Clinical trial NCT03997474
Conditions: Melanoma
Sponsor: Achilles Therapeutics UK Limited
Start date: 2019-08-15; Completion date: 2024-09-03
Enrollment: 13 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a first-in-human, open-label, multi-centre, phase I/IIa study to characterize the safety and clinical activity of ATL001, autologous clonal neoantigen reactive T cells (cNeT) administered intravenously in adults with metastatic or recurrent melanoma.

Detailed description:
This is a first-in-human, open-label, multi-centre, phase I/IIa study to characterize the safety and clinical activity autologous clonal neoantigen reactive T cells (cNeT) administered intravenously in adults with metastatic or recurrent melanoma.

Patients will initially enter the study for procurement of tumour materials required to manufacture ATL001.Following manufacture of ATL001, the product will be given back to eligible patients following lymphodepletion.

Patients will be followed up for a period of 24 months post ATL001 infusion in the study.

Patients will continue to be followed up for a minimum of 5 years, as part of a separate Long Term Follow Up Protocol, or, if the separate protocol is not available at the study site, within this protocol.

Arms: arm 1: Following lymphodepletion, infusion of cell therapy product ATL001, followed by a low dose regimen of IL- 2. arm 2: Following lymphodepletion, infusion of cell therapy product ATL001 in combination with a checkpoint inhibitor, followed by a low dose regimen of IL-2. arm 3: Following lymphodepletion, infusion of cell therapy product ATL001, followed by a higher dose regimen of IL-2.
Interventions: intervention 1: ATL001 intervention 2: Checkpoint Inhibitor
Intervention descriptions: intervention 1: ATL001 infusion intervention 2: Nivolumab

Protocol documents:
Prot_SAP_000.pdf: 
ACHILLES THERAPEUTICS 
 
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CLINICAL STUDY PROTOCOL  
An Open-Label, Multi-Centre Phase I/IIa Study Evaluating the Safety and Clinical Activity of 
Neoantigen Reactive T cells in Patients with Metastatic or Recurrent Melanoma (THETIS) 
 
Investigational Medicinal Product: ATL001 
Protocol Number: ATX-ME-001  
Version: 11.0 (Master) 
Date: 02 October 2023 
Replaces Version: 10.0 (Master) 
 
PHASE I/IIa 
 
EudraCT Number: 2018-003446-16 
IND Number: 19347 
 
Sponsor: ACHILLES THERAPEUTICS UK LIMITED 
 
 
Confidential 
This protocol includes information and data that contain trade secrets and privileged or 
confidential information that is the property of Achilles Therapeutics UK Limited. This 
information must not be made public without written permission from Achilles Therapeutics UK 
Limited. These restrictions on disclosure will apply equally to all future information supplied to 
you. This material may be disclosed to and used by your staff and associates as may be necessary 
to conduct the clinical study. 






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KEY TRIAL CONTACTS 
 
CHIEF INVESTIGATOR 
 
 
Sponsor 
Achilles Therapeutics UK Limited  
 
 
 
 
 
Funder(s) 
Achilles Therapeutics UK Limited 
Medical Monitor 
 
  
Statistician 
 
 
 


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 PROTOCOL SYNOPSIS 
Title 
An Open-Label, Multi-Centre Phase I/IIa Study Evaluating the 
Safety and Clinical Activity of Neoantigen Reactive T cells in 
Patients with Metastatic or Recurrent Melanoma. 
Protocol Number 
ATX-ME-001 
Sponsor 
Achilles Therapeutics UK Limited 
Development Phase 
I/IIa 
Investigational Product 
ATL001, Autologous clonal neoantigen reactive T cells 
Indication 
Treatment of patients with metastatic or recurrent melanoma who 
have received at least one prior systemic therapy, including a PD-
1/PD-L1 inhibitor 
Objective(s) and 
endpoints 
The objectives and relevant endpoints of the study are as follows: 
Objectives 
Endpoints 
Primary: To 
assess the safety 
and tolerability of 
ATL001 as a 
monotherapy and 
in combination 
with nivolumab 
Frequency and severity of adverse events 
(AEs) and serious adverse events (SAEs) 
following tissue procurement and 
administration of lymphodepletion agents, 
ATL001 (monotherapy or in combination 
with nivolumab) and IL-2. 
Secondary: To 
evaluate the 
clinical activity of 
ATL001 treatment 
as a monotherapy 
and in combination 
with nivolumab 
• 
Percentage change from baseline in 
tumour size at 6 weeks, 12 weeks and 
best change from baseline. 
• 
Overall Response Rate (ORR) (based 
on RECIST v1.1 and imRECIST). 
• 
Time to response (based on RECIST 
v1.1 and imRECIST). 
• 
Duration of response (based on 
RECIST v1.1 and imRECIST). 
• 
Disease Control Rate (CR + PR + 
durable SD) (based on RECIST v1.1). 
• 
Progression free survival (PFS) (based 
on RECIST v1.1 and imRECIST). 
• 
Overall survival (OS). 


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Exploratory:  
1. To evaluate 
the 
persistence, 
phenotype and 
functionality 
of cNeT and to 
explore 
possible 
relationships 
with clinical 
outcomes 
 
Measures of numbers, phenotype and 
functionality of immune cells in starting 
materials, product intermediates and 
ATL001 product. 
Measures of the persistence, phenotype and 
functionality of infused T cells in the 
peripheral blood. 
2. To evaluate 
potential 
biomarkers of 
clinical 
activity and 
factors 
affecting 
response 
Changes from baseline in bespoke clonal 
and subclonal mutation/neoantigen specific 
circulating tumour DNA (ctDNA) panels. 
Potential factors affecting response to be 
explored include but are not limited to: 
patient factors e.g. previous therapies; 
tumour biology factors e.g. total tumour 
mutation burden at baseline, tumour T cell 
infiltrate, major histocompatibility complex 
(MHC) expression and loss of 
heterozygosity (LOH-HLA), tumour 
expression of PD-L1 and other immune 
checkpoint proteins and primary vs 
acquired resistance to a PD-1/PD-L1 
inhibitor; product factors e.g. cNeT dose; 
cNeT engraftment. 
3. To evaluate 
the 
manufacturing 
rate and 
factors that 
may affect the 
quality of 
ATL001 
Number of products made from procured 
samples. 
Reasons for not manufacturing products. 
Potential factors affecting ATL001 quality 
include but are not limited to: patient 
factors e.g. previous therapies; procurement 
sample quality; tumour biology factors e.g. 
PD-L1 expression and TIL phenotype. 
4. To evaluate 
the utility of a 
bespoke 
plasma ctDNA 
assay 
Changes from baseline in bespoke clonal 
and subclonal mutation/neoantigen specific 
ctDNA panels and relationship with clinical 
outcomes. 
Study Design 
This is a first-in-human, open-label multi-centre phase I/IIa study 
to characterise the safety and clinical activity of ATL001 (as a 
monotherapy and in combination with nivolumab), administered 


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intravenously in up to 40 adults with metastatic or recurrent 
melanoma who have received at least one prior systemic therapy, 
including a PD-1/PD-L1 inhibitor. 
In Cohort A, ATL001 will be given as a single dose monotherapy 
with lymphodepletion followed by a daily regimen of low dose, 
subcutaneous IL-2 for 10 days.  
In Cohort B, eligible patients will receive ATL001 treatment as per 
Cohort A in combination with one dose of nivolumab between 
days -13 and -7 before receiving ATL001 and will then re-start 
treatment with nivolumab 2 weeks after receiving ATL001 
(provided any immune-related adverse events have resolved at that 
time). Patients will then continue nivolumab, if tolerated, for up to 
12 months, up to 6 months following a complete response (CR) or 
until RECIST v1.1 confirmed disease progression, whichever is 
sooner. See Section 2 for full details. 
In Cohort C, eligible patients will be treated as per Cohort A 
(ATL001 given as a single dose monotherapy with 
lymphodepletion) but followed by a regimen of (up to) 6 higher 
doses of intravenous IL-2. 
The study will be considered to have proceeded from Phase I to 
Phase II following an Independent Data Safety Monitoring 
Committee (IDSMC) review of the first six patients on this study, 
provided that the IDSMC agrees that the study can proceed 
without modification. 
Number of Patients 
Approximately 40 patients will be enrolled for treatment. 
Cohort A (monotherapy): A minimum of 20 evaluable patients.  
Cohort B (combination with nivolumab): Up to approximately 20 
evaluable patients. 
Cohort C (monotherapy with higher dose IL-2): Up to 
approximately 20 evaluable patients. 
Additional patients may be enrolled if it is considered appropriate 
to further explore clinical activity in a subgroup of patients. 
An interim analysis is planned in this study, after which the 
protocol may be amended to increase the sample size by 
approximately 100 patients to further explore clinical activity. 
Study Duration 
Each patient who receives ATL001 will be followed up for 24 
months or to withdrawal of consent or death, following the 
infusion of ATL001.  Patients will continue to be followed up for a 
minimum of 5 years, as part of a separate Long Term Follow Up 
Protocol, or, if the separate protocol is not available at the study 
site, within this protocol. Once the final patient has completed or 
withdrawn from this study, this protocol will close.  


