 
Protocol summary (section 1) 
 
Update to diagram (wording) 
 
Overall design (section 4.1) 
 
Change to wording in Paragraph 4 
 
Schedule of trial procedures (section 8.1) 
 
Table 3 updated to include Relapse procedures  
 
18.6 Version 6 (22 March 2017) 
 
Changes from Protocol V5 
 
Protocol summary (section 1) 
 
Update to diagram (spelling) 
 
Schedule of trial Procedures (section 8.1) 
 
Removal of requirement for Bone Marrow at Month 37 
 
Removal of 30mls blood for Liverpool patients at Month 37 
 
Addition of follow up for patients after Month 37 
 
Update to Reference Safety Information (section 10.5) 
 
Correction to references to Reference Safety Information 
 
 
18.7 Version 7 (24 May 2018) 
Changes from protocol V6 
 
Removal of secondary end point: 
Proportion of patients who develop a BCR-ABL1 kinase domain mutation at a level of >20% of 
all BCR-ABL1 transcripts on at least 2 consecutive occasions  
 
Contact details: 
Update to study statistician 
 

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Updates to Trial Treatment (Section 7) 
Updated references to SmPCs.  Clarified processes for non-protocol dosing.  Removed wording 
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19 
REFERENCES 
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