Conditions: Adult Solid Tumor Diffuse Large B Cell Lymphoma Burkitt Lymphoma
Keywords: Phase I Cancer Solid Tumours Diffuse Large B Cell Lymphoma Monocarboxylate Transporter 1 Inhibitor lactate Burkitt Lymphoma
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 53
Healthy volunteers: no

Brief summary:
The main aims of this clinical study are to find out the maximum dose that can be given safely to patients, the potential side effects of the drug and how they can be managed and what happens to AZD3965 inside the body.

AZD3965 is a type of drug called a monocarboxylate transporter 1 inhibitor which is being used to stop the growth of cancer cells and kill cancer cells by blocking the action of one of the proteins involved in moving chemical compounds in and out of the cells of the body. This will be the first time that this type of drug has been given to patients.

The drug is a capsule and is taken daily. The study is in two parts. In Part 1 of the study, small groups of patients are treated at increasing doses to find the highest safe dose and best dose to give to patients in Part 2 of the study. It is planned that 40 patients will be entered into Part 1 of the trial.

In Part 2, the dose found to be safe in Part 1 is given to patients with diffuse large B-cell lymphoma (DLBCL) and Burkitt's lymphoma (BL). It is planned that 20 patients will be entered into Part 2 of the trial.

Patients will need to visit the hospital weekly for two months and then every fortnight. Patients will have regular blood and urine tests, scans, heart traces and eye tests amongst other clinical tests. Research blood samples will also be taken to look at what happens to the drug inside the body. Treatment is planned to be given for up to 6 months, but patients benefiting from treatment will be able to keep having it for as long as they continue to benefit. It is important to explain that this is the first study of this drug and patients will have advanced cancer so it is unlikely that patients will benefit directly from taking part but the study may help improve future treatment of cancer.

Detailed description:
Part 1 follows a rolling six dose escalation schedule of AZD3965 given once daily (OD) or twice daily (BD) until the maximum tolerated dose (MTD) is defined.

The recommended Phase II dose (RP2D) is based on the safety and pharmacokinetic (PK) results from Part 1.

All patients in Part 2 are treated at this RP2D to further explore the tolerability of this dose and schedule and to explore proof of principle of MCT1 inhibition in tumour types that were shown to express MCT1 and in which AZD3965 showed some effect pre-clinically (DLBCL and BL).

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None arm 7: None

Interventions: intervention 1: AZD3965 intervention 2: AZD3965 intervention 3: AZD3965 intervention 4: AZD3965 intervention 5: AZD3965 intervention 6: AZD3965 intervention 7: AZD3965
Intervention descriptions: intervention 1: Day -7: single dose of 5 mg AZD3965 orally prior to start of continuous treatment.

Cycle 1, Day 1: commenced dosing of 5 mg AZD3965 OD orally for up to 6 28-day cycles.

Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor. intervention 2: Day -7: single dose of 10 mg AZD3965 orally prior to start of continuous treatment.

Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 OD orally for up to 6 28-day cycles.

Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor. intervention 3: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment.

Cycle 1, Day 1: commenced dosing of 20 mg AZD3965 OD orally for up to 6 28-day cycles.

Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor. intervention 4: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment.

Cycle 1, Day 1: commenced dosing of 30 mg AZD3965 OD orally for up to 6 28-day cycles.

Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor. intervention 5: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment.

Cycle 1, Day 1: commenced dosing of 15 mg AZD3965 BD orally for up to 6 28-day cycles.

Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor. intervention 6: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment.

Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles.

Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor. intervention 7: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment (first 3 trial participants in the Expansion Cohort only; subsequent patients started treatment at Cycle 1, Day 1).

Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles.

Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.

Protocol document:
Prot_000.pdf: 
ClinicalTrials.gov 
Document Cover Page 
ClinicalTrials.gov Upload Document Cover Page 
NCT Number 
EudraCT Number 
Sponsor Protocol Number 
Official Title 
Document, Version & Date 
NCT No.: NCT01791595 
Protocol No.: CRUKD/12/004 
NCT0l 791595 
2010-024463-41 
CRUKD/12/004 
A Cancer Research UK Phase I trial of AZD3965, a monocarboxylate 
transporter 1 inhibitor (MCTl) in patients with advanced cancer 
Protocol Version 14.0 dated 04Feb2020 
Version 14.0 04Feb2020 


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©Cancer Research UK 
 
 
 
 
 
 
CANCER RESEARCH UK 
Centre for Drug Development 
 
A Cancer Research UK Phase I trial of AZD3965, a 
monocarboxylate transporter 1 inhibitor (MCT1) in 
patients with advanced cancer 
 
Sponsor protocol number: 
CRUKD/12/004 
 
EudraCT number:  
2010-024463-41 
 
 
Chief Investigator: 
Professor Elizabeth Ruth Plummer   
Director of Sir Bobby Robson Cancer Trials Research Centre  
  
 
  
 
 
 
 
 
 
 
 
 
Sponsor: 
Cancer Research UK 
 
 
 
 
 
 
 
 
 
 
 
 
 
 










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TABLE OF CONTENTS 
 
 
 
 
 
TITLE PAGE 
 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
PROTOCOL SIGNATURES 
 
1 
PROTOCOL SUMMARY ......................................................................................................... 15 
1.1 
Full title ..................................................................................................................................... 15 
1.1.1 
Short title .................................................................................................................................. 15 
1.2 
Clinical trial objectives and endpoints ...................................................................................... 15 
1.2.1 
Primary objectives and endpoints ............................................................................................ 15 
1.2.2 
Secondary objectives and endpoints ....................................................................................... 15 
1.2.3 
Tertiary objectives and endpoints ............................................................................................ 16 
1.3 
Design ...................................................................................................................................... 16 
1.4 
Administration schedule ........................................................................................................... 16 
1.5 
Treatment group ....................................................................................................................... 17 
1.6 
Trial timelines ........................................................................................................................... 17 
2 
INTRODUCTION ...................................................................................................................... 18 
2.1 
Background .............................................................................................................................. 18 
2.1.1 
Monocarboxylate transporter 1 (MCT1) and Cancer ............................................................... 18 
2.2 
Investigational medicinal product ............................................................................................. 19 
2.2.1 
Structure of AZD3965 .............................................................................................................. 19 
2.2.2 
Mechanism of action of AZD3965 ............................................................................................ 19 
2.2.3 
Non-clinical pharmacology ....................................................................................................... 19 
2.2.4 
Safety pharmacology ............................................................................................................... 20 
2.2.5 
Pharmacokinetics and metabolism .......................................................................................... 21 
2.2.6 
Toxicology ................................................................................................................................ 22 
2.2.7 
Starting dose for Phase I and dose escalation considerations ................................................ 25 
2.2.8 
Starting dose ............................................................................................................................ 25 
2.2.9 
Maximum Exposure ................................................................................................................. 26 
2.3 
Clinical experience ................................................................................................................... 26 
2.4 
Rationale for the proposed trial ................................................................................................ 26 
3 
TRIAL DESIGN ........................................................................................................................ 27 
3.1 
Clinical trial objectives and endpoints ...................................................................................... 27 
3.1.1 
Primary objectives and endpoints ............................................................................................ 27 
3.1.2 
Secondary objectives and endpoints ....................................................................................... 27 
3.1.3 
Tertiary objectives and endpoints ............................................................................................ 28 
3.1.4 
Definition of dose limiting toxicity ............................................................................................. 28 
3.1.5 
Definition of maximum tolerated dose ...................................................................................... 30 
3.2 
Patient evaluability ................................................................................................................... 30 
3.3 
Design of the clinical trial ......................................................................................................... 30 
4 
PATIENT SELECTION ............................................................................................................ 32 
4.1 
Eligibility criteria........................................................................................................................ 32 
4.1.1 
Inclusion criteria: ...................................................................................................................... 32 
4.1.2 
Exclusion criteria: ..................................................................................................................... 34 
4.2 
Patient enrolment ..................................................................................................................... 35 
5 
TREATMENT ........................................................................................................................... 35 
5.1 
Selection of the Phase I starting dose and schedule (Part 1) .................................................. 35 
5.2 
Maximum Exposure Limit ......................................................................................................... 35 
5.3 
Dosing schedule/treatment schedule (Parts 1 and 2) .............................................................. 36 
5.4 
Dose escalation scheme (Part 1) ............................................................................................. 36 


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5.4.1 
Intra-patient dose escalations .................................................................................................. 37 
5.4.2 
Expansion of dose level(s) ....................................................................................................... 37 
5.5 
Dose modifications ................................................................................................................... 37 
5.5.1 
Dose withdrawal ....................................................................................................................... 37 
5.5.2 
Dose reductions ....................................................................................................................... 38 
5.5.3 
Dose delays .............................................................................................................................. 38 
5.6 
Missed Doses ........................................................................................................................... 38 
5.7 
Duration of treatment ............................................................................................................... 38 
5.7.1 
Replacement of patients .......................................................................................................... 39 
5.8 
Concomitant medication and treatment ................................................................................... 39 
6 
PHARMACEUTICAL INFORMATION ..................................................................................... 40 
6.1 
Supply of AZD3965 .................................................................................................................. 40 
6.2 
Pharmaceutical data ................................................................................................................ 40 
6.2.1 
Formulation of AZD3965 .......................................................................................................... 40 
6.2.2 
Storage conditions ................................................................................................................... 41 
6.2.3 
Stability of AZD3965 ................................................................................................................ 41 
6.2.4 
Dispensing of AZD3965 ........................................................................................................... 41 
6.2.5 
AZD3965 administration ........................................................................................................... 41 
6.3 
AZD3965 accountability ........................................................................................................... 42 
7 
INVESTIGATIONS SCHEDULE FOR PART 1 OF THE STUDY ............................................ 43 
8 
INVESTIGATIONS SCHEDULE FOR PART 2 OF THE STUDY ............................................ 44 
8.1 
Pre-treatment evaluations ........................................................................................................ 44 
8.1.1 
Obtaining written informed consent ......................................................................................... 44 
8.1.2 
Pre-screening ........................................................................................................................... 45 
8.1.3 
Evaluations within four weeks prior to first dose (Day -28 to Day -1) ...................................... 45 
8.1.4 
Evaluations within two weeks prior to first dose (Day -14 to Day -1) ....................................... 45 
8.1.5 
Evaluations within one week prior to first dose (Day -7 to Day -1) .......................................... 46 
8.2 
Evaluations on Cycle 1 Day 1 (+/- 24 hours) ........................................................................... 46 
8.3 
Evaluations at 24 hours (± 2 hours) after the first dose of AZD3965 treatment ...................... 47 
8.4 
Evaluations during continuous AZD3965 treatment Cycles 1–12 (excluding Cycle 1 Day 1) . 47 
8.5 
Evaluations from Cycle 13 onwards ......................................................................................... 48 
8.6 
Evaluations at ‘Off-Study’ visit .................................................................................................. 50 
8.7 
Follow-up .................................................................................................................................. 50 
8.8 
Schedule of events for Part 2 (Cycles 1-12) of the study ........................................................ 51 
8.8.1 
Schedule of events for Part 2, Cycle 13 onwards .................................................................... 53 
9 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS ................................. 54 
9.1 
Part 1 Sampling summary ........................................................................................................ 54 
9.2 
Part 2 Sampling summary ........................................................................................................ 55 
9.3 
Primary assay – Pharmacodynamic - Lactate accumulation in PBMCs (Part 1 only) ............. 57 
9.4 
Secondary assays .................................................................................................................... 57 
9.4.1 
Secondary Assays - AZD3965 Pharmacokinetics ................................................................... 57 
9.4.2 
Secondary assays – Pharmacodynamics - Cell Death Biomarkers (M65, M30, nDNA) (Part 1 
only) .......................................................................................................................................... 57 
9.5 
Tertiary/research assays .......................................................................................................... 57 
 
 
 
 
 
 
 
 
 
 
 
9.6 
Storage and Shipment of Samples .......................................................................................... 61 
10 
ASSESSMENT OF SAFETY ................................................................................................... 61 
10.1 
Investigator responsibilities ...................................................................................................... 61 
10.1.1 Medical cover ........................................................................................................................... 61 


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10.2 
Adverse event definitions ......................................................................................................... 61 
10.2.1 Adverse event .......................................................................................................................... 61 
10.2.2 Serious adverse events ............................................................................................................ 61 
10.2.3 Suspected, unexpected, serious adverse reactions ................................................................ 62 
10.2.4 Determining adverse event causality ....................................................................................... 62 
10.2.5 Expectedness ........................................................................................................................... 63 
10.3 
Collecting of safety information ................................................................................................ 63 
10.3.1 Pre-Screening .......................................................................................................................... 63 
10.3.2 Screening failures .................................................................................................................... 64 
10.3.3 Eligible patients ........................................................................................................................ 64 
10.3.4 Follow-up of AEs and SAEs ..................................................................................................... 64 
10.3.5 Other safety information of interest .......................................................................................... 64 
10.4 
Reporting of SAEs to the Pharmacovigilance Department, CDD ............................................ 64 
10.4.1 Events exempt from being reported as SAEs to the Pharmacovigilance department ............. 65 
10.5 
Recording of adverse events and serious adverse events in eCRFs ...................................... 65 
10.6 
Urgent safety measures ........................................................................................................... 65 
10.7 
Pregnancy ................................................................................................................................ 65 
11 
ASSESSMENT OF EFFICACY ............................................................................................... 66 
11.1 
Measurement of disease .......................................................................................................... 66 
11.2 
Timing and type of tumour assessments ................................................................................. 66 
11.2.1 Baseline evaluations ................................................................................................................ 67 
11.2.2 Evaluations during and at Off-study visit .................................................................................. 67 
11.3 
Tumour response ..................................................................................................................... 67 
11.3.1 Recording of response in the eCRF ......................................................................................... 68 
11.3.2 Other definitions of outcome .................................................................................................... 68 
12 
PATIENT WITHDRAWAL BEFORE COMPLETION OF TREATMENT SCHEDULE ............ 68 
13 
DEFINING THE END OF TRIAL .............................................................................................. 68 
14 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ................................................. 69 
14.1 
Presentation of data ................................................................................................................. 69 
14.2 
Safety ....................................................................................................................................... 69 
14.3 
Pharmacokinetics ..................................................................................................................... 70 
14.4 
Pharmacodynamics – lactate accumulation in PBMCs (Part 1 only) ....................................... 70 
14.5 
Anti-tumour activity ................................................................................................................... 70 
14.6 
Exploratory work ...................................................................................................................... 70 
15 
ADMINISTRATION .................................................................................................................. 70 
15.1 
Protocol deviations and amendments ...................................................................................... 70 
15.2 
Completion of the electronic case report form (eCRF) ............................................................ 70 
15.3 
Trial performance and monitoring ............................................................................................ 71 
15.4 
Source document verification ................................................................................................... 71 
15.5 
Clinical study report (CSR) ....................................................................................................... 72 
15.6 
Record retention ....................................................................................................................... 72 
15.7 
Ethical considerations .............................................................................................................. 72 
15.8 
Indemnity .................................................................................................................................. 72 
15.9 
Publication policy and press releases ...................................................................................... 72 
16 
REFERENCES ......................................................................................................................... 74 
17 
APPENDICES .......................................................................................................................... 75 
17.1 
APPENDIX 1: WHO PERFORMANCE SCALE ....................................................................... 75 
17.2 
APPENDIX 2A: MEASUREMENT OF DISEASE IN SOLID TUMOURS ................................. 76 
17.3 
APPENDIX 2B: MEASUREMENT OF DISEASE IN LYMPHOMA .......................................... 86 
17.4 
APPENDIX 3: CONCURRENT MEDICATION WITH A KNOWN RISK OF QT PROLONGATION
 
89 
17.5 
APPENDIX 4: MANAGEMENT OF EYE TOXICITY ................................................................ 99 


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17.6 
APPENDIX 5: Severe valvular heart disease (as defined by British Society of 
Echocardiography) ................................................................................................................. 100 








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PROTOCOL SIGNATURES 
 
 
Sponsor Signature 
The Sponsor has read and agrees to the protocol, as detailed in this document. I am aware of my 
responsibilities as the Sponsor under the UK Clinical Trials Regulations1, the guidelines of Good Clinical 
Practice (GCP)2, the Declaration of Helsinki3, the applicable regulations of UK law and the trial protocol. 
The Sponsor agrees to conduct the trial according to these regulations and guidelines and to 
appropriately direct and assist sponsor’s staff who will be involved in the trial, and ensure that all staff 
members are aware of their clinical trial responsibilities. 
 
 
Name: 
 
 
 
 
 
Title 
 
 
 
 
 
Signature: 
 
 
 
 
 
Date: 
 
 
 
 
 
1 The Medicines for Human Use (Clinical Trials) Regulations (S.I. 2004/1031) and any subsequent amendments to it. 
2 ICH Harmonised Guideline Integrated Addendum to ICH E6: Guideline for Good Clinical Practice E6(R2) Step 4 dated 
09 November 2016).  
3 WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects adopted by the 18th WMA 
General Assembly, Helsinki, Finland, June 1964 and all subsequent amendments including Oct 2013. 


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PROTOCOL SIGNATURES 
 
 
Investigator’s Signature 
I have read and agree to the protocol, as detailed in this document. I am aware of my responsibilities as 
an Investigator under the UK Clinical Trials Regulations1, the guidelines of Good Clinical Practice 
(GCP)2, the Declaration of Helsinki3, the applicable regulations of the relevant NHS Trusts and the trial 
protocol. I agree to conduct the trial according to these regulations and guidelines and to appropriately 
direct and assist the staff under my control, who will be involved in the trial, and ensure that all staff 
members are aware of their clinical trial responsibilities. 
 