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If the sample size is increased, the protocol will be amended, and 
timelines revised. 
Study Population 
To be eligible to participate in this study, eligibility criteria will 
apply at two timepoints: at study entry prior to procurement of 
tumour and blood for manufacture of ATL001, and then prior to 
lymphodepletion for treatment with ATL001. 
Inclusion Criteria: 
1. Patient must be at least 18 years old at the screening visit. 
2. Patient must have given written informed consent to 
participate in the study. 
3. Patients must have histologically confirmed diagnosis of 
melanoma. 
4. Patients must have received a PD-1/PD-L1 inhibitor prior 
to treatment with ATL001 (unless contraindicated). 
5. Patients whose tumour is known to have a BRAF V600 
mutation must have received BRAF targeted therapy (as 
well as a PD-1/PD-L1 inhibitor unless contraindicated) 
prior to treatment with ATL001. 
6. Patient is considered medically fit enough to undergo all 
study procedures and interventions: procedures to procure 
blood and tumour tissue, including a general anaesthetic if 
required, and to receive fludarabine, cyclophosphamide 
and IL-2 at protocol doses and schedules. 
7. Patient is considered, in the opinion of the Investigator, 
capable of adhering to the protocol. 
8. Eastern Cooperative Oncology Group (ECOG) 
Performance Status 0-1. 
9. Adequate organ function indicated by the following 
laboratory parameters: 
a. Haemoglobin ≥ 10.0 g/dL. 
b. White Blood Cell Count (WBC) ≥ 3.0 x10⁹/L. 
c. Absolute Neutrophil Count (ANC) ≥ 1.5 x10⁹/L. 
d. Platelets ≥ 100 x10⁹/L. 
e. INR/PT and APTR/APTT < 1.5x ULN, unless 
receiving therapeutic anticoagulation. Investigator 
discretion is required to ensure surgery is safe or 
that anticoagulants can be safely stopped. 
f. AST or ALT ≤ 2.5x ULN. 


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g. Bilirubin < 1.5x ULN (or < 3x ULN if Gilbert’s 
Syndrome) 
h. Creatinine clearance/estimated glomerular 
filtration rate (GFR) ≥ 50 mL/min. 
10. Female patients who are of childbearing potential must 
agree to use a highly effective method of contraception 
during the study and for at least 12 months after the 
ATL001 infusion. Non-sterilised male participants who 
intend to be sexually active with a female partner of 
childbearing potential must use an acceptable method of 
contraception from the time of screening, throughout the 
duration of the study and for at least 6 months after the 
ATL001 infusion. Refer to Appendix G for pregnancy 
testing requirements in Germany. See Section 4.3 for 
details of acceptable methods of contraception. 
In addition to a re-evaluation of criteria 1-10, the following 
inclusion criteria must also be met prior to tissue procurement: 
11. To be eligible to enter this study for procurement, the 
patient must fall into one of the following groups: 
a. Patients with metastatic or recurrent disease who 
have had no prior systemic therapy for advanced 
disease and who have accessible sites of disease 
suitable for collection of adequate tissue for 
ATL001 manufacture. 
b. Patients with metastatic or recurrent disease who 
are on or have completed first line systemic 
therapy and have accessible sites of disease 
suitable for collection of adequate tissue for 
ATL001 manufacture. 
c. Other patients with advanced stage disease for 
whom no other alternative approved treatments are 
available, may be considered on a case-by-case 
basis and should be discussed with the Sponsor 
prior to enrolment. 
12. Anticipated life expectancy ≥ 6 months at the time of 
tissue procurement. 
In addition to a re-evaluation of criteria 1-10, the following 
inclusion criteria must also be met prior to lymphodepletion for 
treatment with ATL001: 
13. Patients must have metastatic melanoma and: 
a. Whose disease has progressed or recurred 
following standard of care. This includes patients 
who have received a component of standard of 


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care therapy as part of a previous clinical trial in 
first line treatment; or 
b. Who are ineligible for, or who cannot tolerate, 
standard of care therapies. Patients who stop 
treatment due to immunotherapy toxicities do not 
need to progress in order to receive treatment with 
ATL001. 
14. Patients must have measurable disease according to 
RECIST v1.1 criteria prior to lymphodepletion.  
15. Patient is considered, in the opinion of the Investigator, 
well enough (i.e. ECOG Performance Status 0-1) to 
receive ATL001 treatment (this will be checked prior to 
lymphodepletion and again prior to receiving ATL001). 
In addition to 1-15, except inclusion 13a, the following 
inclusion criteria must be met for patients to be eligible for 
treatment in Cohort B: 
16. Prior to treatment with ATL001, the treatment regimen 
must have included a PD-1/PD-L1 inhibitor and patients 
should have experienced: 
a. Radiological disease progression; or  
b. Stable disease following at least 4 doses of a PD-
1/PD-L1 inhibitor. 
17. In addition to the need for highly effective contraception 
as outlined in Inclusion Criterion 10 above, female patients 
in Cohort B of childbearing potential must agree to use 
effective contraception during treatment with nivolumab 
and for at least 5 months after the last dose of nivolumab. 
Patients must also agree to provide a serum or urine 
pregnancy test before each nivolumab administration 
during the treatment period in Cohort B. 
Exclusion Criteria: 
1. 
Patients with known leptomeningeal disease or central 
nervous system (CNS) metastases that are untreated or 
symptomatic or progressing. Lesions should be clinically 
and radiologically stable for 2 months after treatment, as 
determined by MRI or CT evaluation, in line with 
accepted standard of care procedures, and should not 
require steroids. 
2. 
Patients with ocular, acral or mucosal melanoma. 
3. 
Patients with hepatitis B or C, human immunodeficiency 
virus infection (HIV1/2), syphilis or HTLVI/II infection 
(see Section 6.1.1). 


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4. 
Patients with active, known, or suspected, autoimmune 
disease requiring immunosuppressive treatments. 
5. 
Patients requiring regular treatment with steroids at a 
dose higher than prednisolone 10 mg/day (or equivalent). 
6. 
Patients with a current or recent history, as determined by 
the Investigator, of clinically significant, progressive, 
and/or uncontrolled renal, hepatic, haematological, 
endocrine, pulmonary, cardiac, gastroenterological or 
neurological disease. 
7. 
Patients with a history of immune mediated central 
nervous system toxicity that was caused by, or suspected 
to be caused by, immunotherapy. 
8. 
Patients with a history of ≥ Grade 2 diarrhoea/colitis 
caused by previous immunotherapy within 6 months of 
screening. Patients that have been asymptomatic for at 
least 6 months or have had a normal colonoscopy post-
immunotherapy (with uninflamed mucosa by visual 
assessment following discontinuation of immune 
suppression other than permitted modified release 
steroids) are not excluded. 
9. 
Patients who are pregnant or breastfeeding. 
10. Patients who have undergone major surgery in the 
previous 3 weeks. 
11. Patients with an active concurrent cancer or a history of 
cancer within the past 3 years (except for in situ 
carcinomas, early prostate cancer with normal Prostate-
Specific Antigen (PSA) or non-melanomatous skin 
cancers).  
12. Patients with a history of organ transplantation. 
13. Patients who have previously received any investigational 
cell or gene therapies. 
14. Patients with contraindications for cyclophosphamide, 
fludarabine and IL-2 at per protocol doses (see 
Investigator’s Brochure for details). 
15. Patients with a confirmed history of allergic reactions to 
amphotericin b, penicillin and/or streptomycin. 
In addition to 1-15, the following exclusion criteria apply to 
patients who have received anti-cancer therapy prior to study 
entry: 
16. Patients who have received any cytotoxic chemotherapy 
within the 3 weeks prior to tissue and blood procurement. 


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In addition, the following exclusion criteria will apply for 
eligibility for Cohort B: 
17. Patients with a history of (non-infectious) pneumonitis 
that required systemic steroids, or current 
pneumonitis/interstitial lung disease. 
18. Patients with a history of severe hypersensitivity to a 
monoclonal antibody, allergy or hypersensitivity to 
nivolumab itself and/or its components. 
19. Patients who have received a live vaccination within the 
28 days prior to the first dose of nivolumab. 
20. Patients with any contraindications for nivolumab (Refer 
to the latest available prescribing information (e.g. 
SmPC/Package Insert) for reference safety information 
for nivolumab). 
In addition, the following exclusion criteria will apply prior to 
lymphodepletion for eligibility for Cohort C: 
21. Patients with a Left Ventricular Ejection Fraction (LVEF) 
< 45%. 
22. Patients with a forced expiratory volume in one second 
(FEV1) of less than or equal to 60% of their predicted 
normal.  
All exclusion criteria, except 3 and 16, will apply again to all 
patients prior to lymphodepletion for treatment with ATL001. 
In addition, the following criteria will apply: 
23. Patients who have received a live vaccination within the 
28 days prior to lymphodepletion. 
24. Patients with an active infection requiring antibiotics. 
25. Patients who have received any cytotoxic chemotherapy 
within the 3 weeks prior to lymphodepletion. 
Study Product Dose, 
Dosing Regimen and 
Administration  
Eligible patients will receive an intravenous infusion of ATL001, 
following pre-conditioning treatment. The infusion should be 
administered as soon as possible after thawing and within 30 
minutes. The active cell dose range to be administered will be 5-
1000 x 107 CD3+ cells, and a minimum of 20 patients with the 
target cell dose will be treated within each cohort. 
In the event that a product is manufactured for a patient but does 
not meet the IMP product release specifications for total CD45+ 
and/or CD3+ cells and/or autologous cell based impurities and/or 
potency, the treating Investigator may make a request for the 
product to be released for use by an individual patient under 
his/her direct responsibility following suitable assessment of the 


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potential benefits and risks for the patient. In such cases the 
patients will be treated and followed up within this protocol, 
according to the scheduled visits and assessments. 
Pre-conditioning 
Treatment 
All patients will receive a lymphodepletion regimen of fludarabine 
30 mg/m2 i.v. and cyclophosphamide 300 mg/m2 i.v. on each of 
Days -6, -5, and -4 prior to cell infusion. These can be 
administered according to local standard operating procedures 
(SOPs). 
Pre-infusion Medication 
Patients will be pre-medicated with a standard regimen to prevent 
infusion reactions (e.g. chlorphenamine and 
paracetamol/acetaminophen) according to local SOPs prior to the 
infusion of ATL001. This prophylactic regimen should not contain 
corticosteroids. 
Patients in Cohort B will receive a dose of nivolumab 240 mg i.v. 
between days -13 and -7 prior to the infusion of ATL001. 
Post-infusion  
Patients in Cohort A will receive 10 doses of IL-2 1M IU/m2 s.c. 
daily from days 0-9 of the study, starting between 3 and 12 hours 
post-infusion. 
Patients in Cohort B will receive IL-2 as per Cohort A with the 
addition of nivolumab starting 2 weeks post infusion and continue 
for up to 12 months, up to 6 months following a CR or until 
RECIST v1.1 confirmed disease progression, whichever is sooner. 
See Section 2 for more details. 
Patients in Cohort C will receive IL-2 at a dose of 600,000 IU/kg, 
administered by intravenous infusion at a frequency of 8-12 
hourly, starting between 3 and 24 hours post-infusion, and 
continued for up to a maximum of six doses as tolerated. 
Safety Evaluation 
Safety will be assessed by regular assessments of infusion 
reactions, adverse events, physical examinations, ECOG 
performance status, laboratory tests, vital signs, 
electrocardiograms, and concomitant medication usage. The 
severity of AEs will be assessed using National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0. Cytokine Release Syndrome (CRS) and 
Immune effector Cell-Associated Neurotoxicity Syndrome 
(ICANS) will be assessed using American Society for 
Transplantation and Cellular Therapy (ASTCT) criteria. For 
patients in Cohort B, AEs related to nivolumab will be assessed 
against NCI CTCAE Version 4.0, as per the SmPC/Package Insert. 
An Independent Data Safety Monitoring Committee (IDSMC) will 
be formed to monitor patient safety during the study. Details of 
IDSMC reviews and study stopping criteria are described in 
Section 7.8. 