 
Investigator's Name: 
 
 
 
 
 
Name of site: 
 
 
 
 
 
Signature: 
 
 
 
 
 
Date: 
 
 




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1.2.3 
Tertiary objectives and endpoints 
 
 
1.3 
Design 
This is a multi-centre, dose escalation, Phase I trial in two parts. 
In Part 1 each patient cohort included up to six evaluable patients following a rolling six dose escalation 
scheme (Skolnik A.M. et al., 2008) of AZD3965 until a recommended Phase II dose (RP2D) and/or the 
maximum tolerated dose (MTD) was defined.  
42 patients with advanced solid tumours or Lymphoma were entered into Part 1.  The final number 
depended on the number of dose escalations required to reach MTD or the tolerated dose at which 
monocarboxylate transporter 1 (MCT1) was inhibited.  A RP2D was proposed from the safety and 
pharmacokinetic (PK) results from Part 1. 
All patients in Part 2 will be treated at this RP2D to further explore the tolerability of this dose and 
schedule and to explore proof of principle of MCT1 inhibition in tumour types that were shown to express 
high MCT1 and low monocarboxylate transporter 4 (MCT4) or in which AZD3965 showed some effect 
pre-clinically.  
In Part 2 there will be up to 20 evaluable patients entered with relapsed or refractory diffuse large B cell 
Lymphoma (DLBCL) and Burkitt Lymphoma (BL). 
1.4 
Administration schedule 
AZD3965 is available as 5, 10, 20 and 30 mg capsules and patients will take their dose orally once or 
twice every day (in the absence of toxicity).  


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One treatment cycle will consist of 28 days (with Cycle 1 including an additional dosing day at Day -74 
for Part 1 of the trial only). 
In the Part 1 dose escalation, up to six evaluable patients were treated at each dose level with a dose 
on Day -7 followed by continuous daily dosing starting on Day 1 (in the absence of toxicity after the 
Day -7 dosing).  
The starting dose was 5 mg once daily and the next total daily dose level was 10 mg.  
Pharmacokinetic (PK) assessments were performed to assess the half-life and potential accumulation 
of the drug in order to inform whether dosing for future cohorts should be once or twice daily.   
The total daily dose was doubled in successive cohorts until a Grade 2 highly probable or probably 
related adverse drug reaction was reported according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.02. Subsequent dose increases 
between cohorts were up to a maximum of 50% (to the nearest 5 mg) driven by reported safety, PK and 
pharmacodynamic (PD) data. However, an upper limit on dose escalation was set using PK data (see 
Section 2.2.9).  If continuous daily dosing is not tolerated at levels that inhibit MCT1 then intermittent 
schedules will be explored. 
Up to six evaluable patients were treated at each dose level.  At least one male patient was treated in 
each cohort 
  If a dose 
limiting toxicity (DLT) was observed then the cohort was expanded to six patients.  If a second DLT was 
reported no further dose escalation was performed and a total daily dose level below was expanded to 
six patients to identify the MTD. 
An interval of 14 days (from Day -7 (7 days prior to Day 1) was observed between the recruitment of the 
first and second patients in a cohort but the subsequent patients were treated in parallel.  Twenty-eight 
days (from Day 1) of data (safety, PK and PD) was available for a minimum of three patients in a cohort 
in order to make the decision to dose escalate. 
In both Parts 1 and 2, AZD3965 will be administered as continuous daily dosing in 28 day cycles for up 
to six cycles.  If the patient is benefitting from the treatment, a further six cycles may be administered 
after discussions between the Investigator and the Sponsor, Cancer Research UK’s Centre for Drug 
Development (CRUK CDD).  In the case of toxicity, treatment will be interrupted and then resumed when 
all toxicities have returned to Grade 1 or baseline.  Intermittent dosing schedules may be explored based 
on observed toxicities. 
In Part 2 all patients will be treated at the RP2D determined in Part 1. There will be no Day -7 dose in 
Part 2. All patients in Part 2 will be treated at the RP2D as continuous daily dosing in 28 day cycles for 
up to six cycles starting on Day 1. If the patient has not progressed after six cycles, further cycles may 
be given after discussion between the Investigator and the CDD (see Section 5.7). 
An interval of 14 days (from Cycle 1 Day 1) must be observed between the recruitment of the first and 
second patient in the expansion cohort but subsequent patients can be treated in parallel.  Data must 
be available (safety and PK) for a minimum of three evaluable patients in order to make any decision to 
change the Part 2 dose (RP2D). Any changes to the Part 2 dose (RP2D) will be for safety reasons and 
to decrease the total daily dose only. 
1.5 
Treatment group 
42 patients with advanced solid tumours were entered into Part 1, and up to 20 evaluable patients with 
DLBCL and BL will be entered into Part 2.  The final total patient numbers will depend on the number of 
dose levels explored in Part 1 and the number of patients recruited to Part 2.  
1.6 
Trial timelines  
It was expected that the trial would have a minimum duration of 36 months in Part 1 and will have a 
minimum duration of 24 months in Part 2.  
 
4 Day -7 dosing may be performed on Day -8 to Day -6. See Section Error! Reference source not found. 




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In many tissues, more than one MCT isoform is found which would appear to correlate with either the 
influx or efflux of lactic acid into different cell types.  For example in skeletal muscle, the white fibres are 
glycolytic and contain primarily MCT4, the lactic acid effluxed by this transporter is then taken up and 
oxidised by the red fibres that express primarily MCT1.  Similarly glial cells in the brain, which contains 
both MCT1 and MCT4, can export lactic acid to be oxidised by the neurons that contain MCT1 and 
MCT2.  As AZD3965 is a selective and potent MCT1 inhibitor global MCT inhibition across all isoforms 
should not occur.  It is therefore hypothesised that in normal cells, when MCT1 is inhibited, the presence 
of other MCTs will transport lactate out of the cells to maintain the body’s normal homeostasis.  
Accordingly the presence of MCT4 has been validated as a resistance mechanism in tumour cells since 
introduction of MCT4 into a cell line expressing only MCT1 prevents both lactate accumulation and the 
inhibition of cell growth by MCT1 inhibitors.  This is supported by cell panel data which shows that 
tumour cell lines that predominantly express MCT1 tend to be highly sensitive to AZD3965, whereas 
those that co-express MCT4 are far less sensitive or resistant. 
2.2 
Investigational medicinal product 
2.2.1 
Structure of AZD3965 
Details of the physical and chemical characteristics of AZD3965 are provided in the investigator 
brochure. 
 
 
2.2.2 
Mechanism of action of AZD3965 
The scientific rationale for the proposed trial is that many tumours have an increased dependency on 
the glycolytic pathway for ATP generation either via aerobic glycolysis or anaerobic glycolysis.  
Intracellular lactate produced by glycolysis is transported out of cells by the MCTs 1, 2, 3 and 4.  
Therefore by inhibiting MCT1, AZD3965 has the potential to inhibit the export of lactate from tumour 
cells, leading to lactate accumulation resulting in acidosis and cell death. 
2.2.3 
Non-clinical pharmacology 
 
 
  
 
  
 
 
 
 
  
 
 


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2.2.4 
Safety pharmacology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 


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2.2.5 
Pharmacokinetics and metabolism 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 


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 be relevant in man and this effect may be confined to the high doses used in 
preclinical studies. 
2.2.6 
Toxicology 
 
  
 
 
 
  
 
 
  
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.2.9 
Maximum Exposure  
Based on the nature of adverse effects observed in non-clinical studies, dose escalation to maximum 
tolerated dose would not be appropriate for AZD3965 in man.  Dose escalation could be stopped based 
on pharmacodynamic (PD) effects, e.g. PBMC lactate accumulation.  However, there is limited clinical 
experience with the planned PD assays in this study, and these assays alone are not felt to be sufficient 
to inform dose escalation decisions with the appropriate degree of certainty.  Instead an upper limit to 
the dose escalation of AZD3965 has been based on exposure levels. 
 
  
 
 
  
 
 
 
 
In the CRUKD/12/004 trial, patients will undergo extensive clinical monitoring for potential retinal toxicity, 
which is expected to be reversible should it occur.  A maximum AZD3965 exposure limit in humans is 
therefore set as a dose of AZD3965 producing a Cmax not in excess of 5 µM and an AUC not in excess 
of 20 µmol•h/L.  These levels of AZD3965 should allow dose escalation into the anticipated therapeutic 
range while remaining below the levels likely to affect retinal function.  These levels may produce some 
QTc effects but these are likely to be minor and short-lived post-dosing. Based on extrapolation from 
nonclinical data, these exposure levels might be reached with a daily dose of around 500 mg/day. 
 
 
 
 
 
Assessments of exposure will be based on Day -7, Day 1 and Day 29 pharmacokinetics from Part 1.  If 
pharmacokinetics from any of these analyses indicate that the exposure cap has been exceeded the 
cohort will be completed (toxicity permitting) but no further dose escalations will take place.  
Pharmacokinetic data from all patients in a cohort must be available prior to dose escalation.  If the drug 
demonstrates a good safety profile at doses producing exposures close to the planned cap a substantial 
amendment will be requested to allow further dose escalation. 
2.3 
Clinical experience  
This is the first time an MCT-1 inhibitor will be given to humans. 
2.4 
Rationale for the proposed trial 
AZD3965 is a first-in class agent in clinical development and this trial will be the first time AZD3965 will 
be administered in humans.  Many tumours have an increased dependency on the glycolytic pathway 
for ATP generation either via aerobic glycolysis or anaerobic glycolysis.  Intracellular lactate produced 
by glycolysis is transported out of cells by the MCTs 1, 2, 3 and 4.  Therefore by inhibiting MCT1, 
AZD3965 has the potential to inhibit the export of lactate from tumour cells, leading to intracellular lactate 
accumulation resulting in lactic acidosis and cell death. 
The first part of the trial followed a rolling six dose escalation schedule. 
 
 
  In addition, a dose of AZD3965 was given one week before the continuous 
treatment started to ensure patient safety. 
In Part 2, up to 20 evaluable patients with relapsed or refractory diffuse large B cell Lymphoma (DLBCL) 
or Burkitt Lymphoma (BL) will be treated at the recommended phase II dose (RP2D) determined in Part 
1. These tumour types were chosen based on AZD3965 activity that has been demonstrated in 
preclinical models of DLBCL and BL and on high MCT1 expression that has been reported in DLBCL 
and BL samples analysed by immunohistochemistry (IHC). 




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2. Part 2: To assess the potential anti-tumour 
activity of AZD3965 in patients with relapsed or 
refractory DLBCL and/or BL. 
2. Objective response: SD, PR, or CR according to 
RECIST, (version 1.1) or International Working 
Group criteria for Lymphoma (see Appendix 2A and 
2B),  
3.1.3 
Tertiary objectives and endpoints 
 
3.1.4 
Definition of dose limiting toxicity 
The DLT and MTD are defined using the NCI CTCAE Version 4.02. 
Only DLTs identified during Part 1 Cycle 1 (including Day-7 in Part 1) informed the decision to dose 
escalate through the increasing dose levels.  Dose limiting toxicities will be defined throughout the 
treatment period and will be considered in determining the RP2D for Part 2.   
Any DLTs experienced during Part 2 will be collected to assist with assessment of adverse events (AEs) 
and patient safety profiles and the dose may be adjusted accordingly. Any changes to the Part 2 dose 
(RP2D) will be for safety reasons and to decrease the total daily dose only. 
A DLT is defined as highly probably or probably drug related: 
Haematological: 
• 
neutropenia Grade 4 for 5 days duration  
• 
febrile neutropenia (fever of unknown origin without clinically or microbiologically documented 
infection) with Grade 3 or 4 neutropenia (absolute neutrophil count - ANC <1.0x109/L and fever 
38.5oC) 
• 
infection (documented clinically or microbiologically) with Grade 3 or 4 neutropenia (ANC 
<1.0x109/L) 


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• 
thrombocytopenia Grade 4: a) for 5 days*, or b) associated with active bleeding, or c) requiring 
platelet transfusion. 
Cardiac: 
• 
QTc interval >500 msec or an increase of >60 msec from baseline (verified manually 
(Fridericia’s correction (QTcF)) 
• 
Any other Grade 3 or 4 cardiac toxicity excluding Grade 3 hypertension  
• 
Non-sustained ventricular tachycardia (<30s) associated with syncope or pre-syncope  
• 
Sustained ventricular tachycardia (≥30s) with or without symptoms 
• 
Ejection Fraction (EF):  ≥20% reduction in left ventricular ejection fraction (LVEF) to below the 
lower limit of normal (<50% on echocardiography) 
Ophthalmic:  
Part 1: 
• 
25% (or more) reduction on electroretinography (light and dark adapted) which does not resolve 
to baseline or 25% (or less) within 2 weeks following dose delay 
• 
50% (or more) reduction on electroretinography (light and dark adapted) 
Part 2: 
• 
25% (or more) a- wave reduction on electroretinography (light and dark adapted) which does 
not resolve to baseline or 25% (or less) within 2 weeks following dose delay 
• 
50% (or more) a - wave reduction on electroretinography (light and dark adapted) 
• 
50% (or more) b- wave reduction on electroretinography (light and dark adapted) which does 
not resolve to baseline or 50% (or less) within 2 weeks following dose delay 
 
*Note: If a patient is withdrawn from the study due to eye toxicity, ERG assessments will be 
repeated within 14 days and performed at least monthly thereafter until resolution or return to 
baseline. See Section 17.5 for further guidance.  
Other 
• 
Grade 3 or 4 toxicity to organs other than the bone marrow including Grade 3 and 4 biochemical 
AEs and DLTs 
EXCLUDING: 
o Grade 3 nausea 
o Grade 3 vomiting in patients who have not received optimal treatment with anti-emetics 
o Grade 3 diarrhoea in patients who have not received optimal treatment with anti-diarrhoeals 
• 
Death  
• 
Any drug related toxicity that causes interruption of treatment for >2 weeks (14 successive 
days).  If a patient is deemed fit to restart treatment on the fifteenth day then this is not a DLT. 
 
* Note: In the event of a Grade 4 neutropenia or Grade 4 thrombocytopenia, a full blood count 
must be performed at least on Day 5 after the onset of the event to determine if a DLT has 
occurred.  The Investigator must continue to monitor the patient closely until resolution to Grade 
3 or less. 
Should any change be made to the grade or causality of an AE during the trial that may alter its DLT 
status, the CDD must be informed immediately as this may affect dose escalation decisions. 
PLEASE NOTE: In the event of an Ophthalmic and/or Cardiac DLT (as defined above) these must 
be reported as a serious adverse event (SAE) to the CDD (see Section 10 for guidance on SAE 
reporting). 


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3.1.5 
Definition of maximum tolerated dose  
In Part 1 if two out of up to six evaluable patients at the same dose level experienced a DLT as defined 
in Section 3.1.4, the MTD was determined as the total daily dose level below.  The MTD, was used to 
determine the RP2D following discussion of all the relevant safety, PK and PD data between CDD and 
the Investigators.    
3.2 
Patient evaluability 
Part 1: 
All patients that met the eligibility criteria and take at least one dose of AZD3965 were evaluable for 
safety decisions.   
Patients who received less than 75% of their first continuous treatment cycle (for reasons other than 
toxicity) would not be evaluable for dose escalation decisions. Patients who completed 75% of their first 
continuous treatment cycle but did not complete the end of Cycle 1 ERG and ophthalmology 
assessments could also not be evaluable for dose escalation decisions. This was discussed on a per 
patient basis between the Investigator, Chief Investigator (CI) and CDD. 
Part 2: 
All patients that meet the eligibility criteria and take at least one dose of AZD3965 will be evaluable for 
safety decisions.  
All patients who meet the eligibility criteria and take at least 75% of their first continuous treatment cycle 
(28 days) of AZD3965 and have a baseline assessment of disease will be evaluable for response.   
To be assigned a status of complete response (CR) or partial response (PR), changes in tumour 
measurements must be confirmed by repeat measurements performed no less than four weeks after 
the response criteria are met.  To be assigned a status of stable disease (SD), follow-up measurements 
must have met the SD criteria at least once and at least six weeks after the initial dose of the IMP 
AZD3965 is given. 
 
 
 
 
 
 
 
 
 
3.3 
Design of the clinical trial 
This is a multi-centre, Phase I, dose escalation trial in two parts. 
Part 1 
In Part 1, a total of 42 patients with advanced solid tumours were recruited into Part 1 of the study, 40 
of which received AZD3965. 
At each dose level, up to six evaluable patients were treated on Day -7 followed by continuous daily 
dosing starting on Day 1.  One treatment cycle was 28 days.  In Part 1, Cycle 1 includes the additional 
dosing day at Day -7.  
The starting dose was 5 mg given as an oral capsule.  Pharmacokinetic assessments were performed 
during this cohort to assess the half-life of AZD3965 in order to inform whether dosing for future cohorts 
should be once or twice daily. 
The next total daily dose level was planned to be 10 mg either once daily or split into two daily doses. 


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The total daily dose was doubled in successive cohorts until an NCI CTCAE Version 4.02 Grade 2 highly 
probably or probably related adverse drug reaction was reported.  Subsequent dose increases between 
cohorts were up to a maximum of 50% driven by reported safety, PK and PD data.  The decision to 
continue with dose escalations was based on drug exposure as measured by PK assessments during 
Cycle 1 and PD effects.  Drug exposure did not exceed the maximum exposure limit as set out in Section 
5.2.  If PK data from Cycle 1 indicated that the exposure cap had been exceeded, the cohort would have 
been completed but no further dose escalations would have take place. 
If continuous daily dosing was not tolerated at levels that inhibit MCT1 then intermittent schedules would 
be explored. 
Up to six evaluable patients were treated at each dose level.  
 
  
 
 
  If a DLT was observed 
then the cohort was expanded to six patients.  In the event of a gender specific DLT, at least one further 
patient of that gender would have been enrolled into an expanded cohort of at least six patients.  If a 
second DLT was reported, a dose level below would have been expanded to six evaluable patients to 
identify the MTD.  
An interval of 14 days (from Day -7 (7 days from Day 1) was observed between the recruitment of the 
first and second patients in a cohort.  The second, third, fourth, fifth and sixth patients could be treated 
in parallel.  Twenty-eight days (from Day 1) of data (safety, PK and PD) was available for a minimum of 
three evaluable patients in a cohort in order to make the decision to dose escalate.  The following cohorts 
and doses were explored: 
 
Cohort Number 
Dose 
1 
5 mg once daily (OD) 
2 
10 mg OD 
3 
20 mg OD 
4 
30 mg OD 
5 
15 mg twice daily (BD) 
6 
10 mg BD 
 
Part 2 
In Part 2, up to 20 evaluable patients with DLBCL or BL will be treated at the RP2D from Part 1 of the 
study. There will be no administration of AZD3965 on Day -7 in Part 2 of the study. AZD3965 will be 
administered as continuous daily dosing in 28 day cycles starting from Cycle 1 Day 1 for up to six cycles. 
If the patient has not progressed after six cycles, further cycles may be given after discussion between 
the Investigator and the CDD and written approval given by the CDD, refer to Section 5.7.  In the case 
of toxicity, treatment will be interrupted and then resumed when all toxicities have returned to Grade 1 
or lower. Intermittent dosing schedules may be explored based on observed toxicities. 
An interval of 14 days (from Cycle 1 Day 1) must be observed between the recruitment of the first and 
second patient in the expansion cohort but subsequent patients can be treated in parallel.  Data must 
be available (safety and PK) for a minimum of three evaluable patients in order to make any decision to 
change the Part 2 dose (RP2D). Any changes to the Part 2 dose (RP2D) will be for safety reasons and 
to decrease the total daily dose only. 
 
 




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Either: 
Calculated creatinine clearance (using the 
Wright or Cockcroft-Gault formula) 
Or: 
Isotope clearance measurement 
(uncorrected) 
≥ 50 mL/min 
 
Prothrombin time (PT) 
<1.5 x ULN 
 
Glucose (fasting) 
<7.8 mmol/L 
 
Lactate 
Between 0.5 and 2.5 mmol/L inclusive 
 
Bicarbonate 
Between 22 mmol/L and 1.5 x ULN inclusive 
 
 
 
5. LVEF>50% 
6. 18 years or over 
7. Written (signed and dated) informed consent and be capable of co-operating with treatment and 
follow-up 


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4.1.2 
Exclusion criteria: 
 
1. Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or 
chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C and 4 
weeks for investigational medicinal products) before treatment.5 Shorter wash out periods may 
be acceptable if patient has recovered from therapy related toxicity and is at least five terminal 
half-lives post last administration. This should be discussed and agreed with the CDD and CI. 
2. Ongoing toxic manifestations of previous treatments greater than NCI CTCAE Grade 1 at the 
time of starting study treatment.  Exceptions to this are alopecia or certain Grade 2 toxicities, 
which in the opinion of the Investigator and the CDD should not exclude the patient.  
3. Symptomatic brain or leptomeningeal metastases. 
4. Patients with known retinal disease or macular degeneration affecting visual acuity as assessed 
by ophthalmologic tests. 
5. Female patients who are able to become pregnant (or are already pregnant or lactating). 
However, those patients who have a negative serum or urine pregnancy test before enrolment 
and agree to use two forms of contraception (one highly effective form plus a barrier method) 
[oral, injected or implanted hormonal contraception and condom; intra-uterine device and 
condom; diaphragm with spermicidal gel and condom] or agree to sexual abstinence, effective 
from the first administration of AZD3965, throughout the trial and for six months afterwards are 
considered eligible.6 
6. Male patients with partners of child-bearing potential (unless they agree to take measures not to 
father children by using a barrier method of contraception [condom plus spermicide] or to sexual 
abstinence effective from the first administration of AZD3965, throughout the trial and for six 
months afterwards. Men with partners of child-bearing potential must also be willing to ensure 
that their partner uses an effective method of contraception for the same duration for example, 
hormonal contraception, intrauterine device, diaphragm with spermicidal gel or sexual 
abstinence). Men with pregnant or lactating partners must be advised to use barrier method 
contraception (for example, condom plus spermicidal gel) to prevent exposure of the foetus or 
neonate.6 
7. Any major surgery in the preceding eight weeks prior to the start of treatment or major thoracic 
or abdominal surgery from which the patient has not yet recovered  
8. Patients who are unable to swallow oral medication. 
9. Alterations to corticosteroid dose within 2 weeks prior to first dose of AZD3965. An exception to 
this is usage of prednisolone or an equivalent steroid which is acceptable during screening but 
must be stopped at least 72 hours days prior 
 
 
10 Gastrointestinal disorders likely to interfere with absorption of the study drug (e.g. partial bowel 
obstruction or malabsorption). 
11 At high medical risk because of non-malignant systemic disease including active uncontrolled 
infection. 
12 Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus 
(HIV). (N.B. Mandatory testing not required). 
13 History of serious allergy or auto-immune disease.  
14 Diabetes mellitus treated with oral anti-diabetic medication (patients with diet controlled or insulin 
controlled diabetes may be included with fasting glucose <7.8 mmol/l and normal HbA1c).  
15 Cardiac conditions as follows: 
• 
Clinically significant cardiovascular event within 6 months prior to study entry to include: 
a. Acute coronary syndrome (myocardial infarction or unstable angina) 
b. congestive heart failure requiring therapy;  
 
5 Baseline measurements must be performed within four weeks before the patient receives the first dose.  The interval between 
the last anti-cancer therapy and these measurements must be at least four weeks (28 days). Shorter wash out periods may be 
acceptable if patient has recovered from therapy related toxicity and is at least five terminal half-lives post last administration. This 
should be discussed and agreed with the CDD and CI. 
6 Abstinence is only considered to be an acceptable method of contraception when this is in line with the preferred and usual 
lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are 
not acceptable methods of contraception 


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• 
Severe valvular heart disease (as defined by British Society of Echocardiography – see 
Appendices 6) 
• 
Presence of an atrial or ventricular arrhythmia, other than atrial fibrillation with well 
controlled ventricular rate, for which treatment is indicated (anti-arrhythmic drugs or 
implantable cardioverter defibrillator)7 
• 
Second degree Mobitz type 1 (Wenckebach) heart block with symptoms, or second degree 
Mobitz type 2 or third degree heart block with or without symptoms, are exclusions unless 
the patient has a functional pacing system7  
• 
QTc > 450 msec in adult male and > 460 msec in adult females (QTc to be verified 
manually (QTcF correction)) 
• 
History of congenital long QT syndrome 
• 
History of Torsade de Pointes (TdP) (or any concurrent medication with a known risk of 
QT prolongation) – See Appendix 3for further details  
• 
Uncontrolled hypertension (BP ≥ 160/100mmHg despite medical therapy) 
16 Patients who have had extensive radiotherapy to greater than 25% of bone marrow within 8 
weeks.  Prior autologous bone marrow transplant will not exclude a patient 
17 Is a participant, or plans to participate in another interventional clinical trial, whilst taking part in 
this Phase I study of AZD3965.  Participation in an observational trial or interventional clinical 
trial which does not involve administration of an IMP would be acceptable. 
18 Any other condition which in the Investigator’s opinion would not make the patient a good 
candidate for the clinical trial. 
19 For Part 2 only: Current malignancies of other types, with the exception of adequately treated 
cone-biopsied in situ carcinoma of the cervix uteri; basal or squamous cell carcinoma of the skin; 
and patients with low risk prostate cancer on surveillance (with a Gleason score of ≤6 and a PSA 
of ≤10) 
4.2 
Patient enrolment 
Before enrolling the patient in the trial, the Investigator or designated representative should determine 
the eligibility of the patient during the trial screening period.  This determination must be clearly 
documented in the patients’ hospital records. 
Eligible patients must be enrolled in the electronic data capture (EDC) system by site staff and then 
registered at the CDD before they start treatment with AZD3965.  If the patient is eligible for the trial, 
then a patient number will be automatically allocated by the EDC system during the enrolment 
process.  The CDD will send confirmation of the patient registration including the assigned dose level to 
the Investigator following enrolment of the patient. Study treatment may only be administered after 
confirmation has been received. 
 
5 
TREATMENT 
5.1 
Selection of the Phase I starting dose and schedule (Part 1) 
The starting dose was 5 mg given as a capsule once daily.   
The justification for the starting dose can be found in Section 2.2.7 
5.2 
Maximum Exposure Limit 
 
 
   
 
 
 
 


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5.3 
Dosing schedule/treatment schedule (Parts 1 and 2) 
For Part 1 of the study, AZD3965 was administered orally on Day -7 and then continuously for a 28 day 
cycle starting on Day 1.  
For Part 2 of the study, AZD3965 will be administered orally continuously for a 28 day cycle starting on 
Cycle 1 Day 1. There will be no administration of AZD3965 on Day -7 in Part 2 of the study.  
In Part 1, the total daily dose was initially administered once daily and was reviewed throughout Part 1, 
the total daily dose was spilt into a twice daily dosing schedule.  
In both Part 1 and 2 a maximum of six cycles will be administered (further cycles can be given upon 
review of the data and approval by CRUK CDD where patients are benefiting from receiving AZD3965 
i.e. tumour assessments show a stable or partial/complete response, refer to Section 5.7). 
The AZD3965 capsules must be swallowed whole (with water) and not chewed, crushed, dissolved or 
divided. 
Patients in Part 1 were instructed to take AZD3965 with food, except for their first dose at Day -7 which 
was taken fasted. In Part 2 as there is no Day -7 dose, AZD3965 is to be taken with food and should be 
taken at the same time(s) every day.  
For the once daily dosing in Part 1, the total daily dose of AZD3965 was taken at the same time once a 
day, and for twice daily dosing, the total daily dose of AZD3965 was spilt into two doses and should be 
taken in the morning and 12 hours later, respectively.   
In Part 2 a twice daily dosing is planned unless emerging data suggests a once daily dosing is indicated.  
On the days of PK sampling (see Section 9.4.1) patients should take their scheduled dose at the hospital 
so that the exact time of administration can be recorded. 
In cases of toxicity, treatment may be interrupted and then resumed when all toxicities have returned to 
Grade 1 or lower. In the event of Grade 3 or 4 QTc prolongation (QTc interval >500 msecs or increase 
of > 60 msecs from baseline (QTcF correction)), treatment with AZD3965 will be withdrawn. 
Intermittent dosing schedules and administration with or without food may be explored based on 
observed toxicities or if continuous daily dosing is not tolerated at levels that inhibit MCT1. 
5.4 
Dose escalation scheme (Part 1) 
Each patient cohort included a maximum of six evaluable patients following a rolling six dose escalation 
scheme (Skolnik A.M. et al., 2008).   
The starting dose was 5 mg given as an oral capsule.  5, 10, 20, and 30 mg capsules can be 
manufactured.  Pharmacokinetic assessments were performed during this cohort to assess the potential 
half-life of AZD3965 in order to inform whether dosing for future cohorts should be once or twice daily. 
The next total daily dose level will be 10 mg either once daily or split into two daily doses. 
The total daily dose was doubled in successive cohorts until an NCI CTCAE Version 4.02 Grade 2 highly 
probably or probably related adverse drug reaction was reported. Subsequent dose increases between 
cohorts was up to a maximum of 50% driven by reported safety, PK and PD data.  If continuous daily 
dosing is not tolerated at levels that inhibit MCT1 then intermittent schedules will be explored. 
A maximum of six evaluable patients were treated at each dose level with at least one male patient in 
each cohort.  It is acceptable that the fourth, fifth and sixth patients can begin treatment at the same 
time as the second and third patients which must be after the first patient has completed Cycle 1 Day 7 
of treatment although this will be assessed and confirmed by the CDD based on emerging data from 
the study. 


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The dose level of AZD3965 was assigned according to the number of patients already enrolled at the 
current dose level, the number of DLTs (and any other drug-related AEs) observed at the current dose 
level and the number of patients enrolled who are at risk of developing a DLT (see Section 3.2 Definition 
of dose limiting toxicity).  When sufficient data, as deemed by the Sponsor and CI, was available to 
assess these, the AZD3965 dose level was assigned according to the following: 
• 
If the data is available from a minimum of three patients who have been treated in a cohort and 
no DLTs have been observed at that dose level, then dose escalation can be considered. 
• 
If the data is available from three patients who have been treated in a cohort and one DLT has 
been observed at that dose level, then the cohort will be expanded to include at least 6 patients. 
• 
If two DLTs have been observed at any dose level, the dose will be de-escalated and the 
previous total daily dose level will be expanded to include up to six patients.  If the previous total 
daily dose level already included a cohort of six patients then this will be identified as the MTD.  
If a patient has already started treatment at a higher dose level at the time when two DLTs are 
identified at a lower dose level, their dose will be assessed and confirmed by the Sponsor based 
on the reported safety data. 
• 
If not all data are available from at least three patients in order to take a decision on dose 
escalation but an eligible patient is ready to begin treatment, the dose level will remain the same.  
Up to six patients may be enrolled at that dose level.   
 
Twenty-eight days of data (safety and PK) should be available for a minimum of three evaluable patients 
in a cohort in order to make the decision to dose escalate.   
The decision to continue with dose escalations was guided by drug exposure.  Assessments of drug 
exposure was based on Day -7, Day 1 and Day 29 PK from Part 1 only.  Drug exposure was not to 
exceed the maximum exposure limit as set out in Section 5.2.  If PK data from any of these time points 
indicated that the exposure cap has been exceeded, the cohort would be completed (toxicity permitting) 
but no further dose-escalations will take place.   
5.4.1 
Intra-patient dose escalations  
No intra-patient dose escalation is allowed. 
5.4.2 
Expansion of dose level(s) 
If one instance of DLT (as defined in Section 3.1.3) was observed in three patients, at least six evaluable 
patients would be treated at that dose level.  If one out of six patients experienced a DLT, dose 
escalation would continue.  If two out of up to six (i.e. between two and six) patients experience a DLT 
dose escalation would stop and this dose would be defined as the maximum administered dose (MAD).  
At least six patients would be treated at the total daily dose level below the MAD to define the MTD. 
The MAD could also equal the MTD in the event that dose escalation was stopped before two DLTs 
were observed at a given dose level, due to the expectation that higher dose levels would be too toxic 
to administer to patients. 
5.5 
Dose modifications  
5.5.1 
Dose withdrawal 
In the event of CTCAE Grade 3 or 4 QTc prolongation (QTc interval >500 msecs or increase of 
>60 msecs from baseline (QTcF correction)) treatment with AZD3965 will be withdrawn.  


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5.5.2 
Dose reductions 
In Part 1 the dose of AZD3965 would be reduced to the previous dose level for any patient who 
experienced a DLT (with the exception of QTc prolongation, these patients would be withdrawn from 
the trial, see Section 5.5.1).  If a patient had a dose reduction, their dose would not be re-escalated. 
Treatment at the reduced dose would start when the toxicities had resolved to Grade ≤1 or returned to 
baseline (if within 14 days). 
If the patient experienced the same or different DLT toxicity again at this reduced dose, there would be 
no further dose reductions and the patient was withdrawn from the study. 
In Part 2, the PK profile of AZD3965 and patient safety data will be reviewed after the first three 
evaluable patients. Following this review, the RP2D may switch to once or twice daily dosing (at the 
same total daily dose level) or a lower total daily dose at the discretion of the CDD and CI. Any DLTs 
experienced during Part 2 will be collected to assist with assessment of patient safety profiles and the 
RP2D may be adjusted accordingly. 
5.5.3 
Dose delays 
In the event of toxicity, treatment should be delayed for up to two weeks until these toxicities have 
resolved to Grade ≤1 or returned to baseline.  If there is no recovery after a two week delay, the patient 
should be withdrawn from the trial. 
Intermittent dosing schedules may be explored based on observed toxicities, PK and PD data. 
5.6 
Missed Doses  
Patients should take the correct number of AZD3965 capsules at the same time(s) every day. 
Should a patient miss a scheduled dose in error, for example, forgetting to take the drug, then AZD3965 
may be administered up until 12 hours after the scheduled dosing time (this applies to once a day dosing 
only).  If it is not taken within this time then the patient should wait until the next scheduled dose and 
continue as per normal drug administration. 
If the dosing schedule is twice daily dosing and the patient should miss a dose in error, then AZD3965 
may be administered up until two hours after the scheduled time of dose. If it is not taken within this time 
then the patient should wait until the next scheduled dose and continue as per normal drug 
administration. Any missed doses should be recorded in the patient diary card. 
An occasional shift in dosing may be permitted by CDD, to accommodate study visits and study 
assessments. This must be discussed and agreed in advance. On these occasions dosing should be 
brought back to the original dosing schedule as soon as possible.  
Should a patient vomit after taking the drug, then the patient should be instructed not to take another 
capsule until their next scheduled dosing time. 
5.7 
Duration of treatment 
Treatment should continue for six cycles unless (a) the patient asks to be withdrawn, (b) there is 
evidence of disease progression (c) the patient is experiencing unacceptable toxicity or (d) the 
Investigator feels the patient should be withdrawn from any other reason including those listed in 
Section 12. 
If a patient is benefiting from treatment with AZD3965 (i.e. has stable or responding disease as 
measured by RECIST version 1.1 or International Working Group criteria for Lymphoma) and the patient 
is not experiencing any Grade 2 or greater drug-related AEs then the CI and / or Principal Investigator 
(PI) can ask the CDD if the patient can continue with treatment.  The CDD will request a full toxicity 
profile of that patient when considering the request.  Should the decision be to allow further treatment, 
6 further cycles may be given. After completion of 12 cycles, a further review will be conducted by the 
Sponsor, CI and treating clinician(s). A patient may continue on study as long as they are benefiting 
from treatment with AZD3965 and IMP stock is available.  If the CDD decides not to allow the patient to 