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Efficacy Evaluation 
Efficacy will be assessed by MRI/CT scans every 6 weeks to week 
24 and then every 12 weeks. Efficacy will be evaluated per 
RECIST v1.1 criteria. Immune modified response criteria 
(imRECIST) will also be evaluated.  
Exploratory Evaluations 
Biomarker evaluation will include the following: 
• 
Engraftment, expansion, reactivity and persistence of 
ATL001 as determined by T cell receptor (TCR) 
repertoire, enzyme-linked immunospot (ELISpot) and flow 
cytometry in peripheral blood. 
• 
Changes from baseline in ctDNA in blood. 
Manufacturing rate will be assessed: 
• 
The number of products released out of the number of 
patients undergoing tissue procurement will be reported.  
• 
The reasons for not manufacturing products will be 
reported.  
Factors affecting the quality of the final product will be explored 
including tumour characteristics, sample quality and prior 
therapies. 
Special Study 
Procedures 
Tumour tissue procurement for manufacture of ATL001 
(Section 6.1.1): 
A surgical procedure will be necessary to acquire at least 1.5 g (1.5 
cm3) tumour tissue for assessment, T cell extraction and 
manufacturing of ATL001. The surgical procedures for tumour 
tissue procurement should be clinically relevant procedures which 
do not cause undue risk to patients, as determined by the 
Investigator, taking into consideration the risk/benefit for the 
patient. 
Blood procurement for manufacture of ATL001 (Section 
6.1.2): 
A blood sample (target volume 140 mL) will be required from all 
patients as part of the ATL001 manufacturing procedure. Samples 
for infectious disease monitoring, germline DNA sequencing and 
human leukocyte antigen (HLA) typing will also be required as 
part of this process. 
Additional Blood Samples: 
Prior to, and following ATL001 infusion, serial blood samples will 
be required for monitoring of response by ctDNA, and monitoring 
the expansion, persistence and functionality of ATL001 cells. 
At week 6, an additional 150 mL blood will be required to perform 
an extended panel of immunological assays to aid the 


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interpretation of the RECIST response at that time-point, unless 
the clinical condition of the patient precludes it (see Section 8.4). 
Archival Tumour Sample: 
For patients with metastatic disease, access to an archived tumour 
sample (primary or metastatic) may be requested for analysis of 
the tumour microenvironment. 
Optional tumour biopsies to assess tumour immune status:  
If a patient has a tumour that can be safely accessed, optional pre- 
and post-treatment tumour biopsies will be requested to assess 
changes in the tumour microenvironment at one or more of the 
following times: 
• 
Between procurement and treatment with ATL001. 
• 
Following treatment with ATL001. 
• 
At the time of disease progression. 
Optional samples to be acquired from standard of care 
procedures: 
If a patient undergoes any standard of care procedures that involve 
the collection of biological material deemed relevant to ATL001 
treatment, at any time during the period that they are enrolled in 
the study, a sample may be requested for research purposes if one 
can be provided at no additional risk to the patient.  
Statistical 
Considerations and 
Analysis 
Since this is a Phase I/IIa study, there will be no formal hypothesis 
testing and as such, the study has not been formally powered. The 
sample size has been selected to provide adequate information 
about the safety and efficacy of ATL001, whilst also exposing 
minimal numbers of patients to experimental therapy and 
procedures prior to an initial signal of efficacy. 
In Cohort A, a minimum of 20 patients will receive ATL001, at the 
target cell dose, after standard therapies. It is expected that most 
patients will have received a PD-1/PD-L1 inhibitor as part of this 
standard therapy unless patients have contraindications to these 
agents.  
The expectation is that ATL001 could achieve a response in at 
least 30% of patients, based on a response rate of 35% in studies of 
first generation TIL in patients with metastatic melanoma that has 
recurred following treatment with PD-1 inhibitors.  
Based on a sample size of 20 evaluable patients treated at the 
active dose range (5-1000 x 107 CD3+ cells), if the true ORR were 
30%, there would be approximately a 90% probability of 
observing 4 or more responders out of 20 patients. Conversely, if 


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the true response rate were only 10% there would be a 13% 
probability of observing 4 or more responses by chance. 
In Cohort B, up to 20 patients will receive at least one dose of 
nivolumab between days -13 and -7 before receiving ATL001 and 
will then re-start treatment with nivolumab 2 weeks after receiving 
ATL001 (provided there are no ongoing immune-related adverse 
events at that time). Patients will then continue nivolumab, if 
tolerated, for up to 12 months, up to 6 months following a CR or 
until RECIST v1.1 confirmed disease progression, whichever is 
sooner. The sample size of 20 patients has been selected to 
establish the safety, tolerability, and clinical activity of ATL001 
followed by nivolumab, in the context of the overall safety and 
efficacy profile of ATL001 from Cohort A. The totality of the 
safety and tolerability data from the study will contribute to 
decisions regarding the continuation of the combination to the next 
stage of development. 
In Cohort C, up to 20 patients will receive ATL001 followed by 
higher dose IL-2 (600,000 IU/kg) administered by intravenous 
infusion, after standard of care therapies. IL-2 will be given 8-12 
hourly and continued for up to a maximum of six doses as 
tolerated. The sample size of 20 patients has been selected to 
establish the safety, tolerability, and clinical activity of ATL001 
followed by higher doses of IL-2, in the context of the overall 
safety and efficacy profile of ATL001 from Cohort A. 
Decisions about study conduct will be made taking into 
consideration the totality of the safety and efficacy data for the 
cohort. In addition to ORR, the magnitude of tumour regression, 
the disease control rate and the durability of response and PFS 
times will also be considered. 
Analysis plans are described in detail in Section 9. 
Unless otherwise stated, data from Cohorts A, B and C (if latter 
two performed) will be presented separately.  
The data will be summarised using descriptive statistics. 
Continuous variables will be summarised using the number of 
observations, mean, standard deviation, coefficient of variation, 
median, and range as appropriate. Categorical values will be 
summarised using the number of observations and percentages as 
appropriate. Time-to-event endpoints will be estimated using 
Kaplan-Meier methodology. 
The Surgical Population will include all patients who undergo 
tissue procurement. The safety of the tumour and blood 
procurement procedures, the manufacturing rate, and the factors 
affecting product quality will be reported for this population and 
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Data from all patients treated with ATL001 (the Treated 
Population) will be used for safety analyses. Exposure to 
fludarabine, cyclophosphamide, ATL001 and IL-2, along with 
reasons for discontinuation of any study drug will also be 
tabulated. Associations of administered cell dose with safety and 
efficacy outcome measures may be explored. All RECIST and 
imRECIST-based endpoints will be evaluated in the evaluable for 
response (EFR) population. Overall survival will be evaluated in 
the Treated Population (TP). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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STUDY FLOW CHART 
  
 
PATIENT SCHEMA 
 
 
 
 
 


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TABLE OF CONTENTS 
DECLARATION(S) ..................................................................................................................2 
INVESTIGATOR SIGNATURE PAGE ...................................................................................3 
KEY TRIAL CONTACTS ........................................................................................................4 
PROTOCOL SYNOPSIS ..........................................................................................................5 
STUDY FLOW CHART .........................................................................................................18 
PATIENT SCHEMA ...............................................................................................................18 
TABLE OF CONTENTS .........................................................................................................19 
LIST OF ABBREVIATIONS ..................................................................................................24 
1 
INTRODUCTION ...........................................................................................................27 
1.1. 
Background: Standard Treatments for Patients with Melanoma ...........................27 
 
Adjuvant Therapy to Prevent Disease Recurrence Post Resection ..............28 
 
Treatment for Metastatic Melanoma ............................................................28 
 
Second and Later Line Treatments ..............................................................30 
1.2. 
Rationale for Targeting Tumour Neoantigens with Immunotherapies ..................31 
1.3. 
Adoptive Cell Therapy ...........................................................................................32 
 
ACT Using Autologous Tumour Infiltrating Lymphocytes ........................32 
 
ACT Using Genetically Modified T Cells ...................................................32 
 
Differential Toxicity Profile of TILs and CAR-T Cells ..............................33 
1.4. 
ATL001: A Novel Personalised Immunotherapy for Patients with Melanoma .....33 
 
Pre-clinical Experience ................................................................................34 
 
Clinical Experience ......................................................................................35 
2 
TRIAL DESIGN ..............................................................................................................36 
2.1. 
Rationale for Study Design, Treatment Groups and Cell Dose .............................38 
2.2. 
Assessment of Benefit and Risk ............................................................................40 
 