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continue treatment, based on the information provided or on other information received, then the CDD’s 
decision is final. 
For the purposes of this trial a patient who completes six or more treatment cycles is considered to have 
completed the trial.   
For patients who continue on study for extended treatment, i.e. for longer than 6 or 12 cycles, these 
patients must continue to show that benefit is being derived from receiving AZD3965.  After each disease 
assessment the PI will relay findings to CDD for this determination to be met. 
5.7.1 
Replacement of patients 
In Part 1, patients were replaced if they fulfilled the following criteria and three evaluable patients had 
not yet been treated at the same dose level: 
• 
Patients who miss more than 25% of their first AZD3965 cycle (for reasons other than drug 
related toxicity). 
Patients who missed more than 50% of their first AZD3965 cycle due to toxicity which was not dose 
limiting were discussed between the CDD and CI and a decision will be taken on whether the patient 
should be replaced by another at the same dose level.  
Patients could be replaced if they were unable to complete 
 
 the end of Cycle 1 ERG and ophthalmology assessments.  The decision 
as to whether to replace such a patient depended on the status of the other patients within that cohort 
 ERG data already obtained at that dose level.  This 
decision was made by the CDD in consultation with the CI.  
In Part 2, patients will be replaced in this phase if they fulfil the following criteria: 
• 
Patients who miss more than 25% of their first AZD3965 cycle (for reasons other than drug 
related toxicity). 
Patients who complete more than 75% of their first AZD3965 cycle (for reasons other than drug related 
toxicity) but fulfil one of the following additional criteria may also be replaced in Part 2. This will be 
discussed on a per patient basis between the Investigator, CI and CDD. 
• 
 
 
 
 
 
 
5.8 
Concomitant medication and treatment 
Concomitant medication may be given as medically indicated.  Details (including doses, frequency, route 
and start and stop dates) of the concomitant medication given must be recorded in the patient’s medical 
records but only the medication name, start date and stop date is required to be entered into the 
electronic case report form (eCRF). 
Radiotherapy may be given for the control of bone pain; however this cannot be given concomitantly 
during AZD3965 administration.  Please note that in exceptional circumstances, if the patient’s 
radiotherapy cannot be completed within a two week period, this may be extended to three weeks after 
consultation with CDD.  Irradiated lesions will not be evaluable for response.  
The patient must not receive other anti-cancer therapy or investigational drugs while on the trial. 
Patients may continue the use of bisphosphonates for bone disease and corticosteroids provided the 
dose has not been changed in the two weeks prior to administration of the first dose of AZD3965 and is 
not altered during the first 15 days post administration of AZD3965 on Day 1.   
For patients who require prednisolone (or equivalent) for a short duration to improve their quality of life 
during screening, this is acceptable, 
 
 


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The concomitant administration of potent CYP3A inhibitors, specifically: protease inhibitors (atanazavir, 
indinavir, nelfinavir, ritonavir, saquinavir), macrolide antibiotics (clarithromycin, telithromycin), azole 
antifungals (ketoconazole, itraconazole, voriconazole), nefazodone should be avoided. 
The concomitant administration of CYP3A inducers, specifically: rifampicin, rifapentine, rifabutin, 
phenytoin, carbamazepine, phenobarbitol, St John’s Wort should also be avoided. 
An up to date list of CYP3A inhibitors and inducers can be found at https://drug-
interactions.medicine.iu.edu/Clinical-Table.aspx. 
Drugs with a known risk of inducing TdP should not be taken during the trial. These drugs (see 
Appendix 3) have been sourced from https://www.crediblemeds.org. As drugs are reviewed on an 
ongoing basis to assure that the available evidence supports their continued placement on this list, the 
list changes regularly. Therefore, check the website at crediblemeds.org for the most up-to-date 
information. If these drugs are to be used in an emergency once the patient is off AZD3965 treatment, 
they should be taken a minimum of 24 hours after the patient’s last dose of AZD3965. Before a patient 
re-starts AZD3965 treatment, a maximum of 5 half-lives of the concomitant drug must be reached. 
If a patient is taking any dietary supplements or complementary medicines/botanicals, the CDD must be 
informed at the earliest opportunity. 
Use of potential prohibited concomitant medications will be discussed on a patient by patient 
basis with the CDD and CI before a patient is enrolled on the study. 
 
6 
PHARMACEUTICAL INFORMATION 
6.1 
Supply of AZD3965 
A complete certificate of analysis and a Qualified Person (QP) certification must be supplied with each 
shipment of AZD3965 and be retained in the Pharmacy File. 
For information on AZD3965 and re-ordering of supplies, contact the Clinical Research Associate 
(CRA)/Clinical Study Manager (CSM) responsible for the trial who will arrange further supplies.  
AZD3965 will be supplied by: 
 
 
  
  
  
 
 
 
 
 
Fisher Clinical Services (UK) Limited must send confirmation of shipment to the CRA/CSM once 
AZD3965 has been despatched to the clinical trial site. 
The primary packaging for AZD3965 will be labelled according to Eudralex Volume 4: Annex 13 
‘Investigational Medicinal Products’ of the European Union guide to Good Manufacturing Practice 
(GMP).  An example of the label can be found in the Pharmacy file.  
6.2 
Pharmaceutical data 
6.2.1 
Formulation of AZD3965 
 
  
 
 
 
  


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6.2.2 
Storage conditions 
All supplies must be stored in a secure, limited access storage area. AZD3965 must be stored at ambient 
temperature between 15C and 30C.   
AZD3965 must be stored in its original bottle with the cap on tightly.  Study medication must not be 
refrigerated.  Please refer to the current Investigator’s Brochure (IB) for detailed information on storage 
conditions and stability. 
Patients must ensure that AZD3965 is kept out of sight and reach of children. 
6.2.3 
Stability of AZD3965 
Please refer to the label on the bottle (primary package) for the expiry date of the unopened AZD3965. 
Opened bottles of AZD3965 MUST NOT be refrigerated.  Bottles must be stored between 15°C and 
30°C and must be kept out of sight and reach of children.  Opened bottles of AZD3965 that have passed 
the expiry date stated on the bottle must be returned to the pharmacy.  Patients must close the cap of 
the bottle tightly immediately after dispensing the number of capsules they are required to take. 
Please refer to the current Investigator Brochure for detailed information on storage conditions and 
stability 
6.2.4 
Dispensing of AZD3965 
Sufficient capsules of AZD3965 must be dispensed on each occasion to cover the prescribed dose over 
the period to the next scheduled dispensing. 
6.2.5 
AZD3965 administration 
The AZD3965 capsules must be swallowed whole (with water) and not chewed, crushed, dissolved or 
divided. 
AZD3965 should be taken as directed with food. For once daily dosing AZD3965 should be taken at the 
same time every day and for twice daily dosing AZD3966 should be taken in the morning and 12 hours 
later. 
Should a patient miss a scheduled dose in error, for example, forgetting to take the drug, then AZD3965 
may be administered up until 12 hours after the scheduled dosing time (this applies to once a day dosing 
only).  If it is not taken within this time then the patient should wait until the next scheduled dose and 
continue as per normal drug administration. 
If the dosing schedule is twice daily dosing and the patient should miss a dose in error, then AZD3965 
may be administered up until two hours after the scheduled time of dose. If it is not taken within this time 
then the patient should wait until the next scheduled dose and continue as per normal drug 
administration. 
An occasional shift in dosing may be permitted by the CDD to accommodate study visits and study 
assessments. On these occasions dosing should be brought back to the original dosing schedule as 
soon as possible.  
If the patient vomits after taking the AZD3965 capsule, the patient should not take another capsule and 
should wait for the next scheduled dose. 
On the days of PK sampling (see Section 9.3) patients should take their scheduled dose (morning dose 
if twice daily dosing) at the hospital so that the exact time of administration can be recorded. 


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6.3 
AZD3965 accountability 
Accurate records of AZD3965 shipments received, capsules dispensed, and returned must be 
maintained.  This inventory record must be available for inspection at any time by CRAs or CSMs of the 
CDD.  AZD3965 supplies are to be used only in accordance with this protocol and under the supervision 
of the Investigator. 
Patients will be asked to complete a patient diary to document drug administration and to return the 
bottle and any remaining capsules at each visit.  The Investigator should make every effort to ensure 
patients’ compliance to treatment. 
The Investigator undertakes not to destroy any unused AZD3965 unless directed to by CDD staff.  Any 
unused capsules must be destroyed according to hospital procedures and properly accounted for using 
the IMP Destruction Form (when instructed to do so) and also on the IMP Accountability Record.  During 
the course of the trial the CRA will check the numbers of bottles of capsules of AZD3965 shipped to the 
centre, the number used and the number destroyed or returned.  The pharmacy will give an account of 
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7 
INVESTIGATIONS SCHEDULE FOR PART 1 OF THE STUDY 
RECRUITMENT TO PART 1 OF THE STUDY IS NOW CLOSED 
For details of investigations performed in Part 1 of this clinical trial, please 
refer to Protocol V 12.0 dated 22Aug2018 which still includes the details from 
this part of the trial. 
 


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8 
INVESTIGATIONS SCHEDULE FOR PART 2 OF THE STUDY 
In cases where a patient has investigations at a different hospital, for example weekly blood samples, 
then it is the Investigator’s responsibility to ensure he/she receives and reviews the results in a timely 
manner.  The results must be recorded on the eCRF and the reports from the other hospitals must be 
available for source data verification.  Laboratory reference ranges, including effective dates, and 
evidence of laboratory accreditation must be obtained from all laboratories used. 
8.1 
Pre-treatment evaluations 
Details of all evaluations/investigations for enrolled patients, including relevant dates, required by the 
protocol must be recorded in the medical records so that the eCRF can be checked against the source 
data. 
Please also refer to the tabulated Schedule of Assessments for Part 2 of the study in Section Error! R
eference source not found.. 
8.1.1 
Obtaining written informed consent 
Written informed consent must be obtained from the patient before any protocol-specific procedures are 
carried out.  
The patient must be given adequate time to think about their commitment to the study.  If more than 28 
days has passed since informed consent was obtained before the start of AZD3965 dosing then the 
Investigator should consider whether repeat consent should be obtained from a patient.  
Consent for analysis of initial historical archived or (if historical tissue not available) fresh (new) 
screening tumour sample for MCT1 and MCT4 IHC profiling must be obtained prior to analysis of the 
sample for the trial and should be obtained pre-screening or at the time of full trial consent.  Analysis of 
the sample can occur in parallel to screening and the result does not need to be confirmed before the 
patient enrols onto the study. 
Only the Principal Investigator (PI) and those Sub-Investigator(s) delegated responsibility by the PI, and 
have signed the Delegation Log, are permitted to gain informed consent from patients and sign the 
consent form.  All signatures must be obtained before the occurrence of any medical intervention 
required by the protocol (ICH GCP 4.8.8 and 8.3.1.2).  The patient should sign and date the consent 
form in the presence of the Investigator, followed by the Investigator signature. The date of the 
signatures of both the patient and the PI/Sub-Investigator should be the same. 
The PI or the Sub-Investigator must inform the patient about the background to, and present knowledge 
of the normal management of their disease and the AZD3965 and must also ensure that the patient is 
aware of the following points. 
• The known toxicity of AZD3965 and the possibility of experiencing side-effects. 
• That AZD3965 is new and that the exact degree of activity is at present unknown, but that 
treating him/her will contribute to further knowledge. 
• The potential dangers of becoming pregnant (or the patient’s partner becoming pregnant) and 
he/she has been given information about appropriate medically approved contraception (refer 
to Section 10.7). 
• That he/she may refuse treatment either before or at any time during the trial and that refusal to 
participate will involve no penalty or loss of benefits to which they are otherwise entitled. 
• Whom to contact for answers to pertinent questions about the research and their rights, and 
also who to contact in the event of a research-related injury. 
A copy of the consent form and patient information sheet must be given to the patient to keep and the 
original consent form and patient information sheet, must be filed in the Investigator Trial File (ITF) 
(unless otherwise agreed that the original consent form will be filed in the medical records and the copies 
kept in the ITF). 


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8.1.2 
Pre-screening 
The following should be performed/obtained within six months before the patient receives the first 
dose. 
• 
Written informed consent (as detailed in Section Error! Reference source not found.).  
• 
Confirmation that tumour samples are available and can be used for the study to confirm MCT1 
and MCT 4 expression as demonstrated by IHC either during pre-screening, screening or once 
the patient is enrolled on the study.   
All patients in Part 2 should give separate written consent before analysis of historical or fresh (new) 
screening tumour biopsy sample taken for MCT1 and MCT4 IHC profiling.  
Historical tumour biopsy samples can be used if they were obtained more than 6 months prior to Day 1. 
However, it’s preferred that fresh (new) samples are used to provide a more accurate result. 
For those patients where a historical tumour biopsy sample is not available or the MCT1 and MCT4 IHC 
profiling is inconclusive and the patient hasn’t yet been enrolled on to the study, a fresh (new) screening 
tumour biopsy will be preferred. The fresh (new) screening sample tumour biopsy must be 
performed/obtained within eight weeks before the patient receives the first dose. 
8.1.3 
Evaluations within four weeks prior to first dose (Day -28 to Day -1)  
The following should be performed/obtained within the four weeks before the patient receives the first 
dose. 
• 
Written informed consent (as detailed in Section 8.1.1); 
• 
Demographic details; 
• 
Medical history including prior diagnosis, prior treatment, concomitant diseases and 
concomitant treatment; 
• 
  
 
 
  
 
 
 
 
• 
Radiological disease assessments: Radiological measurements (chest computerised 
tomography (CT) scan of neck, chest, abdomen and pelvis, FDG-PET/CT for those patients with 
PET-avid disease (as applicable) magnetic resonance imaging (MRI), bone scan (as applicable) 
– must be performed within four weeks before the patient receives the first dose.   
Note that all adverse events (AEs), including serious adverse events (SAEs), must be monitored and 
recorded in the eCRF from the time the patient consents to any protocol-specific procedure (see Section 
10 for further details).  
8.1.4 
Evaluations within two weeks prior to first dose (Day -14 to Day -1) 
The following should be performed within the two weeks before the patient receives the first dose: 
• 
Serum or urine human chorionic gonadotropin (HCG) test to rule out pregnancy at trial entry; 
results must be obtained and reviewed before the first dose of the AZD3965 is taken, if 
applicable (i.e. women of child bearing potential); 
• 
Echocardiogram (ECHO); 
• 
Ophthalmic test: Best corrected visual acuity; 
 


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• 
Pattern electro-retinography (pERG) and full-field electro-retinography (ffERG) (light and dark 
adapted) (or equivalent ERG assessment as previously agreed with the CDD). 
8.1.5 
Evaluations within one week prior to first dose (Day -7 to Day -1)  
The following should be performed within one week before the patient receives the first dose: 
• 
Clinical disease measurements, if applicable (i.e. patients with clinically assessable disease); 
• 
Tumour serum markers (if applicable); 
• 
Complete physical examination;  
• 
WHO performance status; 
• 
Weight and temperature;   
• 
Seated blood pressure (BP) and pulse rate; 
• 
Chest X-ray (CXR); If the baseline CT/MRI scan included the thorax, a CXR may not be 
necessary provided all windows are presented for review.   
• 
Laboratory tests (blood/urine samples) to confirm eligibility (see section 4.1.1 for required 
values): 
o 
Haematology – haemoglobin (Hb), white blood cells (WBC) with differential count 
(neutrophils, lymphocytes, monocytes, reticulocytes) and platelets 
o 
Biochemistry – sodium, potassium, adjusted calcium, phosphate, urea, creatinine, total 
protein, albumin, bilirubin, alkaline phosphatase (ALP), alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), glucose 
(fasting at baseline to confirm eligibility and then non-fasting at subsequent 
timepoints. If non-fasting result is ≥7.8mmol/l fasting glucose should be repeated), 
lactate and bicarbonate (at baseline [screening] to confirm eligibility and Cycle 1 Day 1 
only).  
o 
Urinalysis – pH, specific gravity, glucose, protein, blood, ketones 
o 
Coagulation – PT (screening only) 
• 
Cardiac Troponin T or I; 
• 
Electrocardiogram (ECG); including measurement of QTc and verified manually (QTcF 
correction).  ECG traces must be checked by an attending physician, consultant or specialist 
registrar, at the time of generation.  A comment confirming normal/abnormal must be added 
along with a signature and date on the ECG to confirm review (abnormal ECGs to be reviewed 
by a Cardiologist prior to patient registration); 
• 
 
 
 
 
 
 
 
 
 
 
8.2 
Evaluations on Cycle 1 Day 1 (+/- 24 hours)   
• 
Administration of first dose of AZD3965; 
• 
Blood tests to include bicarbonate and lactate: See section 8.1.5 (blood to be taken after first 
dose); 


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• 
Blood 
 for PK 
 
 
 
 
 
 
 
 
 
 
 
8.3 
Evaluations at 24 hours (± 2 hours) after the first dose of AZD3965 treatment  
• Cardiac Troponin T or I; to be repeated at 48 +/-2 hours post-dose; 
• ECGs (including measurement of QTc and verified manually (QTcF correction); 
ECG traces must be checked by an attending physician, consultant or specialist registrar, at the 
time of generation.  A comment confirming normal/abnormal must be added along with a 
signature and date on the ECG to confirm review.  Abnormal ECGs to be reviewed by a 
Cardiologist prior to dosing;   
• 
 
 
8.4 
Evaluations during continuous AZD3965 treatment Cycles 1–12 (excluding Cycle 1 Day 1) 
(See Section 8.2 for Cycle 1 Day 1 and Section 8.5 for Cycle 13 onwards) 
• Adverse events and concomitant treatments: At each visit an assessment of any AE 
experienced since the previous visit must be made by the Investigator or Research Nurse and 
the start and stop dates of the AE together with the relationship of the event to treatment with 
AZD3965 must be recorded in the medical records.  All AEs must be graded according to NCI 
CTCAE Version 4.02.  Any concomitant treatment must also be recorded in the medical records 
and in the eCRF (see Section 10 for further details regarding AE reporting requirements); 
• Physical examination:  When clinically indicated, a symptom-directed physical examination will 
be performed weekly during the first cycle and on the first day of each cycle in subsequent 
cycles (±1 day).  N.B. Dermatological assessment to include questioning on genital skin 
changes or sores and experience of testicular pain in male patients; 
• WHO performance status and weight on the first day of each cycle (±1 day);    
• Temperature, seated BP and pulse rate every week in Cycle 1 and 2, and every 2 weeks 
thereafter (±1 day);   
• Laboratory tests (blood/urine) must be repeated weekly in Cycle 1 and 2, and every 2 weeks 
thereafter (±1 day): see Section8.1.5; 
• ECGs (include measurement of QTc and verified manually (QTcF correction)): weekly in Cycle 
1 and 2, and every 2 weeks thereafter (±1 day); 
 
ECG traces must be checked by an attending physician, consultant or specialist registrar, at the 
time of generation.  A comment confirming normal/abnormal must be added along with a 
signature and date on the ECG to confirm review.  Abnormal ECGs to be reviewed by a 
Cardiologist prior to dosing.   
 