Unmet Medical Need ...................................................................................40 
 
Potential Benefit...........................................................................................40 
 
Assessment and Management of Risk .........................................................40 
2.3. 
Overall Benefit-Risk and Ethical Assessment .......................................................43 
3 
OBJECTIVES AND OUTCOME MEASURES .............................................................43 
3.1. 
Objectives ..............................................................................................................43 
 
Primary Objective ........................................................................................43 
 
Secondary Objective ....................................................................................43 
 
Exploratory Objectives ................................................................................43 
3.2. 
Outcome Measures/Endpoints ...............................................................................44 
 
Primary Endpoint .........................................................................................44 
 
Secondary Endpoints ...................................................................................44 
 
Exploratory Endpoints .................................................................................44 
4 
PARTICIPANT ELIGIBILITY CRITERIA....................................................................44 
4.1. 
Inclusion Criteria ...................................................................................................44 
4.2. 
Exclusion Criteria ..................................................................................................46 


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4.3. 
Restrictions, Contraception Requirements and Prohibited Medications during 
the Study ................................................................................................................48 
4.4. 
Criteria for Participant Discontinuation .................................................................49 
 
Discontinuation from Study Treatment .......................................................49 
 
Discontinuation from Study .........................................................................52 
5 
INVESTIGATIONAL AND AUXILIARY MEDICINAL PRODUCTS .......................52 
5.1. 
Investigational Medicinal Products........................................................................52 
 
ATL001 ........................................................................................................52 
 
Nivolumab (Cohort B Only) ........................................................................54 
5.2. 
Auxiliary Medicinal Products ................................................................................55 
 
Lymphodepletion Agents: Fludarabine and Cyclophosphamide .................55 
 
IL-2 ..............................................................................................................56 
5.3. 
Prior and Concomitant Medications ......................................................................56 
6 
STUDY PLAN AND PROCEDURES ............................................................................56 
6.1. 
Tumour and Blood Procurement for Manufacture of ATL001 .............................56 
 
Tumour Procurement for Manufacture of ATL001 .....................................56 
 
Blood Procurement for Manufacture of ATL001 ........................................57 
 
Situations Requiring Recollection of Blood or Tumour ..............................58 
6.2. 
Lymphodepletion and Administration of ATL001 and IL-2 .................................58 
 
Possibility to Re-administer ATL001 ..........................................................58 
6.3. 
Schedule of Assessments .......................................................................................60 
 
Schedule of Assessments for Cohorts A and C ...........................................60 
 
Schedule of Assessments for Cohort B ........................................................64 
6.4. 
Study Procedures by Visit ......................................................................................68 
 
Consent and Enrolment Procedure ...............................................................68 
 
Screening Visit (30 Days to 7 Days before Tissue Procurement) ...............68 
 
Tissue and Blood Procurement for ATL001 Manufacture ..........................69 
 
Pre-Lymphodepletion Re-screening (Day -28 to Day -7)............................70 
 
Pre-Treatment Evaluation and ATL001 Infusion (Study Days -1 to 0 [+5 
Days]) ...........................................................................................................72 
 
Post Infusion Monitoring (Study Days 1 - 10).............................................73 
 
Early Follow-Up Period (Day 14 - 28) ........................................................74 
 
Intermediate Follow-Up Period (Week 6 - Week 24) ..................................75 
 
Long Term Follow-Up Period (Week 36 - Week 104) ................................76 
 
Survival Follow Up Visits ...........................................................................77 
 
Withdrawal/Completion Visit ......................................................................77 
 
Unscheduled Visit ........................................................................................78 
 
Efficacy Monitoring .....................................................................................78 
 
Cohort B: Nivolumab Treatment Administration ........................................79 
7 
SAFETY MONITORING AND MANAGEMENT GUIDELINES ...............................79 
7.1. 
Anticipated Safety Risks ........................................................................................79 
7.2. 
General Precautions ...............................................................................................80 


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7.3. 
Adverse Events Related to Tissue Procurement Procedures .................................81 
7.4. 
Management of Adverse Events Related to Lymphodepletion Regimen ..............81 
7.5. 
Management of Adverse Events Related to IL-2 ...................................................81 
7.6. 
Management of Adverse Events Related to Nivolumab (Cohort B Patients 
Only) ......................................................................................................................82 
7.7. 
Management of Adverse Events Related to ATL001 Infusion ..............................85 
 
Infusion Reactions .......................................................................................85 
 
DMSO Toxicities .........................................................................................85 
 
Autoimmune Related Toxicity .....................................................................85 
 
Cytokine Release Syndrome ........................................................................86 
 
Immune Effector Cell-Associated Neurotoxicity Syndrome .......................88 
7.8. 
Study Safety Stopping Criteria and Procedures .....................................................91 
8 
MEASUREMENT OF STUDY VARIABLES ...............................................................92 
8.1. 
Screening and On Study Measurements ................................................................92 
 
Performance Status ......................................................................................92 
 
Physical Examination...................................................................................92 
 
Vital Signs ....................................................................................................92 
 
Pulse Oximetry.............................................................................................92 
 
Electrocardiogram ........................................................................................92 
 
Echocardiogram ...........................................................................................92 
 
Colonoscopy ................................................................................................92 
 
Body Weight ................................................................................................92 
 
Pregnancy Test (Female Patients) ................................................................93 
 
Safety Laboratory Measurements ................................................................93 
 
Melanoma Risk Factors ...............................................................................94 
 
Demographics ..............................................................................................94 
 
Archival Tumour Tissue (if available) .........................................................94 
8.2. 
Adverse Events ......................................................................................................94 
 
Definitions per ICH E2A .............................................................................94 
 
Reporting and Recording of Adverse Events...............................................95 
 
Reporting and Recording of Serious Adverse Events..................................96 
 
Adverse Events of Special Interest ..............................................................97 
 
Pregnancy Reporting ....................................................................................98 
 
Expedited Safety Reporting .........................................................................98 
8.3. 
Clinical Efficacy Measurements ............................................................................98 
8.4. 
Immunomonitoring Measurements ........................................................................99 
8.5. 
Exploratory Measurements ....................................................................................99 
 
Circulating Tumour DNA (ctDNA) .............................................................99 
 
Optional Tumour Biopsies .........................................................................100 
 
Optional Samples to be Acquired from Standard of Care Procedures .......100 
9 
STATISTICAL METHODS ..........................................................................................100 


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9.1. 
Sample Size Calculation ......................................................................................100 
9.2. 
Analysis Populations ............................................................................................101 
 
All Patients .................................................................................................101 
 
Surgical Population ....................................................................................101 
 
Full Analysis Set (FAS) .............................................................................101 
 
Treated Patient Population .........................................................................101 
 
Evaluable for Response (EFR) Population ................................................101 
 
Per Protocol Evaluable for Response (PPEFR) Population .......................102 
9.3. 
Study Endpoints ...................................................................................................102 
 
Safety and Tolerability ...............................................................................102 
 
Efficacy Endpoints .....................................................................................102 
 
Exploratory Endpoints ...............................................................................105 
9.4. 
Methods of Statistical Analysis ...........................................................................106 
 
Assessment of Safety and Tolerability ......................................................106 
 
Demographics and Baseline Characteristics ..............................................107 
 
Medical History and Medications ..............................................................108 
 
Efficacy Data .............................................................................................108 
 
Exploratory Endpoint Data ........................................................................108 
9.5. 
Independent Data Safety Monitoring Committee Reviews .................................109 
9.6. 
Interim Analyses ..................................................................................................110 
10 ETHICAL AND REGULATORY REQUIREMENTS .................................................110 
10.1. Ethical Conduct of the Study ...............................................................................110 
10.2. Independent Ethics Committee (IEC) / Institutional Review Board (IRB) 
Review & Reports ................................................................................................110 
10.3. Peer Review .........................................................................................................111 
10.4. Regulatory Compliance .......................................................................................111 
10.5. Notification of Serious Breaches to GCP and/or the Protocol .............................111 
11 STUDY MANAGEMENT ............................................................................................111 
11.1. Patient Information and Consent .........................................................................111 
11.2. Data Protection and Patient Confidentiality ........................................................111 
11.3. Case Report Form Completion ............................................................................112 
11.4. Monitoring and Data Verification ........................................................................112 
11.5. Data Management ................................................................................................113 
11.6. Management and Archiving of Study Documents ...............................................113 
11.7. Audits and Inspections .........................................................................................114 
11.8. Training of Staff ...................................................................................................114 
11.9. Amendments to the Protocol ................................................................................114 
11.10. Study Agreements ................................................................................................115 
11.11. Financial Disclosure.............................................................................................115 
11.12. Study Timetable and Termination .......................................................................115 
11.13. Sample Management ............................................................................................115 


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12 USE OF INFORMATION AND PUBLICATION POLICY ........................................116 
13 EMERGENCY PROCEDURES ....................................................................................116 
13.1. Medical Emergency Contact Procedure...............................................................116 
13.2. Overdose ..............................................................................................................116 
14 REFERENCES ..............................................................................................................117 
15 APPENDICES ...............................................................................................................122 
Appendix A: ECOG Performance Status Score ...............................................................122 
Appendix B: Summary of Differences Between RECIST v1.1 and imRECIST .............123 
Appendix C: Prohibited and Concomitant Medications ..................................................124 
Appendix D: CRS Monitoring Chart ...............................................................................126 
Appendix E: Neurotoxicity Monitoring Charts ...............................................................127 
Appendix F: Expected IL-2 Toxicities and Their Management ......................................128 
Appendix G: Country Specific Requirements – Germany ..............................................129 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ACT 
Adoptive cell therapy 
ADME 
Absorption, distribution, metabolism and excretion 
ADR  
Adverse Drug Reaction 
AE 
Adverse Event 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
ANC 
Absolute neutrophil count 
APTR 
Activated partial thromboplastin ratio 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate transaminase 
ASTCT 
American Society for Transplantation and Cellular Therapy 
ATIMP 
Advanced therapy investigational medicinal product 
BOR 
Best Overall Response 
BP 
Blood pressure 
BUN 
Blood Urea Nitrogen 
CAR 
Chimeric antigen receptor 
CD3 
Cluster of differentiation 3 
CD45 
Lymphocyte common antigen 
CFR 
Code of Federal Regulations 
CHMP 
Committee for Human Medicinal Products 
CLL 
Chronic lymphocytic leukaemia 
CNS 
Central nervous system 
cNeT 
Clonal neoantigen reactive T cells 
CPI 
Checkpoint inhibitor 
CR 
Complete Response 
CRF 
Case Report Form 
CRP 
C-reactive protein 
CRS 
Cytokine release syndrome 
CSP 
Clinical Study Protocol 
CT 
Computed tomography 
CTCAE  
Common terminology criteria for adverse events 
ctDNA 
Circulating tumour DNA 
Cy 
Cyclophosphamide 
DCO 
Data cut-off 
DCR 
Disease Control Rate 
DMSO 
Dimethyl sulphoxide 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of Response 
EBMT 
European Society for Blood and Marrow Transplantation 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EFR 
Evaluable for Response 
EGFR 
Epidermal growth factor receptor 
ELISpot 
Enzyme-linked immunospot 
EMA 
European Medicines Agency 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
U.S. Food and Drug Administration 


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Abbreviation 
Definition 
FEV1 
Forced expiratory volume in one second 
FFPE 
Formalin Fixed Paraffin Embedded  
Flu 
Fludarabine 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
Hb 
Haemoglobin 
HIV 
Human immunodeficiency virus 
HLA  
Human leukocyte antigen 
HR 
Hazard ratio 
i.v. 
Intravenous 
ICANS 
Immune effector Cell-Associated Neurotoxicity Syndrome 
ICE 
Immune effector Cell-associated Encephalopathy 
ICF 
Informed Consent Form 
ICH 
International Committee on Harmonisation 
ICP 
Intracranial pressure 
IDM 
Infectious disease marker 
IDSMC 
Independent Data Safety Monitoring Committee 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
IL 
Interleukin 
imBOR 
imRECIST-based Best Overall Response 
imDOR 
imRECIST-based Duration of Response 
imORR 
imRECIST-based Overall Response Rate 
IMP 
Investigational Medicinal Product 
imPFS 
imRECIST-based Progression Free Survival 
imRECIST 
Immune modified Response evaluation criteria in Solid Tumours 
imTTR 
imRECIST-based Time to Response 
INR 
International normalised ratio 
IRB 
Institutional Review Board 
IU 
International units 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
JACIE 
Joint Accreditation Committee of ISCT and EBMT 
KM 
Kaplan-Meier 
LDH 
Lactate dehydrogenase 
LLN 
Lower limit of normal 
LOH-HLA 
Loss of heterozygosity of HLA 
LP 
Lumbar Puncture 
LVEF 
Left Ventricular Ejection Fraction 
MAP 
Mitogen-activated protein 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHC 
Major histocompatibility complex 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NICE 
The National Institute for Health and Care Excellence 
NMA 
Non-myeloablative 
NSCLC 
Non-small cell lung cancer 
NTL 
Non-target lesion 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMC 
Peripheral blood mononuclear cells 
PD 
Progressive disease 


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Abbreviation 
Definition 
PD-1 
Programmed cell death receptor-1 
PD-L1 
Programmed cell death ligand-1 
PFS 
Progression free survival 
PPEFR 
Per Protocol Evaluable for Response 
PR 
Partial Response 
PS 
Performance Status 
PSA 
Prostate-Specific Antigen 
PT 
Prothrombin time 
QC 
Quality control 
RECIST v1.1 
Response Evaluation Criteria In Solid Tumours v1.1 
RNA 
Ribonucleic acid 
RSI 
Reference safety information 
s.c. 
Subcutaneous 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 
SD 
Stable disease 
SEER  
Surveillance, Epidemiology, and End Results 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SmPC 
Summary of Product Characteristics 
SOP 
Standard operating procedure 
SP 
Surgical Population 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBNK 
T cell, B cell and NK cell phenotyping 
TBI 
Total body irradiation 
TCR 
T cell receptor 
TFT 
Thyroid function test 
TIL 
Tumour infiltrating lymphocyte 
TMB 
Tumour mutational burden 
TNF 
Tumour necrosis factor 
TP 
Treated Population 
TPS 
Tumour proportion score 
TS 
Tumour size 
TTR 
Time to Response 
UK 
United Kingdom 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell count 
 
 


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1 
INTRODUCTION 
1.1. 
Background: Standard Treatments for Patients with Melanoma 
In the UK ~16,000 new cases of melanoma were diagnosed in 2015 with approximately 2,200 deaths 
[Cancer Research UK, 2017]. In the US the corresponding figures are 87,000 and 10,000 [American 
Cancer Society, 2017]. The incidence is rising annually. Risk factors include older age, male sex, light 
skin tones, a history of intermittent intense sun exposure or use of tanning beds, immunosuppressive 
procedures or drugs, pre-existing moles or skin cancers and a family history of melanoma. 
Staging of melanoma is based on the thickness of the cutaneous tumour (T) the presence or absence of 
ulceration or satellite lesions, the status of local lymph nodes (N) the presence or absence of distant 
metastases (M) and whether these are limited to skin, subcutaneous tissues or lymph nodes or involve 
the lung or visceral organs. Figure 1 summarises the staging groups which carry prognostic 
implications. Most patients are diagnosed with early stage disease (stage I or II) which can be cured by 
surgical excision; these patients can expect to survive for at least 5 years. However, for patients 
diagnosed with metastatic disease (Stage IV), the 5-year survival falls to 25%.  
 
Figure 1: Staging of Melanoma 
Source: American Joint Committee on Cancer Melanoma of the Skin Staging 8th edition 
The risk of recurrence is related to the stage at diagnosis and is increased in patients with ulcerated or 
> 1 mm thick lesions. Recurrence may occur at the original site, in the local lymph nodes or at distant 
sites. A retrospective study recently reported clinical outcomes in 173 UK patients with high-risk 
resected Stages II and III cutaneous melanoma who had undergone imaging surveillance every 6 months 
for 3 years, then annually for 2 years [Lim et al, 2018]. Most of the patients (79%) had Stages IIIB and 
IIIC disease. With a median follow-up of 23.3 months, 82 patients (47%) had relapsed. Median time to 
relapse in these patients was 10.1 months while the median relapse free survival in the overall group 
was 21.2 months. Most (68%) of the patients recurred with Stage IV disease. 


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Systemic treatment options for patients with melanoma include immunotherapies, targeted therapies for 
cancers with specific mutations and cytotoxic chemotherapy. The most effective agents are the immune 
checkpoint inhibitors and agents that inhibit the BRAF/MEK signalling pathway. 
Melanoma has the highest known tumour mutation burden of all cancers and is also an immunogenic 
tumour, having the capacity to induce adaptive immune responses that can prevent its growth [Chalmers 
et al, 2017]. Checkpoint Inhibitors are monoclonal antibodies that enhance the ability of tumour 
infiltrating lymphocytes (TILs) to recognise and kill tumour cells. Activated cytotoxic T cells express 
the Programmed Death Receptor 1 (PD-1), which recognise a ligand (PD-L1) that is expressed on a 
proportion of tumour cells and antigen presenting cells. When PD-1 binds to PD-L1, T cell anti-tumour 
activity is suppressed. Pembrolizumab and nivolumab both bind to PD-1 and in doing so they enhance 
the ability of tumour infiltrating lymphocytes (TILs) to recognise and kill tumour cells. Ipilimumab is 
an antibody that binds to cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), another checkpoint 
molecule expressed on T cells that down-regulates the immune response. 
Approximately 40% of advanced melanoma patients have detectable activating mutations in the gene 
encoding the BRAF V600 protein kinase, which leads to constitutive activation of downstream 
signalling in the MAP kinase pathway. This pathway can be targeted by agents that inhibit BRAF 
signalling (dabrafenib or vemurafenib) or MEK signalling (trametinib). 
 
Adjuvant Therapy to Prevent Disease Recurrence Post Resection 
The risk of recurrence for high risk resectable disease can be reduced using adjuvant therapy following 
surgery. For patients whose tumours have a BRAF V600 mutation, the combination of dabrafenib and 
trametinib is authorised in Europe and the USA, and recommended by NICE (UK), as an adjuvant 
treatment for resectable stage III disease. In the randomised phase III COMBI-AD study, the estimated 
3-year rate of relapse-free survival was 58% in the combination-therapy group and 39% in the placebo 
group (HR 0.47; P<0.001) [Long et al, 2017]. 
The PD-1 inhibitors pembrolizumab, nivolumab and ipilimumab are authorised in the USA as adjuvant 
therapies for patients with completely resected Stage III/IV disease who are at high risk of recurrence. 
Nivolumab improved the recurrence free survival rate at 1 year from 60.8% with ipilimumab to 70.5% 
(HR 0.66 p<0.0001) based on the results of the Checkmate 238 study [Weber et al, 2017.] 
Pembrolizumab has also demonstrated efficacy in the adjuvant setting in the phase III KEYNOTE-054 
study, in which pembrolizumab improved the relapse-free survival rate at 1 year from 61% with placebo 
to 75.6% (HR 0.57, P<0.0001) [Eggermont et al, 2018].   
 
Treatment for Metastatic Melanoma 
Figure 2 summarises the approach to selecting initial systemic therapy in patients with extracranial 
metastatic cutaneous melanoma. 