• Cardiac Troponin T or I: weekly in Cycle 1 and 2, and every 2 weeks thereafter (±1 day);   
 


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• Questionnaire for eye toxicity: weekly in Cycle 1 (±1 day).  If the patient reports any changes in 
their vision, Ophthalmic tests listed in the bullet point below and ERG assessments should be 
performed (as per the ‘Management of eye toxicity’ appendix 4);  
 
• Ophthalmic test: Best corrected visual acuity. To be conducted on the first day of each cycle 
(±3 days); 
 
If a reduction or changes are identified on the ophthalmic test, ERG should be performed 
immediately (refer to Appendix 4 Management of eye toxicity); 
 
• 
Pattern and full-field ERG (light and dark adapted) (or equivalent ERG assessment as 
previously agreed with the CDD) to be performed at the end of Cycle 1 ±3 days and then 
repeated every 28±3 days if the patient reports symptoms of eye toxicity/changes in their vision.  
ERGs can be stopped after the end of Cycle 1 if no symptoms are reported and the 
Ophthalmologist agrees no further ERG testing is required; 
• 
Assessment of disease (radiological, clinical – if applicable, and tumour markers):  This must 
be repeated at the end of every 2 cycles (±3 days) unless assessment has been performed within 
the previous 4 weeks (28 days).  
 
PLEASE NOTE: If patient presents with disease progression, assessment of tumour disease should be 
performed at the last study visit unless assessment has been performed within the previous four weeks 
(28 days). If assessment is to be conducted on Cycle 1 Day 29 (or Day 1 Cycle 2), assessment 
must be performed prior to the fresh (new) on study paired tumour biopsy. 
• Blood 
 PK assays: see Section 9. 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
8.5 
Evaluations from Cycle 13 onwards 
From Cycle 13 onwards, the patient will attend the study site on Day 1 of each cycle. A telephone call 
or on-site visit on Day 15 will be conducted if deemed required (either by site staff or by the patient).   
PLEASE NOTE: Abnormal or out of range laboratory results from tests carried out on Day 1 will require 
an onsite visit or telephone call on Day 15 to ensure continuing patient safety and well-being is reviewed 
during the treatment cycle. 
The frequency of the following investigations may be adjusted (increased or decreased) if clinically 
indicated or deemed required by the Investigator. 


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At each study visit: 
• Adverse events and concomitant treatments: At each visit an assessment of any AE 
experienced since the previous visit must be made by the Investigator or Research Nurse and 
the start and stop dates of the AE together with the relationship of the event to treatment with 
AZD3965 must be recorded in the medical records.  All AEs must be graded according to NCI 
CTCAE Version 4.02.  Any concomitant treatment must also be recorded in the medical records 
and in the eCRF (see Section 10 for further details regarding AE reporting requirements). 
• AE assessments must include any visual changes which should be managed as per Section 
10. 
On the first day of each cycle (±1 day):  
• Physical examination:  When clinically indicated or deemed required by the Investigator, a 
symptom-directed physical examination will be performed.  N.B. Dermatological assessment to 
include questioning on genital skin changes or sores and experience of testicular pain in male 
patients. 
• WHO performance status and weight. 
• Temperature, seated BP and pulse rate. May be conducted at Cycle Day 15 (±1 day) if onsite 
visit. 
• Laboratory tests (blood/urine); see Section 8.1.5. May be conducted at Cycle Day 15 (±1 day) 
if onsite visit.  
Every 3 cycles (±3 days): 
• 
Assessment of disease (radiological, clinical – if applicable, and tumour markers):  This must 
be repeated at the end of every 3 cycles (±3 days) unless assessment has been performed within 
the previous 4 weeks (28 days).  
PLEASE NOTE: If patient presents with disease progression, assessment of tumour disease 
should be performed at the last study visit unless assessment has been performed within the 
previous four weeks (28 days).  
• 
Opthalmic test: Best corrected visual acuity. To be conducted on the first day of every third cycle 
(±3 days). 
If a reduction or changes are identified on the ophthalmic test, ERG should be performed 
immediately (refer to Appendix 4 Management of eye toxicity). 
• 
Pattern and full-field ERG (light and dark adapted) (or equivalent ERG assessment as 
previously agreed with the CDD). 
Every 6 cycles (±3 days): 
• Echocardiogram (ECHO) – may also be performed in case of ECG or clinical abnormalities. 
As described in Section 9: 
• Blood 
 PK assays. 
 
 
 
As necessary: 
• Electrocardiogram (ECG). 
ECG traces must be checked by an attending physician, consultant or specialist registrar, at the 
time of generation.  A comment confirming normal/abnormal must be added along with a 
signature and date on the ECG to confirm review.  Abnormal ECGs must be reviewed by a 
Cardiologist prior to dosing.   
• Cardiac Troponin T or I. 


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8.6 
Evaluations at ‘Off-Study’ visit  
Evaluations at the ‘Off-Study’ visit should be performed 28 days ±7 days after the last dose of AZD3965.  
The following investigations must be done: 
• 
Symptom-directed physical examination including WHO performance status, temperature, 
pulse rate, seated BP, and bodyweight. 
• Haematology tests: detailed in Section 8.1.5. 
• Biochemistry tests: detailed in Section 8.1.5. 
• Urinalysis: detailed in Section 8.1.5. 
• Chest X-ray (unless otherwise indicated by the patient’s condition or, in the case of chest X-ray, 
to monitor the tumour status). A CXR may not be required if a CT/MRI scan has included the 
thorax. 
• Assessment of tumour disease (radiological, clinical – if applicable, and tumour markers), unless 
assessment has been performed within the previous four weeks (28 days).  
• Assessment of AEs (also see Section 10). 
• Assessment of concomitant treatments. 
• ECG (include measurement of QTc and verified manually (QTcF correction)). 
ECG traces must be checked by an attending physician, consultant or specialist registrar, at the 
time of generation. A comment confirming normal/abnormal must be added along with a 
signature and date on the ECG to confirm review. Abnormal ECGs should be reviewed by a 
Cardiologist. 
• Cardiac Troponin T or I. 
• Ophthalmic test: Best corrected visual acuity. 
• 
Pattern and full-field ERG (or equivalent ERG assessment as previously agreed with the CDD) 
at the discretion of the ophthalmologist. 
 
 
 
 
 
 
 
 
 
 
8.7 
Follow-up 
If any AEs and SAEs are considered to have a highly probable, probable or possible causal relationship 
to AZD3965, and are still present 28 days after the last administration of AZD3965 or occur in the 
28 days post AZD3965 administration; then the patient will be followed up monthly afterwards until 
resolution, to baseline or stabilisation of these events, unless the patient starts another anti-tumour 
treatment.








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9 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS  
9.1 
Part 1 Sampling summary  
RECRUITMENT TO PART 1 OF THE STUDY IS NOW CLOSED 
For details of sampling in Part 1 of this clinical trial, please refer to Protocol V 12.0 dated 22Aug2018 which still includes 
the details from this part of the trial. 


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9.2 
Part 2 Sampling summary 
 
Name of assay 
 
Purpose of assay 
Type of sample  
Approximate 
volume 
per 
patient (a) 
Timings (see exact timings later in this section)  
Primary endpoint (Part 1 only) 
Secondary endpoints 
PK 
Determination of plasma PK 
Plasma 
15 mL 
Cycle 1 Day 1, pre- and post-dose 
 
 


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(a) The total amount of blood taken per patient will be approximately 195 mL and a maximum of 215 mL (Cycles 1-12). From Cycle 13-24, approximately 100 mL will be 
drawn. 
(b) If treatment continues after 24 cycles, approximately 80 mL of blood will be drawn over each 12 cycles. 
  
Please refer to the study laboratory manual for current details of sample volumes, sample handling and storage instructions and shipment details.


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9.3 
 Primary assay – Pharmacodynamic - Lactate accumulation in PBMCs (Part 1 only) 
Part 1 only 
For details of assays performed in Part 1 of this clinical trial, please refer to Protocol V 12.0 dated 
22Aug2018 which still includes the details from this part of the trial. 
9.4 
Secondary assays   
9.4.1 
Secondary Assays - AZD3965 Pharmacokinetics  
AZD3965 will be measured in whole blood according to agreed SOPs and validated methods. 
A sample of blood will be collected into EDTA vacutainers from patients at the following time-points: 
Part 1: 
For details of assays performed in Part 1 of this clinical trial, please refer to Protocol V 12.0 dated 
22Aug2018 which still includes the details from this part of the trial. 
Part 2: 
• 
Pre-treatment (pre-dose on Cycle 1 Day 1) and after the first dose on Cycle 1 Day 1 at 4 
and 6 hours post dose and at 24 hours post-morning dose (prior to next dose).  For patients 
receiving AZD3965 on a twice daily dosing schedule, an extra sample will be required at 
12 hours post the morning dose (prior administration of their second dose of the day). 
For Part 2 the approximate total volume of blood withdrawn from each patient for PK analysis will be 
15mL depending on the dosing schedule for the patient. The total amount of blood taken per patient will 
be approximately 195 mL and a maximum of 215 mL (Cycles 1-12). From Cycle 13-24, approximately 
100 mL will be drawn. If treatment continues after 24 cycles, approximately 80 mL of blood will be drawn 
over each 12 cycles. 
Timing tolerances of ± the following are acceptable. 
• 
15 to 30 minutes: 5 minutes 
• 
1 to 2 hours: 10 minutes 
• 
4 to 6 hours: 1 hour 
• 
12 to 48 hours: 2 hours 
 
These time-points may be revised as more data on AZD3965 PK becomes available, but the overall 
number of sample timepoints will not be increased. 
Please refer to the Study Laboratory Manual for handling, storage and shipment of samples. 
9.4.2 
Secondary assays – Pharmacodynamics - Cell Death Biomarkers (M65, M30, nDNA) 
(Part 1 only) 
Part 1 only 
For details of assays performed in Part 1 of this clinical trial, please refer to Protocol V 12.0 dated 
22Aug2018 which still includes the details from this part of the trial. 
9.5 
Tertiary/research assays 
 
 
 


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9.6 
Storage and Shipment of Samples 
Blood and tumour samples will be taken at the local participating clinical site for either local storage 
(until the Sponsor confirms shipping requirements and receiving laboratory) or will be shipped to a 
central analysing laboratory. The Sponsor will define the local storage requirements prior to shipment 
or will coordinate the shipment of the sample to the central laboratory. Thereafter, storage of remaining 
samples will be as per Sponsor agreements with the relevant laboratories. 
 
10 
ASSESSMENT OF SAFETY 
10.1 Investigator responsibilities 
The investigator is responsible for monitoring the safety of patients who have enrolled in the study and 
for accurately documenting and reporting information as described in the following sections.  
10.1.1 
Medical cover 
The Chief/Principal Investigator (CI/PI) is also responsible for ensuring patients have access to 24 hour 
advice and/or care.  Patients will be provided with the necessary contact numbers for both normal 
working and out of hours care.  A copy of the protocol must be made available out of hours to ward staff 
and clinicians on call so that the appropriate advice may be given to the patient, the patient’s relative or 
other care giver (for example General Practitioner).  The CI/PI must ensure that should the on call 
clinician or ward staff require more advice than is in this protocol, that they have access to the 
Investigator or delegated members of the investigator’s team who can answer any questions.  
10.2 Adverse event definitions 
10.2.1 
Adverse event 
An AE is any untoward, undesired or unplanned occurrence in a patient administered an IMP, a 
comparator product or an approved drug.   
An AE can be a sign, symptom, disease, and/or laboratory or physiological observation that may or may 
not be related to the IMP or comparator.   
An AE includes but is not limited to those in the following list.  
• 
A clinically significant worsening of a pre-existing condition.  This includes conditions that may 
resolve completely and then become abnormal again.  
• 
AEs occurring from an overdose of an IMP, whether accidental or intentional. 
• 
AEs occurring from lack of efficacy of an IMP, for example, if the Investigator suspects that a 
drug batch is not efficacious or if the Investigator suspects that the IMP has contributed to 
disease progression. 
10.2.2 
Serious adverse events 
A serious adverse event (SAE) is any AE, regardless of dose, causality or expectedness, that: 


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• 
results in death; 
• 
is life-threatening *; 
• 
requires in-patient hospitalisation or prolongs existing in-patient hospitalisation (some 
hospitalisations are exempt from SAE reporting – e.g. hospital admissions planned prior to the 
patient entering the trial; overnight stays for planned procedures such as blood transfusions 
(Section 10.4.1); 
• 
results in persistent or significant incapacity or disability; 
• 
is a congenital anomaly or birth defect; 
• 
is any other medically important event**. 
* A life-threatening event is defined as an event when the patient was at substantial risk of dying at the 
time of the adverse event, or use or continued use of the device or other medical product might have 
resulted in the death of the patient. 
** A medically important event is defined as any event that may jeopardise the patient or may require 
intervention to prevent one of the outcomes listed above. Examples include allergic bronchospasm (a 
serious problem with breathing) requiring treatment in an emergency room, serious blood dyscrasias 
(blood disorders) or seizures/convulsions that do not result in hospitalization. The development of drug 
dependence or drug abuse would also be examples of important medical events. 
Trial-specific medically important events 
Any ophthalmic and/or cardiac event that meets DLT criteria is considered a medically important 
event in this trial. Therefore, all ophthalmic and cardiac DLTs must be reported as SAEs.  
For fatal SAEs, wherever possible report the cause of death as an SAE with a fatal outcome rather than 
reporting death as the SAE term.  When available the autopsy report will be provided to the Sponsor. 
If during the course of the study, other medically important events are identified and there is a 
requirement to report specific events outside of the standard criteria, this will be communicated to site 
and the protocol will be updated to reflect this. 
Any dose limiting toxicity (DLT) must be reported to the CDD Clinical Study Manager (CSM) and CRA 
within 24 hours of site staff becoming aware of the DLT.  The CDD Pharmacovigilance Department must 
be copied into any initial email notification.  
Other reportable events that must be treated as SAEs are listed below.   
• 
Pregnancy exposure to the IMP.  Any pregnancy occurring in a patient or a patient’s partner 
during treatment with an IMP or occurring within six months of the last IMP administration, must 
be reported to the Pharmacovigilance Department in the same timelines as an SAE.  These 
should be reported even if the patient is withdrawn from the trial. 
• 
Overdose with or without an AE (any dose above that specified in the protocol, not necessarily 
intentional). 
• 
Inadvertent or accidental exposure to an IMP with or without an AE, including for example, 
spillage of the IMP that contaminates staff.   
• 
Any AE that could be related to the protocol procedures, and which could modify the conduct of 
the trial. 
10.2.3 
Suspected, unexpected, serious adverse reactions 
A SUSAR is a suspected, unexpected, serious adverse reaction.  All AEs and SAEs will be assessed 
by CDD for seriousness, causality and expectedness. The Pharmacovigilance department will expedite 
all SUSARs to the relevant Competent Authority/Authorities and the relevant Ethics Committee(s) within 
the timelines specified in legislation (SI 2004/1031 as amended).  
10.2.4 
Determining adverse event causality 
The relationship of an AE to the IMP is determined as follows. 


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Highly probable 
• 
Starts within a time related to the IMP administration and 
• 
No obvious alternative medical explanation. 
Probable 
• 
Starts within a time related to the IMP administration and 
• 
Cannot be reasonably explained by known characteristics of the patient’s clinical state. 
Possible 
• 
Starts within a time related to the IMP administration and 
• 
A causal relationship between the IMP and the AE is at least a reasonable possibility. 
Unlikely 
• 
The time association or the patient’s clinical state is such that the trial drug is not likely to 
have had an association with the observed effect. 
Not related 
• 
The AE is definitely not associated with the IMP administered. 
Note: Drug-related refers to events assessed as possible, probable or highly probable. 
The Investigator must endeavour to obtain sufficient information to determine the causality of the AE 
(i.e. IMP, other illness, progressive malignancy etc) and must provide his/her opinion of the causal 
relationship between each AE and IMP.  This may require instituting supplementary investigations of 
significant AEs based on their clinical judgement of the likely causative factors and/or include seeking a 
further opinion from a specialist in the field of the AE. 
The following guidance should be taken in to account when assessing the causality of an AE: 
• 
Previous experience with the IMP and whether the AE is known to have occurred with the IMP. 
• 
Alternative explanations for the AE such as concomitant medications, concurrent illness, 
non-medicinal therapies, diagnostic tests, procedures or other confounding effects. 
• 
Timing of the events between administration of the IMP and the AE. 
• 
IMP blood levels and evidence, if any, of overdose. 
• 
De-challenge, that is, if the IMP was discontinued or the dosage reduced, what happened to 
the adverse reaction? 
• 
Re-challenge, that is, what happened if the IMP was restarted after the AE had resolved? 
10.2.5 
Expectedness 
Assessment of expectedness for AZD3965 will be made by the Pharmacovigilance Department against 
the current version of the Investigator’s Brochure.   
10.3 Collecting of safety information 
10.3.1 
Pre-Screening 
Following pre-screening informed consent, any SAEs that are considered by the Investigator to be 
related to the pre-screening biopsy must be reported to the Pharmacovigilance Department, CDD. 