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Figure 2: Approach to Selecting Initial Systemic Therapy in Patients with Extracranial Metastatic 
Cutaneous Melanoma 
Source: UpToDate, 2022 
Checkpoint inhibitors are the treatment of choice for the first line therapy of unresectable metastatic 
melanoma. The PD-1 inhibitor pembrolizumab was approved in 2014 based on data from the 
KEYNOTE-006 and KEYNOTE-002 studies. KEYNOTE-006 was a multi-centre, controlled, Phase III 
study of pembrolizumab compared to ipilimumab for the treatment of advanced melanoma (first or 
second line) in 834 patients who were naïve to ipilimumab. Pembrolizumab at a dose of 10 mg/kg every 
2 or 3 weeks for up to 2 years significantly improved progression free survival (PFS) (HR 0.61, 5.6 
months vs 2.8 months), OS (HR 0.68, median not reached) and overall response rate (ORR) (37% vs 
13%) including 14% CRs [Schachter et al, 2017]. KEYNOTE-002 was a controlled Phase II trial of 
pembrolizumab (10 mg/kg and 2 mg/kg every 3 weeks) vs physician choice chemotherapy in melanoma 
patients previously treated with ipilimumab and with a BRAF or MEK inhibitor (if BRAF V600 
mutation-positive). Pembrolizumab at both doses was superior to chemotherapy for PFS (HR 0.58). 
There was no statistically significant difference between pembrolizumab and chemotherapy in OS, 
however of the patients randomised to the chemotherapy arm, 55% subsequently received treatment 
with pembrolizumab [Ribas et al, 2015]. 
Nivolumab, another PD-1 inhibitor, is also indicated for the treatment of advanced (unresectable or 
metastatic) melanoma in adults based on two randomised Phase III studies. In the Checkmate-066 study, 
the safety and efficacy of nivolumab 3 mg/kg was compared to dacarbazine in 405 patients with 
treatment-naive, Stage III or IV, BRAF wild-type melanoma [Robert et al, 2015]. Nivolumab 
significantly improved OS (HR 0.42), PFS (HR 0.43) and ORR (40% vs 14% with 7.6% CR). In a 
second randomised, open-label study (Checkmate-037), nivolumab was compared to physician’s choice 
chemotherapy in 272 patients who had progressed on or after ipilimumab and on or after BRAF inhibitor 
(if mutation positive). The primary endpoint was ORR, which was 31.7% on nivolumab compared to 
10.6% on chemotherapy [Weber et al, 2015]. In the final OS analysis, there was no difference in survival 
(median OS 16 months for nivolumab vs 14 months for chemotherapy; HR 0.95) however, the 
nivolumab group included a higher proportion of poor prognostic factors including brain metastases 
and high LDH, and 41% of the chemotherapy patients crossed over to receive a checkpoint inhibitor 
post progression [Larkin et al, 2018]. There were fewer grade 3 or higher treatment-related adverse 
events in patients on nivolumab (14% v 34%).  


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The CTLA-4 inhibitor ipilimumab was the first approved checkpoint inhibitor for melanoma in 2011, 
but its use in the first line setting has largely been replaced by the combination of nivolumab plus 
ipilimumab, which has shown superior efficacy to ipilimumab monotherapy in the Checkmate-067 
study [Larkin et al, 2015]. In this randomised phase 3 study, nivolumab in combination with ipilimumab 
was compared with nivolumab monotherapy and ipilimumab monotherapy in adult patients with 
confirmed unresectable Stage III or Stage IV melanoma who had not received prior systemic anti-cancer 
therapy for their condition, although prior adjuvant or neoadjuvant therapy was allowed if it was 
completed at least 6 weeks before randomisation. The co-primary endpoints were PFS and OS. The 
combination significantly improved PFS (HR 0.42, p<0.001) compared to ipilimumab, with a median 
PFS of 11.5 months vs 6.9 months for nivolumab and 2.9 months for ipilimumab alone. The response 
rate was also improved on the combination (57.6% vs 43.7% for nivolumab and 19% for ipilimumab). 
At a 3-year analysis of overall survival (OS), the combination showed a statistically significant 
improvement in OS (HR 0.55 p<0.001) compared to ipilimumab with a 3-year survival rate of 58% vs 
34% [Wolchok et al, 2017]. The combination of nivolumab plus ipilimumab was associated with a 
higher rate of high-grade or serious adverse events than ipilimumab alone, notably elevation of 
transaminases, diarrhoea and colitis. Ipilimumab monotherapy remains an option for patients who have 
recurrent disease having previously received a PD-1 inhibitor in the adjuvant treatment setting. 
Immune checkpoint inhibitors have changed the treatment paradigm for patients with advanced 
melanoma, but resistance eventually emerges in the majority of patients. Resistance may be primary or 
acquired, and several mechanisms may contribute to both phenotypes. Primary resistance may be a 
result of intrinsically low antigenicity, low T cell infiltration or a failure of the T cell recognition 
machinery. Acquired resistance may evolve through adaptive loss of antigenicity (e.g. through loss of 
tumour neoantigen expression or defective surface presentation through loss of MHC) and/or 
recognition machinery, and/or modulation of the tumour microenvironment through treatment. 
Patients with melanoma characterized by BRAF mutations have additional treatment options in the form 
of BRAF and MET inhibitors. Dabrafenib demonstrated a statistically significant improvement in PFS 
compared to dacarbazine in the BREAK-3 study [Hauschild et al, 2012]. Median PFS was 6.9 months 
for dabrafenib compared with 2.7 months for dacarbazine (HR 0.37, p<0.0001). There was no 
significant improvement in OS but approximately 57% of patients assigned to receive dacarbazine had 
crossed over to the dabrafenib arm at the time of the final OS analysis. In the BRIM-3 trial [Chapman 
et al, 2017] vemurafenib improved both OS and PFS compared to dacarbazine (OS HR 0.37, p<0.001; 
PFS HR 0.26, p<0.001). The MEK inhibitor, trametinib may be combined with dabrafenib, based on 
the data from two Phase III studies showing that the combination significantly improved OS compared 
to dabrafenib or vemurafenib alone [Flaherty et al, 2012; Grob et al, 2015] with a median OS of 25.1 
and 25.6 months. However, since the checkpoint inhibitors show similar long-term benefits in 
BRAF V600 mutation-positive and negative disease, most patients with BRAF mutations receive 
immunotherapy as first line therapy. BRAF inhibitors appear to be similarly effective when given before 
or after immunotherapy, and so can be reserved for later line therapy for patients who have stopped 
responding to a checkpoint inhibitor. However, for patients with rapidly progressing disease, a high 
disease burden or elevated lactate dehydrogenase levels, in whom a rapid onset of action is needed, they 
remain the first line treatment of choice as it may take three or four months to show a response to 
checkpoint inhibitor therapy. 
 
Second and Later Line Treatments 
In patients with disease progression following first line therapy, treatment options depend on the agent 
that was given first line. BRAF pathway inhibitors remain an option for the 40% of patients with a 
BRAF mutation, and ipilimumab monotherapy is an option for patients who have not received it in the 
first line setting. Other options include cytotoxic chemotherapy agents (e.g. dacarbazine, temozolomide, 


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carboplatin, paclitaxel) or first generation immunotherapeutic agents such as Interferon and high-dose 
IL-2, all of which are associated with considerable morbidity.  
1.2. 
Rationale for Targeting Tumour Neoantigens with Immunotherapies 
Tumorigenesis is driven by the accumulation of genetic mutations in regulatory pathways that ultimately 
confer a survival advantage to a single clone that leads to uncontrolled proliferation. The mutational 
load of cancer can vary significantly and certain cancers such as melanoma are characterised by an 
unusually high mutational burden. Many of these mutations occur within coding regions of a gene and 
are expressed within the cell creating novel, tumour-specific antigens, or neoantigens. The higher the 
mutational load, the higher the number of potential neoantigens, a fraction of which can be presented 
efficiently via host human leukocyte antigen (HLA) molecules to the immune system. However, 
immune evasion is a hallmark of cancer and the tumour develops resistance mechanisms to prevent this 
interaction, including the up-regulation of immune checkpoint molecules such as PD-L1.  
The success of the checkpoint inhibitors demonstrates the benefit of enhancing the power of intra-
tumoural T cells to attack cancers; some patients experience long term survival benefits. Tumours with 
the highest mutational burden present more tumour neoantigens to the host and appear to be more 
susceptible to immunotherapy [Rizvi et al, 2015; McGranahan et al, 2016]. These neoantigens are 
thought to be the major contributors to the clinically relevant responses that have been documented 
following treatment with immune-therapeutic approaches, either checkpoint inhibitors or adoptive T 
cell therapies in patients with melanoma [Lee & Margolin, 2012]. There are also multiple reports of the 
positive prognostic significance of the degree of tumour lymphocyte infiltration in cancer patients 
[Kinoshita et al, 2016; Feng et al, 2016; Zeng et al, 2016] and it is increasingly recognised that the 
proportion of intra-tumoural CD8+ T cells recognising tumour neoantigens is an important predictor of 
outcome to checkpoint inhibitors [Rizvi et al, 2015]. 
Antigens expressed by tumours may be tumour-specific or tumour-associated. Tumour-specific 
neoantigens are unique to the tumour as they arise from tumour-specific mutations, while tumour-
associated antigens may be preferentially expressed by tumours but are shared by normal tissues. As 
cancers are collections of cells which have been exposed to multiple tumour initiating events, they 
include numerous subclones of the original tumour initiating cells. Each of these subclones has a 
different set of mutations but recent data suggest that the mutations arising from the earliest 
transforming mutagenic events (known as truncal or clonal mutations) are retained in all the subclones, 
and are tumour-specific, despite the acquisition of more mutations during the natural history of the 
tumour [Jamal-Hanjani et al, 2017]. Melanoma patients whose tumours contain large numbers of these 
original truncal mutations appear to have a survival benefit over those whose tumours are heavily 
branched [McGranahan et al, 2016], suggesting that T cell responses are more effective in these cases. 
A high clonal mutagenic burden present in every tumour cell offers a profound vulnerability that can 
be exploited by an adoptive T cell therapy that is specifically primed to recognise multiple patient-
specific clonal neoantigens.  
Truncal neoantigens are an ideal target for a cancer therapy as they are expressed exclusively on tumour 
cells and expressed by all tumour cells – endowing low potential for bystander toxicity and low chance 
for immune escape respectively. A therapeutic approach of expanding specific clonal neoantigen 
reactive T cells (cNeT) and treating patients with their own cell therapy product is expected to 
effectively increase the proportion of cNeT in tumours. As these active T cells are able to recognise the 
clonal neoantigens that are present in all the tumour cells, this may bring long term benefits to patients 
with melanoma, either as a stand-alone treatment or in combination with checkpoint inhibitors.  