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10.3.2 
Screening failures 
For patients who fail screening, SAEs must be reported to the Pharmacovigilance Department, CDD 
from the date of consent until the date the patient is confirmed as ineligible. 
10.3.3 
Eligible patients  
For eligible patients, SAE and AE collection and monitoring commences from the time the patient gives 
their written consent to participate in the trial and continues for 28 days after the last administration of 
AZD3965 (IMP). 
10.3.4 
Follow-up of AEs and SAEs  
Follow-up of non-serious AEs with a causality of possible, probable or highly probable will continue until 
the events resolve, stabilise or the patient starts another anti-cancer therapy.   
Any SAEs or AEs considered to be related (possibly, probably or highly probably) to AZD3965 occurring 
either 28 days post AZD3965 administration or are still present 28 days after the last administration of 
AZD3965, should be reported to the CDD Pharmacovigilance department as per the timelines stated in 
section 10.4.  
The Pharmacovigilance Department will make requests for further information on SAEs to the trial site 
at regular intervals. Requested follow-up information should be reported to the Pharmacovigilance 
Department in a timely manner and as soon as possible after receipt of the follow-up request. For fatal 
or life-threatening cases, follow-up information must be reported to the Pharmacovigilance Department 
as soon as possible. 
10.3.5 
Other safety information of interest 
We will also collect information on the following situations, whether they are associated with an AE or 
not: 
• 
Abuse or misuse 
Any occurrences of these should be reported in the same manner as SAEs (Section 10.4). 
10.4 Reporting of SAEs to the Pharmacovigilance Department, CDD 
All SAEs, regardless of causality, must be reported to the Pharmacovigilance Department in an 
expedited manner. 
SAEs should be documented on an SAE report form, using the completion guidelines provided.  
 
The SAE report form should be e-mailed to Pharmacovigilance Department within 24 hours of 
site staff becoming aware of the SAE. 
 
Each episode of an SAE must be recorded on a separate SAE report form. The NCI CTCAE 
Version 4.02 must be used to grade each SAE, and the worst grade recorded. If new or amended 
information on a previously reported SAE becomes available, the Investigator should report this to the 
Pharmacovigilance department on a new SAE report form. 
If the SAE has not been reported within the specified timeframes, a reason for lateness must be added 
on the form when sending the SAE report form to the Pharmacovigilance department. 
Should the Investigator become aware of any drug-related SAEs after the patient goes ‘off study’, these 
must also be reported to the Pharmacovigilance department within the specified timelines above. 


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10.4.1 
Events exempt from being reported as SAEs to the Pharmacovigilance department 
Events specified in this section do not require reporting as SAEs in this trial, unless hospitalisation is 
prolonged for any reason and then an SAE form must be completed. The events must still be recorded 
in the appropriate section of the eCRF. 
Elective admissions – Elective admissions to hospital for procedures which were planned prior to 
entering the trial are not SAEs.  Hospitalisation for administration of the IMP according to the trial 
protocol is also exempt from being reported as an SAE, unless the patient experiences an event during 
the admission which would normally qualify as an SAE. 
Death due to disease progression – Cases of death due to disease progression do not require SAE 
reporting, unless considered related to the IMP.  
10.5 Recording of adverse events and serious adverse events in eCRFs 
All AEs, including SAEs, must be recorded in the eCRF for eligible patients. All concomitant medications, 
including herbal medications and supplements must be recorded. Any therapy used to treat the event 
must be recorded. The eCRF will be reconciled with the safety database during and at the end of the 
trial. Therefore, the sites should ensure the data entered on the SAE report form and the data entered 
into the eCRF are consistent. The CDD Medical Advisor and the Investigator(s) will regularly review the 
safety data from both the safety and the clinical database. 
10.6 Urgent safety measures 
The Sponsor or Investigator may take appropriate urgent safety measures (USMs) in order to protect 
the patient of a clinical trial against any immediate hazard to their health or safety.  This includes 
procedures taken to protect patients from pandemics or infections that pose serious risk to human 
health.  
USMs may be taken without prior authorisation from the competent authority. 
The Medicines and Healthcare products Regulatory Agency (MHRA) and the Research Ethics 
Committee (REC) must be notified within three days of such measures being taken. 
Should the site initiate a USM, the Investigator must inform the Sponsor immediately either by: 
 
 
 
  
The notification must include:  
• 
the date of the USM;  
• 
who took the decision; and  
• 
why action was taken. 
The Sponsor will then notify the MHRA and the REC within three calendar days of USM initiation.   
10.7 Pregnancy 
Female patients who become pregnant from the time of informed consent being signed to off-study, 
must be withdrawn from study treatment immediately. 
The Investigator must make every effort to try and ensure that a clinical trial patient or a partner of a 
clinical trial patient does not become pregnant during the trial or for six months afterwards. This should 
be done as part of the consent process by explaining clearly to the patient (and parent/legal guardian, 
if appropriate) the potential dangers of becoming pregnant and also providing each patient (and 
parent/legal guardian, if appropriate) with information about appropriate medically approved 
contraception. Two forms of medically approved contraception should be used, such as:   


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• 
Oral contraceptives and condom; (oral, injected or implanted hormonal contraceptives should 
be used for four weeks before the patient joins the study) 
• 
intra-uterine device (IUD) and condom; 
• 
diaphragms with spermicidal gel and condom. 
Contraception should be effective before the patient is enrolled on the trial, throughout the trial and for 
six months after completing the trial. 
Alternatively the patient may agree to sexual abstinence, effective from the first administration of IMP, 
throughout the trial and for six months afterwards. Abstinence is only considered to be an acceptable 
method of contraception when this is in line with the preferred and usual lifestyle of the subject. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception. 
It should be explained to a male patient (and parent/legal guardian, if appropriate) that if his partner is 
pregnant or breast-feeding when he is enrolled on the trial, the patient should use barrier method 
contraception (condom plus spermicidal gel) to prevent the unborn baby or the baby being exposed to 
AZD3965. 
However, if a patient or a partner of a patient does become pregnant, the reporting procedures below 
must be followed. 
Any pregnancy occurring in a patient or a patient’s partner during treatment with an IMP or occurring 
within six months of last IMP administration must be reported to the Pharmacovigilance Department 
within 24 hours of the site staff becoming aware of it using a Pregnancy Report Form (provided in the 
ITF). It is the Investigator’s responsibility to obtain consent for follow-up from the patient or patient’s 
partner. In addition, the Investigator must be made aware of the need to obtain contact details for the 
patient’s partner’s General Practitioner. The Pharmacovigilance Department will follow-up all 
pregnancies for the pregnancy outcome via the Investigator, using a Pregnancy Report Form.  
The Investigator must ensure that all patients are aware at the start of a clinical trial of the importance 
of reporting all pregnancies (in themselves and their partners) that occur whilst being treated with the 
IMP and occurring up to six months after the last IMP administration. The Investigator should offer 
counselling to the patient and/or the partner, and discuss the risks of continuing with the pregnancy and 
the possible effects on the foetus. Monitoring of the patient or partner should continue until the 
conclusion of the pregnancy, if the patient or patient’s partner has consented to this. Monitoring of the 
baby should continue until 12 months after birth, if the patient or patient’s partner has consented to this. 
 
11 
ASSESSMENT OF EFFICACY 
11.1 Measurement of disease 
Disease must be measured according to the RECIST criteria v1.1 given in Appendix 2A or to the 
International Working Group (IWG) criteria for lymphoma (Cheson, Pfistner et al, 2014) in Appendix 2B. 
11.2 Timing and type of tumour assessments 
A thorough clinical and radiological evaluation of malignancy, as judged appropriate by the Investigator, 
and in line with the protocol, must be performed before starting the investigational medicinal product 
(IMP).  The same methods that detect evaluable lesions at baseline must be used to follow these lesions 
throughout the trial.  To ensure compatibility, the radiological assessments used to assess response 
must be performed using identical techniques.  Imaging based evaluation is preferred to evaluation by 
clinical examination when both methods have been used to assess the anti-tumour effect of a treatment. 
All radiological assessments must be performed within four weeks before starting treatment.  The 
interval between the last anti-cancer therapy and these measurements must be at least four weeks (28 
days).  All clinical measurements to assess response must be done within one week before the patient 
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All complete (CR) and partial responses (PR) must be confirmed by two consecutive observations not 
less than four weeks apart. 
Copies of the scans must be available for external independent review if requested by the CDD. 
11.2.1 
Baseline evaluations 
These must include radiological measurements and as indicated chest computerised tomography (CT) 
scan, abdominal CT scan, magnetic resonance imaging (MRI), [18F]FDG-PET scan, bone scan and/or 
clinical measurements as appropriate.  All areas of disease present must be documented (even if 
specific lesions are not going to be followed for response) and the measurements of all measurable 
lesions must be recorded clearly on the scan reports.  Any non-measurable lesions must be stated as 
being present.  For clinical measurements, documentation by colour photography including a ruler to 
estimate the size of the lesion is strongly recommended, as this aids external independent review of 
responses (see Appendix 2A and 2B). 
If a lesion is FDG avid it can be considered to contain tumour and be measured.  Any mass, of any size 
that is FDG negative by PET, cannot be considered to be disease.  A positive scan is defined as focal 
or diffuse FDG uptake above background in a location incompatible with normal anatomy or physiology, 
without a specific standardized uptake value cut-off.  Other causes of false-positive scans should be 
ruled out.  Exceptions include mild and diffusely increased FDG uptake at the site of moderate or 
large-sized masses with an intensity that is lower than or equal to the mediastinal blood pool, hepatic or 
splenic nodules 1.5 cm with FDG uptake lower than the surrounding liver/spleen uptake and diffusely 
increased bone marrow uptake within weeks after treatment.  Specific criteria for lung nodules based 
on lesion size have been developed. (Cheson, Pfistner et al, 2014). 
11.2.2 
Evaluations during and at Off-study visit 
Tumour assessments must be repeated every 2 cycles/8 weeks (Cycles 1-12) and every 3 cycles/ 
12 weeks (Cycle 13 onwards) or more frequently, when clinically indicated.  All lesions measured at 
baseline must be measured at every subsequent disease assessment and recorded clearly on the scan 
reports.  All non-measurable lesions noted at baseline must be noted on the scan report as present or 
absent. 
All patients, who are removed from the trial for reasons other than progressive disease, must be 
re-evaluated at the time of treatment discontinuation, unless a tumour assessment was performed within 
the previous four weeks. 
It is the responsibility of the Principal Investigator to ensure that the radiologists are aware of the 
requirement to follow-up and measure every target lesion mentioned at baseline and comment on the 
non-target lesions in accordance with RECIST criteria or the IWG criteria for lymphoma (Appendix 2A 
and 2B). 
11.3 Tumour response 
All patients who meet the eligibility criteria and receive at least 75 % of their first cycle of trial medication 
and have a baseline assessment of disease will be evaluable for response.  To be assigned a status of 
CR or PR, changes in tumour measurements must be confirmed by repeat measurements performed 
no less than four weeks after the response criteria are met.  To be assigned a status of stable disease 
(SD), follow-up measurements must have met the SD criteria at least once and at least six weeks after 
the initial dose of the investigational medicinal product (IMP) AZD3965 is given. 
Should rapid tumour progression occur before the completion of 4 weeks, the patient will be classified as 
having early progression (EP). 
Tumour response should be classified as “not evaluable” (NE), only when it is not possible to classify it 
under another response category, for example, when baseline and/or follow-up assessment is not 
performed or not performed appropriately.  
Expert reviewers appointed by CDD may undertake an independent review of all the Investigator’s 
assessed objective responses (CR and PR).  The expert reviewers will include at least one specialist 
who is not an Investigator in the trial.  In case of disagreement between the Investigator’s and the expert 


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reviewers’ assessment, discussion will take place between the two parties in order to reach a 
consensus.  However, if it is not forthcoming, the assessment of the expert reviewers will be retained in 
the clinical study report.  The eCRF will reflect the Investigator’s opinion. 
11.3.1 
Recording of response in the eCRF 
The applicable overall response category for each visit that includes disease assessment must be 
recorded in the eCRF, even though the criteria for determination of CR or PR by the protocol must be 
confirmed after two consecutive observations, no less than four weeks apart. 
11.3.2 
Other definitions of outcome 
Toxic death:   
Any death to which drug toxicity is thought to have a major contribution. 
Early death:  
Death during the first cycle/28 days of treatment. 
 
12 
PATIENT 
WITHDRAWAL 
BEFORE 
COMPLETION 
OF 
TREATMENT 
SCHEDULE 
The Investigator must make every reasonable effort to keep each patient on trial for the whole duration 
of the trial (i.e. until the Off-Study visit 28±7 days after last dose of AZD3965).  However, if the 
Investigator removes a patient from the trial or if the patient declines further participation, final ‘Off-Study’ 
assessments should be performed before any therapeutic intervention.  All the results of the evaluations 
and observations, together with a description of the reasons for withdrawal from the trial, must be 
recorded in the medical records and in the eCRF. 
Patients who are removed from the trial due to adverse events (clinical or laboratory) will be treated and 
followed according to accepted medical practice. All pertinent information concerning the outcome of 
such treatment must be recorded in the eCRF and on the serious adverse event (SAE) report form 
where necessary. 
The following are justifiable reasons for the Investigator to withdraw a patient from trial. 
• 
AE/SAE 
• 
Withdrawal of consent 
• 
Serious violation of the trial protocol (including persistent patient attendance failure and 
persistent non-compliance) 
• 
Sponsor’s decision to terminate the trial 
• 
Withdrawal by the Investigator for clinical reasons not related to the IMP (AZD3965) 
• 
Evidence of disease progression 
• 
 Pregnancy (for female patients during the trial) 
For the purposes of this trial a patient who completes six or more treatment cycles is considered to have 
completed the trial.   
 
13 
DEFINING THE END OF TRIAL  
The ‘end of trial’ is defined as the date when the last patient has completed the ‘Off-Study’ visit or the 
final follow-up visit (whichever is the later). 
It is the responsibility of the CDD to inform the Medicines and Healthcare products Regulations Agency 
(MHRA) and the Research Ethics Committee (REC) within 90 days of the ‘end of the trial’ that the trial 
has closed. 


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In cases of early termination of the trial (for example, due to toxicity) or a temporary halt by the CDD, 
the CDD will notify the MHRA and the REC within 15 days of the decision and a detailed, written 
explanation for the termination/halt will be given. 
The entire trial will be stopped when: 
• 
The IMP is considered too toxic to continue treatment before the required number of patients 
being recruited. 
• 
The stated number of patients to be recruited is reached. 
• 
The stated objectives of the trial are achieved.  
Regardless of the reason for termination, all data available for the patient at the time of discontinuation 
of follow-up must be recorded in the eCRF.  All reasons for discontinuation of treatment must be 
documented.   
In terminating the trial, CDD and the Investigators must ensure that adequate consideration is given to 
the protection of the patient’s interest. 
 
14 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
The final analysis will be conducted after one of the following conditions is met. 
• 
The trial is terminated early (for example, due to toxicity). 
• 
All patients have had the opportunity to receive treatment and have completed their Off-study 
visit (i.e. 28±7 days after the last dose of AZD3965) or final follow up. 
Once one of the conditions is met, a data cut-off date will be established.  All patient visits occurring on 
or before this date will be analysed and summarised in the final clinical study report.   
A clinical data cut-off date will be established to allow for primary analysis Clinical Study Report (CSR) 
reporting once all recruited patients have received up to 12 cycles of AZD3965. The primary analysis 
CSR will include data from all treated patient visits/assessments up to and including the clinical data 
cut-off date, 
  
Any patients who continue to receive AZD-3965 in the absence of disease progression or unacceptable 
toxicity after the clinical data cut-off date will be included in an addendum to the final CSR. 
 
 
14.1 Presentation of data 
Data will be presented in a descriptive fashion.  Variables will be analysed to determine whether the 
criteria for the trial conduct are met.  This will include a description of patients who did not meet all the 
eligibility criteria, an assessment of protocol violations, IMP accountability and other data that impact on 
the general conduct of the trial. 
Baseline characteristics will be summarised for all enrolled patients.  Patients who died or withdrew 
before treatment started or did not complete the required safety observations will be described and 
evaluated separately. 
Treatment administration will be described for all cycles.  Dose administration, dose modifications or 
delays and the duration of therapy will be described. 
14.2 Safety 
Safety data will be collected from the date of written consent.  Safety variables will be summarised by 
descriptive statistics.  Laboratory variables will be described using the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.02. 
Adverse events will be reported for each dose level and presented as tables of frequency of AEs by 
body system and by worse severity grade observed.  Tables should indicate related and unrelated 
events.  Laboratory data will be presented by dose level at each observation time.  Values outside 
normal limits will be identified in the listings. 


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14.3 Pharmacokinetics 
Plasma will be separated and analysed to determine the concentrations of AZD3965 using a previously 
developed LCMS method.  Parameters to be calculated will include: area under the plasma 
concentration-time curve (AUC0-t), maximum concentration achieved (Cmax), time to maximum 
concentration (Tmax) and elimination half-life (T1/2) for AZD3965. 
At the end of the trial when all the data has been analysed, a full PK report will be produced for inclusion 
in the final clinical study report. 
 