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1.3. 
Adoptive Cell Therapy  
 
ACT Using Autologous Tumour Infiltrating Lymphocytes 
TILs have been isolated successfully from multiple solid tumours and expanded ex vivo for clinical 
trials since the first report in 1986 [Rosenberg, Speiss & Lafrenier, 1986]. In patients with metastatic 
melanoma, ex vivo expanded TILs have achieved clinically meaningful results (ORRs of 50%, CR rates 
of 20%) and patients who achieve CR have demonstrated long term disease free survival for many years 
[Itzhaki et al, 2011; Hinrichs & Rosenberg, 2014; Besser et al, 2013; Dudley et al, 2013; Goff et al, 
2016; Andersen et al, 2016; Ellebaek et al, 2012]. Most of these studies were initiated some years ago, 
before the widespread use of PD-1 inhibitors and may not all be considered clinically relevant based on 
current clinical practice. However, Sarnaik et al, 2019 recently presented data on the safety and efficacy 
of cryopreserved autologous TIL therapy (LN-144, lifileucel) in 66 advanced metastatic melanoma 
patients who progressed on multiple prior line of therapy including anti-PD-1 [Sarnaik et al, 2019]. In 
this heavily pre-treated and PD-1 resistant group, the response rate was 38% with 3% CR and 80% 
disease control rate (DCR). Durable responses were observed, and some responses were observed in 
patients with PD-1 negative tumours, suggesting that TIL-ACT may be an effective option for patients 
with PD-1 resistant cancers or cancers with lower immunogenicity. 
Although these are small single arm studies, the efficacy data appear comparable to the response rates 
and survival data demonstrated by immune checkpoint inhibitors in the same clinical setting. However, 
until recently it has not been possible to expand the therapy beyond one or two clinical trial centres due 
to limitations of manufacturing processes. 
These studies generally utilised TILs selected according to their reactivity to autologous tumour cells, 
expanded ex vivo and infused back into the donating patient after non myeloablative lymphodepletion. 
Patients received IL-2 therapy post TIL transfusion. The tumour antigens recognised by TILs are a 
mixture of tumour-associated antigens (molecules which are expressed preferentially by tumour cells 
but not exclusive to the tumour cells and are present at lower densities on normal cells) and tumour-
specific antigens (neoantigens) which are peptides derived from unique proteins created by the tumour-
specific mutations.  
 
ACT Using Genetically Modified T Cells 
Genetic engineering advances have facilitated the development of ACT by T cells that can recognise 
specific tumour antigens. One approach is to transduce specific T cell receptors into T cells [Morgan et 
al, 2006]. The most successful approach, however, has been the development of chimeric antigen 
receptor (CAR) T-cell therapy, whereby T cells are isolated from a patient’s blood and undergo ex vivo 
expansion followed by genetic engineering to express CAR molecules and are then re-infused. In a 
CAR, the ligand-binding domain is derived from the single chain variable fragment of a monoclonal 
antibody which recognises a specific tumour antigen in a non-HLA restricted context. In 2017, the FDA 
approved two CD19-targeted CAR T-cells, tisagenlecleucel and axicabtagene ciloleucel, based on 
unprecedented efficacy in refractory B cell haematological malignancies. In one trial of 101 patients 
with refractory B-cell lymphoma, 82% patients achieved an objective response, and 54% had a complete 
response [Neelapu et al, 2017]; in another trial of 75 patients with relapsed or refractory B-cell acute 
lymphoblastic leukaemia, an ORR of 81% was seen [Maude et al, 2018] and an 89% ORR was observed 
in a smaller study of 18 patients with relapsed and refractory multiple myeloma [Berdeja et al, 2017]. 
To date, CAR-T cell therapy has not produced efficacy in trials in patients with solid tumours. Potential 
hypotheses for this differential efficacy include the identification of appropriately immunogenic targets, 
poor trafficking of blood derived lymphocytes into the tumour, or the suppressive tumour 
microenvironment. Safety has been a concern with both TCR-transduced T cells and CAR-T cells 


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because their targets are generally shared tumour-associated antigens rather than tumour-specific 
neoantigens which has resulted in unacceptable or life-threatening autoimmune reactions in some 
patients [Johnson et al, 2009; Parkhurst et al, 2011]. Some encouraging results have been observed with 
receptor-engineered T-cells directed against the tumour-germline antigen, NY-ESO-1 which is 
expressed in the majority of synovial sarcomas, and 25% of melanomas. In a phase I study of 38 patients 
selected for the appropriate HLA subtype, objective response rates of 55-61% were observed, including 
some complete and durable responses, and there was no evidence of autoimmunity [Robbins et al, 
2015]. 
 
Differential Toxicity Profile of TILs and CAR-T Cells 
As described above, CAR-T cell therapies have been associated with some severe toxicities related to 
in vivo T cell proliferation and activation, whereas similar toxicities have not generally been reported 
for TIL therapies. The contrasting tolerability profiles of TIL therapies and CAR-T cell therapies 
suggests that ACT can be well tolerated as long as the cell therapy recognises tumour-specific antigens 
only. Furthermore, conventional tumour infiltrating T cells are populations of naturally occurring 
central memory T cells which have been subject to in vivo immune selection for self-tolerance. This 
selection is largely driven by their avidity for self-antigens; the high avidity clones are selected out 
during T cell development. In contrast, CAR-T cells carry artificial high avidity T cell receptors which 
may react against normal tissue that expresses low levels of tumour-associated antigens. 
In addition, use of cells expressing the native T cell receptor reduces the risk of severe cytokine-
associated toxicities that have been documented with CAR-T therapies where the chimeric TCR has a 
supra-physiological affinity for the cognate antigen and inherent co-stimulation within the CAR 
construct. CAR-T cells are capable of far more rapid proliferation than TILs, and both CD4 and CD8 T 
cells are equally triggered by the tumour antigen, with proinflammatory CD4 cells potentially releasing 
pathological levels of inflammatory cytokines. In contrast, expanded, naturally occurring TILs remain 
constrained by their need to be triggered by tumour peptides presented by the HLA molecules expressed 
on the surface of the tumour cells; the majority of which are MHC class I restricted and can only initiate 
CD8 T cell activation and triggering, whilst a smaller number of CD4 TILs can respond to MHC class 
II restricted peptides presented by intra-tumoural antigen presenting cells and releasing physiological 
levels of cytokines to support CD8 TIL expansion and formation of effector memory populations. 
1.4. 
ATL001: A Novel Personalised Immunotherapy for Patients with Melanoma 
ATL001 is a T cell advanced therapy investigational medicinal product (ATIMP) derived from 
autologous tumour-infiltrating lymphocytes enriched for neoantigen specificity following co-culture 
with antigen presenting cells that present predicted immunogenic clonal neoantigen epitopes expressed 
within the patient’s tumour. 
By sequencing a patient’s tumour, comparing it to the germline DNA of the patient and applying 
bioinformatics algorithms, it is possible to identify tumour-specific mutations. As downregulation of 
HLA genes may result in reduced antigen presentation [Tran et al, 2016; McGranahan et al, 2017], this 
is also assessed, to identify the clonal neoantigens that are most likely to be presented to the immune 
system. The corresponding peptide neoantigens are manufactured and cultured with antigen presenting 
cells, which can process them for presentation to T cells. Using these clonal neoantigens to specifically 
activate and expand clones of tumour infiltrating lymphocytes enhances the ability of TILs to recognise 
such neoantigens and to target the cells that express them. 
  


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Figure 3: Outline Principle of cNeT Therapy and Manufacturing Process for ATL001 
 
Pre-clinical Experience 
Clinical Pharmacology 
Animal models in immune compromised mice are not considered relevant for evaluating 
pharmacological activity of cNeT. Whilst murine models of T cell biology are well established they 
have very limited use as pre-clinical correlates of human cNeT since the in vivo homing and of cNeT 
to tumour and penetration of that tissue would require ligation of human adhesion molecules on the 
cNeT to their cognate ligands which are not present in a murine model. 
Experiments using primary human tissues are considered to be the most relevant pre-clinical data. The 
Sponsor has generated CD4+ and CD8+ cNeT from primary NSCLC and melanoma tumours and 
demonstrated that cNeT retained specificity for the predicted neoantigens when re-challenged, 
determined by secretion of effector cytokines, IFN-γ and TNF-α, in functional potency assays. 
The Sponsor has successfully generated pilot-scale cNeT products from patient tumour material in 10 
out of 12 proof-of-concept manufacturing runs in NSCLC and 5 out of 6 proof-of-concept 
manufacturing runs in melanoma. In all cNeT products, the number of reactivities against neoantigen 
peptide pools was between 2 and 20 with both CD4+ and CD8+ T cell responses detected. Further details 
are provided in the Investigator’s Brochure. 
Pharmacokinetics and Toxicology  
In accordance with the EMA Guideline on Human Cell Based Medicinal Products 
(EMEA/CHMP/410869/2006) and FDA Guidance for Industry: Preclinical Assessment of 
Investigational Cellular and Gene Therapy Products, conventional absorption, distribution, metabolism 
and excretion (ADME) studies are not considered relevant for ATL001. Similarly, acute toxicology, 
chronic toxicology, genotoxicity, carcinogenicity, reproductive and developmental toxicity, safety 
pharmacology 
and 
immunotoxicity 
studies 
are 
not 
planned 
(http://www.ich.org/products/guidelines/safety/article/safety-guidelines.html). Animal models are not 
considered relevant for the toxicology evaluation of human cells in this context as there are clear 
challenges to using the human cells in rodent models. 