 
 
  
 
 
 
 
 
 
14.5 Anti-tumour activity 
Documenting anti-tumour activity is a secondary objective of this trial.  Patients must receive at least 
75% of their first cycle of the trial medication to be evaluable for response.  Objective responses, the 
best tumour response achieved by each patient while on trial and the time to progression will be 
presented in the data listings. 
14.6 Exploratory work 
 
 
 
 
15 
ADMINISTRATION 
This trial is conducted under a clinical trial authorisation (CTA) and approval from the Medicines and 
Healthcare products Regulations Agency (MHRA) and the relevant Research Ethics Committee(s) will 
be obtained before the start of this trial.  This trial is sponsored and monitored by the CRUK CDD.  
Applicable regulatory requirements are described in this section. 
15.1 Protocol deviations and amendments 
Do not deviate from the protocol unless approval has been obtained from the CDD.   
Amendments to the protocol may only be made with the approval of the CDD.  A protocol amendment 
may be subject to review by the assigned Ethics Committee, HRA and the MHRA.  Written 
documentation of the Ethics Committee and HRA (and if appropriate the MHRA) ‘favourable opinion’ 
(i.e. approval) must be received before the amendment can be implemented and incorporated into the 
protocol if necessary. 
15.2 Completion of the electronic case report form (eCRF) 
Electronic CRFs approved by the CDD will be used to collect the data.  The Investigator is responsible 
for ensuring the accuracy, completeness, clarity and timeliness of the data reported in the eCRFs. 
Only the Investigator and those personnel who have signed the Delegation Log provided by the CDD 
and have been authorised by the Investigator should enter or change data in the eCRFs.  Authorised 


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users will be included on a User Management Tool Form in order to be provided access to the eCRF.  
All protocol required investigations must be reported in the eCRF.  The Investigators must retain all 
original reports, traces and images from these investigations for future reference.   
Data will be entered directly into electronic screens by authorised site personnel.  Amendments to eCRF 
data will be made directly to the system and the system audit trail will retain details of the original 
value(s), who made the change, a date and time, and a reason for the change. 
Once an eCRF form has been entered by the site personnel, the data are cleaned using manual and 
automated checks.  Queries will be issued electronically to the site.  Authorised personnel must answer 
the queries by making relevant amendments to data or providing a response.  Answered queries will be 
closed or reissued as appropriate. 
Once the patient is ‘off study’ and the eCRF has been fully completed, the Investigator must provide an 
electronic signature to authorise the complete subject casebook. 
At the end of the trial all eCRFs are retained and archived by the CDD and a PDF copy provided to the 
Investigator who is responsible for archiving at site. 
15.3 Trial performance and monitoring 
Before the trial can be initiated, the prerequisites for conducting the trial must be clarified and the 
organisational preparations made with the trial centre.  CDD must be informed immediately of any 
change in the personnel involved in the conduct of the trial. 
During the trial the CDD Clinical Research Associate (CRA) is responsible for monitoring data quality in 
accordance with CDD’s standard operating procedures (SOPs).  Before the trial start, the Investigator 
will be advised of the anticipated frequency of the monitoring visits.  The Investigator will receive 
reasonable notification before each monitoring visit. 
It is the responsibility of the CRA to: 
• 
review trial records and compare them with source documents; 
• 
check pharmacokinetic and pharmacodynamic samples and storage; 
• 
discuss the conduct of the trial and the emerging problems with the Investigator; 
• 
check that the drug storage, dispensing and retrieval are reliable and appropriate; and 
• 
verify that the available facilities remain acceptable. 
All the unused drug supplied must be returned to the supplier, or if authorised by Cancer Research UK 
properly destroyed at the Investigator site by an authorised person who will provide signed confirmation. 
It is the responsibility of the Sponsor to inform the Main REC within 90 days of the ‘end of the trial’ that 
the trial has closed (see definition in Section 13). 
15.4 Source document verification 
Unless agreed in writing, all data collected in the eCRF must be verifiable by the source data.  Therefore 
it is the Investigator’s responsibility to ensure that both he/she and his/her study team records all relevant 
data in the medical records.  The Investigator must allow the CRA direct access to relevant source 
documentation for verification of data entered into the eCRF, taking into account data protection 
regulations.  Entries in the eCRF will be compared with patients’ medical records and the verification 
will be recorded in the eCRF, documented on the source data verification (SDV) form and the monitoring 
report.   
Some source data may exist only electronically and be entered, or loaded directly into the eCRF.   
The patients’ medical records, and other relevant data, may also be reviewed by appropriate qualified 
personnel independent from the CDD appointed to audit the trial, and by regulatory authorities.  Details 
will remain confidential and patients’ names will not be recorded outside the hospital. 


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15.5 Clinical study report (CSR) 
All clinical data will be presented  on final data listings.  CDD will prepare a CSR (plus addendum if 
applicable) based on the final data listings.  The report(s) will be submitted to the Investigator(s) for 
review and confirmation it accurately represents the data collected during the course of the trial.   
Summary results of the trial will be provided by the CDD to the MHRA and to the REC within one year 
of the ‘End of Trial’. 
Any patients who continue to receive AZD-3965 in the absence of disease progression or unacceptable 
toxicity after the clinical cut-off date will be included in an addendum to the final CSR. 
15.6 Record retention 
During the clinical trial and after trial closure the Investigator must maintain adequate and accurate 
records to enable both the conduct of a clinical trial and the quality of the data produced to be evaluated 
and verified.  These essential documents (as detailed in Chapter V of Volume 10 (Clinical Trials) of The 
Rules Governing Medicinal Products in the European Union based upon Section 8 of the ICH GCP 
Guidelines), including source documents such as scans, trial related documents and copies of the 
eCRFs, associated audit trail and SAE report forms, shall show whether the Investigator has complied 
with the principles and guidelines of Good Clinical Practice (GCP). 
All essential documents required to be held by the Investigator must be stored in such a way that 
ensures that they are readily available, upon request, to the Regulatory Agency or Sponsor, for the 
minimum period required by national legislation or for longer if needed by CDD.  Records must not be 
destroyed without prior written approval from CDD. 
The medical files of trial subjects shall be retained in accordance with national legislation and in 
accordance with the maximum period of time permitted by the hospital, institution or private practice. 
15.7 Ethical considerations 
Before starting the trial, the protocol, patient information sheet and consent form must go through the CDD’s 
external review process, and be approved by the PSRB and the appropriate Ethics Committee. 
It is the Chief/Principal Investigator’s responsibility to update patients (or their authorised 
representatives, if applicable) whenever new information (in nature or severity) becomes available that 
might affect the patient’s willingness to continue in the trial.  The Chief/Principal Investigator must ensure 
this is documented in the patient’s medical notes and the patient is re-consented. 
The Sponsor and Chief/Principal Investigator must ensure that the trial is carried out in accordance with 
the GCP principles and requirements of the UK Clinical Trials regulations (SI 2004/1031 and SI 
2006/1928 as amended), the ICH GCP guidelines and the Declaration of Helsinki. 
15.8 Indemnity 
This trial is being carried out under the auspices of Cancer Research UK and therefore injury to a patient 
caused by the compounds under trial will not carry with it the right to seek compensation from the 
pharmaceutical industry.  Cancer Research UK will provide patients with compensation for adverse side 
effects, in accordance with the principles set out in the Association of the British Pharmaceutical Industry 
(ABPI) guidelines on compensation for medicine-induced injury. 
15.9 Publication policy and press releases 
Results of this trial must be submitted for publication.  The CDD must be involved in reviewing all drafts 
of the manuscripts, abstracts, press releases and any other publications.  Manuscripts must be 
submitted to CDD at least 30 days in advance of being submitted for publication to allow time for CDD 
to schedule a review and resolve any outstanding issues.  Abstracts and press releases must be 
submitted to CDD at least 14 days in advance of being released.  Authors must acknowledge that the 
trial was sponsored by and performed with the support of CDD. 


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The contribution of CDD must be recognised by at least one member of staff being included as an author 
on the publication.   


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16 
REFERENCES 
 
Cheson, Pfistner et al (2007). Revised Response Criteria for Malignant Lymphoma.  J Clin Onc 25 (5): 
579-86. 
 
Eisenhauer, E.A., P. Therasse, J. Boagaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, 
S. Gwyther, M. Mooney, l. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij (2009). 
New Response Evaluation Criteria in solid tumours: Revised RECIST guidelines (version 1.1). European 
Journal of Cancer 45: 228-247 
 
Gerhart, D. Z., R. L. Leino and L. R. Drewes (1999). "Distribution of monocarboxylate transporters MCT1 
and MCT2 in rat retina." Neuroscience. 92(1): 367-375. 
Koho, N. M., M. Raekallio, E. Kuusela, J. Vuolle and A. R. Poso (2008). Lactate transport in canine red 
blood cells. Am J Vet Res. 69(8): 1091-1096. 
Sonveaux, P., F. Vegran, T. Schroeder, M. C. Wergin, J. Verrax, Z. N. Rabbani, C. J. De Saedeleer, K. 
M. Kennedy, C. Diepart, B. F. Jordan, M. J. Kelley, B. Gallez, M. L. Wahl, O. Feron and M. W. Dewhirst 
(2008). "Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice." J Clin Invest. 
118(12): 3930-3942. 
Skolnik, J.M., Barrett, J.S., Jayaramen, B., Patel, D., Adamson, P.C. (2008). "Shortening the timeline of 
pediatric Phase I trials: The rolling six design."  J Clin Oncol 26: 190-195. 
 
Yap, Y.G., Camm, A.J. (2003). Drug induced QT prolongation and torsades de pointes. Heart. 89, 1363-
1372. 
 
Guideline on strategies to identify and mitigate risks for first-in-human clinical trials with investigational 
medicinal products. July 2007. EMEA/CHMP/SWP/28367/07 
 
Note for Guidance on Good Clinical Practice.  ICH Topic E6.  CSMP/ICH/135/95.  EMEA, May 1996, 
updated September 1997 with post Step 4 errata included  
 
DIRECTIVE 2001/20/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 4 April 2001 
on the approximation of the laws, regulations and administrative provisions of the Member States 
relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal 
products for human use. Official Journal of the European Communities L121/34-44 
 
Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human 
use to the competent authorities, notification of substantial amendments and declaration of the end of 
the trial. October 2005.  ENTR/F2/BL D(2003) CT 1 (Revision 2) 
 
Detailed guidance on the application format and documentation to be submitted in an application for an 
Ethics Committee opinion on the clinical trial on medicinal products for human use. February 2006. 
ENTR/CT 2 (Revision 1) 
 
Detailed guidance on the collection, verification and presentation of adverse reaction reports arising 
from clinical trials on medicinal products for human use. April 2006.  ENTR/CT 3 (Revision 2) 
 
The Medicines for Human Use (Clinical Trials) Regulations 2004 (Statutory Instrument 1031) 
COMMISSION DIRECTIVE 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines 
for good clinical practice as regards investigational medicinal products for human use, as well as the 
requirements for authorisation of the manufacturing or importation of such products.  Official Journal of 
the European Union L 91/13 
 
The Medicines for Human use (Clinical Trials) Amendment Regulations 2006 (Statutory Instrument 
2006/1928). 




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17.2 APPENDIX 2A: MEASUREMENT OF DISEASE IN SOLID TUMOURS 
New response evaluation criteria in solid tumours (RECIST criteria): 
Revised RECIST guideline (version 1.1)  
 
E.A. Eisenhauer et al. (2009) European Journal of Cancer 45: 228-247 
 
Note that this is an abridged version of the RECIST criteria.  Please refer to the above article for detailed 
appendices and if in doubt. 
 
1. 
Measurability of tumour at baseline 
 
1.1 
Definitions 
 
 
At baseline, tumour lesions/lymph nodes will be categorised measurable or non-measurable as follows: 
 
1.1.1 Measurable 
Tumour lesions: Must be accurately measured in at least one dimension (longest diameter in the plane 
of measurement is to be recorded) with a minimum size of: 
 
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm; see Appendix II on imaging 
guidance). 
• 10 mm calliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable). 
• 20 mm by chest X-ray 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must 
be P15mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed (see 
Schwartz et al. in this Special Issue15). See also notes below on ‘Baseline documentation of target and 
non-target lesions’ for information on lymph node measurement. 
 
1.1.2  Non-measurable 
 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes with 
P10 to <15 mm short axis) as well as truly non-measurable lesions.  Lesions considered truly non-
measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory 
breast disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques. 
1.1.3. Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
 
Bone lesions: 
•  
Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure 
bone lesions.  However, these techniques can be used to confirm the presence or disappearance 
of bone lesions.  
•  
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can 
be evaluated by cross sectional imaging techniques such as CT or MRI can be considered as 
measurable lesions if the soft tissue component meets the definition of measurability described 
above. 
•  
Blastic bone lesions are non-measurable. 


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Cystic lesions: 
•  
Lesions that meet the criteria for radiographically defined simple cysts should not be considered 
as malignant lesions (neither measurable nor non-measurable) since they are, by definition, 
simple cysts. 
•  
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above.  However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
 
Lesions with prior local treatment: 
•  
Tumour lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion.  Study protocols should detail the conditions under which such lesions 
would be considered measurable.  
 
 
 
1.2. Specifications by methods of measurements 
 
1.2.1. Measurement of lesions 
 
All measurements should be recorded in metric notation, using calipers if clinically assessed.  All 
baseline evaluations should be performed as close as possible to the treatment start and never more 
than 4 weeks before the beginning of the treatment. 
 
1.2.2. Method of assessment 
 
The same method of assessment and the same technique should be used to characterise each 
identified and reported lesion at baseline and during follow-up.  Imaging based evaluation should always 
be done rather than clinical examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical exam. 
 
Clinical lesions:  
Clinical lesions will only be considered measurable when they are superficial and P10 mm diameter as 
assessed using callipers (e.g. skin nodules). For the case of skin lesions, documentation by colour 
photography including a ruler to estimate the size of the lesion is suggested.  As noted above, when 
lesions can be evaluated by both clinical exam and imaging, imaging evaluation should be undertaken 
since it is more objective and may also be reviewed at the end of the study. 
 
Chest X-ray:  
Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, since 
CT is more sensitive than X-ray, particularly in identifying new lesions.  However, lesions on chest X-
ray may be considered measurable if they are clearly defined and surrounded by aerated lung.  See 
Appendix II for more details. 
 
CT, MRI:  
CT is the best currently available and reproducible method to measure lesions selected for response 
assessment.  This guideline has defined measurability of lesions on CT scan based on the assumption 
that CT slice thickness is 5 mm or less. As is described in Appendix II, when CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness.  MRI is also acceptable in certain situations (e.g. for body scans). More details concerning 
the use of both CT and MRI for assessment of objective tumour response evaluation are provided in 
Appendix II.  
 
 
 


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Ultrasound:  
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement.  Ultrasound examinations cannot be reproduced in their entirety for independent review 
at a later date and, because they are operator dependent, it cannot be guaranteed that the same 
technique and measurements will be taken from one assessment to the next (described in greater detail 
in Appendix II).  If new lesions are identified by ultrasound in the course of the study, confirmation by 
CT or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
 
Endoscopy, laparoscopy: 
The utilisation of these techniques for objective tumour evaluation is not advised.  However, they can 
be useful to confirm complete pathological response when biopsies are obtained or to determine relapse 
in trials where recurrence following complete response or surgical resection is an endpoint. 
 
Tumour markers:  
Tumour markers alone cannot be used to assess objective tumour response.  If markers are initially 
above the upper normal limit, however, they must normalise for a patient to be considered in complete 
response.  Because tumour markers are disease specific, instructions for their measurement should be 
incorporated into protocols on a disease specific basis.  Specific guidelines for both CA-125 response 
(in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer), have been published.  In 
addition, the Gynecologic Cancer Intergroup has developed CA125 progression criteria which are to be 
integrated with objective tumour assessment for use in first-line trials in ovarian cancer.  
 
Cytology, histology:  
These techniques can be used to differentiate between PR and CR in rare cases if required by protocol 
(for example, residual lesions in tumour types such as germ cell tumours, where known residual benign 
tumours can remain).  When effusions are known to be a potential adverse effect of treatment (e.g. with 
certain taxane compounds or angiogenesis inhibitors), the cytological confirmation of the neoplastic 
origin of any effusion that appears or worsens during treatment can be considered if the measurable 
tumour has met criteria for response or stable disease in order to differentiate between response (or 
stable disease) and progressive disease. 
 
 
2.  Tumour response evaluation 
 
2.1  Assessment of overall tumour burden and measurable disease 
To assess objective response or future progression, it is necessary to estimate the overall tumour 
burden at baseline and use this as a comparator for subsequent measurements.  Only patients with 
measurable disease at baseline should be included in protocols where objective tumour response is the 
primary endpoint.  Measurable disease is defined by the presence of at least one measurable lesion (as 
detailed above in Section 1).  In studies where the primary endpoint is tumour progression (either time 
to progression or proportion with progression at a fixed date), the protocol must specify if entry is 
restricted to those with measurable disease or whether patients having non-measurable disease only 
are also eligible. 
 
2.2. Baseline documentation of ‘target’ and ‘non-target’ lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of five lesions 
total (and a maximum of two lesions per organ) representative of all involved organs should be identified 
as target lesions and will be recorded and measured at baseline (this means in instances where patients 
have only one or two organ sites involved a maximum of two and four lesions respectively will be 
recorded).  For evidence to support the selection of only five target lesions, see analyses on a large 
prospective database in the article by Bogaerts et al..  Target lesions should be selected on the basis 
of their size (lesions with the longest diameter), be representative of all involved organs, but in addition 
should be those that lend themselves to reproducible repeated measurements.  It may be the case that, 
on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance 


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the next largest lesion which can be measured reproducibly should be selected.  To illustrate this point 
see the example in Fig. 3 of Appendix II.   
 
Lymph nodes merit special mention since they are normal anatomical structures which may be visible 
by imaging even if not involved by tumour.  As noted in Section 3 of the article, pathological nodes which 
are defined as measurable and may be identified as target lesions must meet the criterion of a short 
axis of P15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline sum.  The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved by 
solid tumour.  Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT scan this is almost always the axial plane; for MRI the plane of acquisition may be 
axial, saggital or coronal).  The smaller of these measures is the short axis.  For example, an abdominal 
node which is reported as being 20 mm x 30 mm has a short axis of 20 mm and qualifies as a malignant, 
measurable node.  In this example, 20mm should be recorded as the node measurement (See also the 
example in Fig. 4 in Appendix II).  All other pathological nodes (those with short axis P10 mm but <15 
mm) should be considered non-target lesions.  Nodes that have a short axis <10 mm are considered 
non- pathological and should not be recorded or followed.   
 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be included in the 
sum, then as noted above, only the short axis is added into the sum.  The baseline sum diameters will 
be used as reference to further characterise any objective tumour regression in the measurable 
dimension of the disease.  
 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as non-
target lesions and should also be recorded at baseline.  Measurements are not required and these 
lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ (more details 
to follow).  In addition, it is possible to record multiple non-target lesions involving the same organ as a 
single item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver 
metastases’). 
 
 
2.3. Response criteria 
 
This section provides the definitions of the criteria used to determine objective tumour response for 
target lesions. 
 
2.3.1. Evaluation of target lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm. (Note: the appearance of one or more new lesions is also considered progression). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study. 
 
2.3.2. Special notes on the assessment of target lesions 
Lymph nodes.  
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 


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regress to below 10 mm on study.  This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal lymph 
node is defined as having a short axis of <10 mm.  Case report forms or other data collection methods 
may therefore be designed to have target nodal lesions recorded in a separate section where, in order 
to qualify for CR, each node must achieve a short axis <10 mm.  For PR, SD and PD, the actual short 
axis measurement of the nodes is to be included in the sum of target lesions. 
 
Target lesions that become ‘too small to measure’.  
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (e.g. 2 mm). However, 
sometimes lesions or lymph nodes which are recorded as target lesions at baseline become so faint on 
CT scan that the radiologist may not feel comfortable assigning an exact measure and may report them 
as being ‘too small to measure’.  When this occurs it is important that a value be recorded on the case 
report form. If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm.  If the lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned (Note: It is less likely that this rule will be used for 
lymph nodes since they usually have a definable size when normal and are frequently surrounded by 
fat such as in the retroperitoneum; however, if a lymph node is believed to be present and is faintly seen 
but too small to measure, a default value of 5mm should be assigned in this circumstance as well).  This 
default value is derived from the 5 mm CT slice thickness (but should not be changed with varying CT 
slice thickness).  The measurement of these lesions is potentially non-reproducible, therefore providing 
this default value will prevent false responses or progressions based upon measurement error.  To 
reiterate, however, if the radiologist is able to provide an actual measure, that should be recorded, even 
if it is below 5 mm. 
 
Lesions that split or coalesce on treatment.  
As noted in Appendix II, when non-nodal lesions ‘fragment’, the longest diameters of the fragmented 
portions should be added together to calculate the target lesion sum.  Similarly, as lesions coalesce, a 
plane between them may be maintained that would aid in obtaining maximal diameter measurements 
of each individual lesion.  If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the ‘coalesced 
lesion’. 
 
2.3.3. Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumour response for the group 
of non-target lesions.  While some non-target lesions may actually be measurable, they need not be 
measured and instead should be assessed only qualitatively at the time points specified in the protocol. 
 
Complete Response (CR): Disappearance of all non-target lesions and normalisation of tumour marker 
level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumour marker 
level above the normal limits. 
Progressive Disease (PD): Unequivocal progression (see comments below) of existing non-target 
lesions. (Note: the appearance of one or more new lesions is also considered progression). 
 
2.3.4. Special notes on assessment of progression of non-target disease 
The concept of progression of non-target disease requires additional explanation as follows: 
When the patient also has measurable disease.  
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there must 
be an overall level of substantial worsening in non-target disease such that, even in presence of SD or 
PR in target disease, the overall tumour burden has increased sufficiently to merit discontinuation of 
therapy (see examples in Appendix II and further details below).  A modest ‘increase’ in the size of one 
or more non-target lesions is usually not sufficient to quality for unequivocal progression status. The 
designation of overall progression solely on the basis of change in non-target disease in the face of SD 
or PR of target disease will therefore be extremely rare.  
 


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When the patient has only non-measurable disease.  
This circumstance arises in some phase III trials when it is not a criterion of study entry to have 
measurable disease.  The same general concepts apply here as noted above, however, in this instance 
there is no measurable disease assessment to factor into the interpretation of an increase in non-
measurable disease burden.  Because worsening in non-target disease cannot be easily quantified (by 
definition: if all lesions are truly non-measurable) a useful test that can be applied when assessing 
patients for unequivocal progression is to consider if the increase in overall disease burden based on 
the change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: i.e. an increase in tumour burden representing an 
additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable 
lesion).  Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an increase in 
lymphangitic disease from localised to widespread, or may be described in protocols as ‘sufficient to 
require a change in therapy’.  Some illustrative examples are shown in Figs. 5 and 6 in Appendix II. If 
‘unequivocal progression’ is seen, the patient should be considered to have had overall PD at that point.  
While it would be ideal to have objective criteria to apply to non-measurable disease, the very nature of 
that disease makes it impossible to do so, therefore the increase must be substantial. 
 
2.3.5. New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some comments on 
detection of new lesions are important.  There are no specific criteria for the identification of new 
radiographic lesions; however, the finding of a new lesion should be unequivocal: i.e. not attributable to 
differences in scanning technique, change in imaging modality or findings thought to represent 
something other than tumour (for example, some ‘new’ bone lesions may be simply healing or flare of 
pre-existing lesions).  This is particularly important when the patient’s baseline lesions show partial or 
complete response.  For example, necrosis of a liver lesion may be reported on a CT scan report as a 
‘new’ cystic lesion, which it is not. 
 
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline is 
considered a new lesion and will indicate disease progression.  An example of this is the patient who 
has visceral disease at baseline and while on study has a CT or MRI brain ordered which reveals 
metastases.  The patient’s brain metastases are considered to be evidence of PD even if he/she did not 
have brain imaging at baseline. 
 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease.  If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan. 
 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression 
(particularly possible ‘new’ disease).  New lesions on the basis of FDG-PET imaging can be identified 
according to the following algorithm: 
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a new 
lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: 
• 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD. 
• 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly progression occurring at that site (if 
so, the date of PD will be the date of the initial abnormal FDG-PET scan).  A ‘positive’ FDG-
PET scan lesion means one which is FDG avid with an uptake greater than twice that of the 
surrounding tissue on the attenuation corrected image. 
• 
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is 
not progressing on the basis of the anatomic images, this is not PD. 
 
 
 


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2.4. Evaluation of best overall response 
The best overall response is the best response recorded from the start of the study treatment until the 
end of treatment taking into account any requirement for confirmation.  On occasion a response may 
not be documented until after the end of therapy so protocols should be clear if post-treatment 
assessments are to be considered in determination of best overall response.  Protocols must specify 
how any new therapy introduced before progression will affect best response designation. The patient’s 
best overall response assignment will depend on the findings of both target and non-target disease and 
will also take into consideration the appearance of new lesions.  Furthermore, depending on the nature 
of the study and the protocol requirements, it may also require confirmatory measurement (see Section 
4.6).  Specifically, in non-randomised trials where response is the primary endpoint, confirmation of PR 
or CR is needed to deem either one the ‘best overall response’.  This is described further below. 
2.4.1. Time point response 
It is assumed that at each protocol specified time point, a response assessment occurs.  Table 1 on the 
next page provides a summary of the overall response status calculation at each time point for patients 
who have measurable disease at baseline.   
 
When patients have non-measurable (therefore non-target) disease only, Table 2 is to be used. 
2.4.2. Missing assessments and inevaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not evaluable (NE) 
at that time point.  If only a subset of lesion measurements are made at an assessment, usually the 
case is also considered NE at that time point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not change the assigned time point response.  This 
would be most likely to happen in the case of PD.  For example, if a patient had a baseline sum of 50 
mm with three measured lesions and at follow-up only two lesions were assessed, but those gave a 
sum of 80 mm, the patient will have achieved PD status, regardless of the contribution of the missing 
lesion.  
2.4.3. Best overall response: all time points 
The best overall response is determined once all the data for the patient is known.   
 
Best response determination in trials where confirmation of complete or partial response IS NOT 
required:  
 
Best response in these trials is defined as the best response across all time points (for example, a 
patient who has SD at first assessment, PR at second assessment, and PD on last assessment has a 
best overall response of PR).  When SD is believed to be best response, it must also meet the protocol 
specified minimum time from baseline.  If the minimum time is not met when SD is otherwise the best 
time point response, the patient’s best response depends on the subsequent assessments.  For 
example, a patient who has SD at first assessment, PD at second and does not meet minimum duration 
for SD, will have a best response of PD.  The same patient lost to follow-up after the first SD assessment 
would be considered inevaluable.   A ‘positive’ FDG-PET scan lesion means one which is FDG avid with 
an uptake greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
Table 1 – Time point response: patients with target (+/–non-target) disease 
 
Target lesions  
Non-target lesions  
New 
lesions  
Overall 
response  
CR 
CR  
CR  
PR  
SD  
Not all evaluated  
PD  
Any  
CR 
 Non-CR/non-PD  
Not evaluated  
Non-PD or not all evaluated 
Non-PD or not all evaluated 
Non-PD  
Any  
PD  
No  
No  
No  
No  
No  
No  
Yes or No  
Yes or No  
CR  
PR  
PR  
PR  
SD 
NE  
PD  
PD  


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Any  
Any  
 
Yes  
PD  
CR = complete response, PR = partial response, SD = stable disease, PD = 
progressive disease, and NE = inevaluable.  
 
 
Table 2 – Time point response: patients with non-target disease only 
 
Non-target 
lesions  
New lesions  Overall response  
CR  
Non-CR/non-PD  
Not all evaluated 
Unequivocal PD  
Any  
 
No  
No  
No  
Yes or No 
Yes  
CR  
Non-CR/non-PD(a) NE  
PD  
PD  
CR = complete response, PD = progressive disease, and NE = inevaluable.  
(a) ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly 
used as endpoint for assessment of efficacy in some trials so to assign this category when no lesions 
can be measured is not advised. 
 
 
Best response determination in trials where confirmation of complete or partial response is required: 
Complete or partial responses may be claimed only if the criteria for each are met at a subsequent time 
point as specified in the protocol (generally 4 weeks later).  In this circumstance, the best overall 
response can be interpreted as in Table 3. 
 
 
Table 3 – Best overall response when confirmation of CR and PR required 
 
Overall response  
Overall response  
BEST overall response 
First time point   
Subsequent time point  
CR  
 
 
CR  
 
 
CR 
CR  
 
 
PR  
 
 
SD, PD or PR(a) 
CR  
 
 
SD  
 
 
SD provided minimum criteria for SD duration met,  
                                                                              otherwise, PD         
CR  
 
 
PD  
 
 
SD provided minimum criteria for SD duration met,  
                                                                              otherwise PD         
CR  
 
 
NE  
 
 
SD provided minimum criteria for SD duration met,  
                                                                              otherwise NE 
PR  
 
 
CR  
 
 
PR 
PR 
 
 
PR  
 
 
PR 
PR  
 
 
SD  
 
 
SD 
PR  
 
 
PD  
 
 
SD provided minimum criteria for SD duration met,       
                                                                              otherwise, PD 
PR  
 
 
NE  
 
 
SD provided minimum criteria for SD duration met,  
 
 
 
 
 
 
otherwise NE 
NE  
 
 
NE  
 
 
NE 
 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = inevaluable. 
(a) If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR). Best response would depend on whether minimum duration for SD was met.  
However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely 


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still present and in fact the patient had PR, not CR at the first time point.  Under these circumstances, 
the original CR should be changed to PR and the best response is PR. 
 
2.4.4. Special notes on response assessment 
 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ size 
(<10 mm), they may still have a measurement reported on scans.  This measurement should be 
recorded even though the nodes are normal in order not to overstate progression should it be based on 
increase in size of the nodes.  As noted earlier, this means that patients with CR may not have a total 
sum of ‘zero’ on the case report form (CRF).  
 
In trials where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination.  The analysis plan for the trial must address how missing 
data/assessments will be addressed in determination of response and progression.  For example, in 
most trials it is reasonable to consider a patient with time point responses of PR-NE-PR as a confirmed 
response.  
 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as ‘symptomatic deterioration’.  
Every effort should be made to document objective progression even after discontinuation of treatment.  
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for stopping study 
therapy.  The objective response status of such patients is to be determined by evaluation of target and 
non-target disease as shown in Tables 1–3. 
 
Conditions that define ‘early progression, early death and inevaluability’ are study specific and should 
be clearly described in each protocol (depending on treatment duration, treatment periodicity). 
 
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  When the 
evaluation of complete response depends upon this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) before assigning a status of complete response. 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where 
a residual radiographic abnormality is thought to represent fibrosis or scarring.  The use of FDG-PET in 
this circumstance should be prospectively described in the protocol and supported by disease specific 
medical literature for the indication.  However, it must be acknowledged that both approaches may lead 
to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic changes or 
necrosis in existing lesions), treatment may continue until the next scheduled assessment.  If at the next 
scheduled assessment, progression is confirmed, the date of progression should be the earlier date 
when progression was suspected. 
 
2.5. Frequency of tumour re-evaluation 
Frequency of tumour re-evaluation while on treatment should be protocol specific and adapted to the 
type and schedule of treatment.  However, in the context of phase II studies where the beneficial effect 
of therapy is not known, follow-up every 6–8 weeks (timed to coincide with the end of a cycle) is 
reasonable.  Smaller or greater time intervals than these could be justified in specific regimens or 
circumstances.  The protocol should specify which organ sites are to be evaluated at baseline (usually 
those most likely to be involved with metastatic disease for the tumour type under study) and how often 
evaluations are repeated.  Normally, all target and non-target sites are evaluated at each assessment.  
In selected circumstances certain non-target organs may be evaluated less frequently.  For example, 
bone scans may need to be repeated only when complete response is identified in target disease or 
when progression in bone is suspected. 
 
After the end of the treatment, the need for repetitive tumour evaluations depends on whether the trial 
has as a goal the response rate or the time to an event (progression/death).   If ‘time to an event’ (e.g. 
time to progression, disease-free survival, progression-free survival) is the main endpoint of the study, 
then routine scheduled re-evaluation of protocol specified sites of disease is warranted.  In randomised 


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comparative trials in particular, the scheduled assessments should be performed as identified on a 
calendar schedule (for example: every 6–8 weeks on treatment or every 3–4 months after treatment) 
and should not be affected by delays in therapy, drug holidays or any other events that might lead to 
imbalance in a treatment arm in the timing of disease assessment. 
 
 
2.6. Confirmatory measurement/duration of response 
 
2.6.1. Confirmation 
In non-randomised trials where response is the primary endpoint, confirmation of PR and CR is required 
to ensure responses identified are not the result of measurement error.  This will also permit appropriate 
interpretation of results in the context of historical data where response has traditionally required 
confirmation in such trials.  However, in all other circumstances, i.e. in randomised trials (phase II or III) 
or studies where stable disease or progression are the primary endpoints, confirmation of response is 
not required since it will not add value to the interpretation of trial results.  However, elimination of the 
requirement for response confirmation may increase the importance of central review to protect against 
bias, in particular in studies which are not blinded.   
 
In the case of SD, measurements must have met the SD criteria at least once after study entry at a 
minimum interval (in general not less than 6–8 weeks) that is defined in the study protocol. 
 
2.6.2. Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met for CR/PR 
(whichever is first recorded) until the first date that recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest measurements recorded on 
study).   
 
The duration of overall complete response is measured from the time measurement criteria are first met 
for CR until the first date that recurrent disease is objectively documented. 
2.6.3. Duration of stable disease 
Stable disease is measured from the start of the treatment (in randomised trials, from date of 
randomisation) until the criteria for progression are met, taking as reference the smallest sum on study 
(if the baseline sum is the smallest, this is the reference for calculation of PD).   The clinical relevance 
of the duration of stable disease varies in different studies and diseases. If the proportion of patients 
achieving stable disease for a minimum period of time is an endpoint of importance in a particular trial, 
the protocol should specify the minimal time interval required between two measurements for 
determination of stable disease. 
Note: The duration of response and stable disease as well as the progression-free survival are 
influenced by the frequency of follow-up after baseline evaluation.  It is not in the scope of this guideline 
to define a standard follow-up frequency.  The frequency should take into account many parameters 
including disease types and stages, treatment periodicity and standard practice. However, these 
limitations of the precision of the measured endpoint should be taken into account if comparisons 
between trials are to be made. 
 
 
 
 




























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17.5 APPENDIX 4: MANAGEMENT OF EYE TOXICITY 
If the patient reports any changes in vision during the course of the trial and between the scheduled 
assessments or any changes are noted during best correct visual acuity tests, a full assessment by 
ERG will be instigated. 
If a 25% (or more) a-wave reduction and/or a 50% (or more) b-wave reduction on ERG is recorded, 
dosing with AZD3965 will be interrupted. ERG assessments will be repeated within 14 days and if the 
changes have not resolved to baseline or less than 25% and 50% respectively within 2 weeks following 
dose delay the patient will be withdrawn from the study.  
 
If a 50% (or more) a-wave reduction on ERG is recorded, dosing with AZD3965 will be stopped 
immediately and the patient withdrawn from the study.  
 
If a patient is withdrawn from the study due to eye toxicity, repeat ERG examinations will be repeated 
within 14 days and performed at least monthly thereafter or until resolution or return to baseline. 


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17.6 APPENDIX 5: Severe valvular heart disease (as defined by British Society of Echocardiography) 
 
http://www.bsecho.org/media/40509/valve-final-2011 2 .pdf