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Clinical Experience 
There is little clinical information for ATL001 to date. Refer to the Investigator’s Brochure for the latest 
available clinical information on patients treated with ATL001. 
Clinical data have been published from over 1000 patients treated with TIL adoptive cell therapy (ACT), 
mostly in patients with malignant melanoma [Merhavi-Shoham et al, 2017]. ACT with TILs produced 
in this manner appears to be well tolerated, adverse effects reported in the literature being limited to 
transient pancytopenia related to the lymphodepletion regimens employed, febrile neutropenia and/or 
sepsis as a consequence, and effects related to IL-2 treatment. The doses of these auxiliary agents are 
lower in this study than generally used in reported TIL studies and are discussed in Section 5.2. 
Table 1 summarises the clinical activity and safety data observed with TIL therapy in recently published 
Phase 2 clinical trials in patients with melanoma. 
Table 1: Clinical Activity and Safety Data with TIL Therapies in Phase 2 Clinical Trials 
Treatment 
Phase/ 
Design 
N= 
ORR 
(%) 
CR 
(%) 
DoR 
Grade 3+ AEs 
Reference 
TIL  
Phase 2 
Single arm 
93 
56 
22 
Ongoing 
at 3-7 
years if 
CR 
Not reported 
Rosenberg, et al., 
2011 
CD8 
enriched 
young TIL 
Phase 2 
NMA/IL-2 
without 
TBI 
33 
58 
9 
Not 
reported 
50% Neutropenia 
Dudley, et al., 
2010 
NMA/IL-2 
with TBI 
23 
48 
9 
Not 
reported 
TIL  
Phase 2 
NMA/IL-2 
without 
TBI 
51 
46 
24 
mOS 38 
months 
50% Neutropenia 
Goff, et al., 2016 
NMA/IL-2 
with TBI 
50  
62 
24 
mOS 36 
months 
70% Neutropenia 
26% Thrombotic 
microangiopathy 
TIL  
Phase 2 
Uveal 
melanoma 
Single arm 
20 
35 
5 
Not 
reported 
100% 
Thrombocytopen
ia 
67% Anaemia 
29% Infection 
Chandran, et al., 
2017 


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Treatment 
Phase/ 
Design 
N= 
ORR 
(%) 
CR 
(%) 
DoR 
Grade 3+ AEs 
Reference 
TIL + 
Ipilimumab 
Phase 2 
Single arm 
13 
39 
1 
mPFS 
7.3 
months 
(6-30 
months) 
Hypothyroidism 
(3) 
Hepatitis (2) 
Uveitis (1) 
Colitis (1) 
(Ipilimumab 
related) 
Mullinax, et al., 
2018 
TIL 
Phase 2 
post PD-1 
inhibitor 
46 
37* 
(some 
unconf
irmed) 
Not 
reported 
1.3+ – 
14+ 
months- 
ongoing 
Not reported 
Iovance 
Biotherapeutics; 
Press Release, 11 
Oct 2018 
TIL 
Phase 2 
Single arm 
74 
42 
11 
mOS   
17.3 
months   
Fatigue (13%)   
Hyperbilirubine
mia (11%)  
Febrile 
neutropenia 
(8%)   
Capillary leak 
syndrome (4%)   
Forget, et al., 
2018 
TIL 
3rd line 
and later – 
all PD-1 
resistant 
66 
38 
3 
Not 
reported 
Thrombocytopen
ia (80%)   
Anemia (55%)   
Febrile 
neutropenia 
(53%)   
Neutropenia 
(38%)   
Hypophosphatem
ia (33%)   
Lymphopenia 
(29%)   
Sarnaik, et al., 
2019 
2 
TRIAL DESIGN 
This is a first-in-human, open-label, multi-centre, phase I/IIa study to characterise the safety and clinical 
activity of autologous clonal neoantigen reactive T cells (cNeT) administered intravenously in adults 
with metastatic and recurrent melanoma.  


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Following consent and screening, eligible patients will initially enter the study for procurement of tissue 
and blood to manufacture ATL001. Tissue may be procured either before or after commencing standard 
systemic therapies for melanoma. If patients have received prior systemic therapy, they must have no 
therapy induced toxicities at the time of tissue procurement. Procedure-related AEs and all SAEs from 
the time of the procurement to 28 days following procurement, or the start of anti-cancer therapy if 
sooner, will be collected.   
The surgical procedures for tumour tissue procurement should be clinically relevant procedures which 
do not cause undue risk to patients, as determined by the Investigator, taking into consideration the 
risk/benefit for the patient. 
While ATL001 is being manufactured, patients can receive further standard of care therapy for 
melanoma. Any therapies not deemed standard should be discussed with the Sponsor before initiation. 
Patients must have received a PD-1/PD-L1 inhibitor before receiving ATL001 unless contraindicated. 
When ATL001 is ready for infusion, patients will undergo additional screening procedures and if they 
remain eligible, they will undergo 3 days of lymphodepletion therapy followed by administration of 
ATL001, followed by administration of IL-2. For Cohorts A and B, patients will receive 10 daily 
subcutaneous doses of IL-2, while those in Cohort C will receive up to 6 doses of intravenous IL-2 
every 8-12 hours.  
ATL001 will be given as a monotherapy in Cohort A and Cohort C, i.e. no anti-cancer treatments will 
be given after treatment, until the time of confirmed disease progression.  
Once ATL001 monotherapy has been shown to be safe and tolerable in Cohort A, following a planned 
IDSMC safety review when a minimum of 6 patients have been treated and followed up for 28 days, 
there will be an option to open Cohort B and Cohort C. In Cohort B, ATL001 will be given in 
combination with nivolumab. In Cohort C, ATL001 will be given in combination with a higher dose 
IL-2 regimen. Additionally, provided that the IDSMC agrees that the study can proceed without 
modification, the study will be considered to have proceeded from Phase I to Phase II following this 
IDSMC review. Once the IDSMC have approved continuation to Cohort B and Cohort C, the timing of 
opening these cohorts will be decided by the Sponsor.  
Eligible patients for Cohort B must have experienced radiological disease progression after treatment 
with a PD-1/PD-L1 inhibitor or stable disease following 4 doses of a PD-1/PD-L1 inhibitor, prior to 
receiving ATL001, and who are enrolled at a centre where Cohort B is open at the time of re-screening 
for ATL001 infusion. Patients should not have experienced any toxicity that would prevent them from 
receiving nivolumab.  
Patients will be informed about all treatment cohorts and those who may be eligible will be asked if 
they will consider receiving ATL001 either as a monotherapy in treatment Cohort A and Cohort C, or 
in combination with nivolumab in treatment Cohort B, dependent upon which of the cohorts are open 
at the centre at the time of treatment. 
In Cohort B, eligible patients will receive a single dose of nivolumab 240 mg i.v. between day -13 and 
-7, aiming to give it as close to day -6 (the first day of lymphodepletion) as practical, prior to receiving 
ATL001. Following ATL001 dosing, patients will then commence nivolumab at a dose of 480 mg i.v. 
every 4 weeks, starting 2 weeks after receiving ATL001, provided that any treatment related adverse 
events have resolved and that patients have no contraindications to restarting nivolumab. Patients will 
continue treatment, if tolerated, for up to 12 months, or up to 6 months following a complete response 
(CR) or until RECIST v1.1 confirmed disease progression, whichever is sooner.   
In Cohort C, IL-2 dosing will begin between 3 and 24 hours after completion of the ATL001 infusion. 
IL-2 will be administered at a dose of 600,000 IU/kg (based on total body weight) and will be 


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administered by intravenous infusion at a frequency of 8-12 hourly and continued for up to a maximum 
of six doses as tolerated. IL-2 dosing will be interrupted if patient experiences Grade 3 or 4 toxicity 
related to IL-2 (with the exception of reversible Grade 3 toxicities attributable to IL-2 such as diarrhoea, 
nausea, vomiting, hypotension, rash/skin changes, anorexia, mucositis, dysphagia, or constitutional 
symptoms and laboratory changes). Management of IL-2 toxicity is detailed in Appendix F. If toxicities 
can be reversed within 24 hours by supportive measures, then additional doses may continue. If greater 
than two doses of IL-2 are skipped, IL-2 administration will be ceased. In addition, dosing may be held 
or stopped at the discretion of the treating Investigator.  
Patients will be followed up for a period of 24 months post ATL001 infusion, at which time they will 
have completed their participation in the study. Patients who experience disease progression before this 
time should still be followed up for survival and adverse events of special interest. Each patient who 
received ATL001 will continue to be followed up for a minimum of 5 years, as part of a separate Long 
Term Follow Up Protocol, or, if the separate protocol is not available at the study site, within this 
protocol.  
2.1. 
Rationale for Study Design, Treatment Groups and Cell Dose 
Melanoma has the highest known tumour mutation burden of all cancers and is also an immunogenic 
tumour, having the capacity to induce adaptive immune responses that can prevent its growth [Dunn et 
al, 2015]. Melanoma is responsive to immunological therapies which increase T cell infiltration into 
tumour tissue, and first generation TIL products have already demonstrated the capacity to induce long 
term complete responses in patients with recurrent disease with an acceptable safety profile. As such, it 
is a tumour that is likely to benefit from a cNeT therapy.  
Tumour tissue can be obtained via planned surgery from accessible sites with limited risk to patients 
and the Sponsor has demonstrated that TILs can be obtained from metastatic melanoma tumours and 
expanded ex vivo upon recognition of tumour-specific clonal neoantigens. The prediction of clonal 
neoantigens from metastatic tumours may be enhanced by sequencing the primary tumour, so a sample 
of the archived primary tissue will be requested for patients with metastatic disease, where available.  
While ATL001 is being manufactured, patients can receive further standard of care therapy for 
melanoma. Any therapies not deemed standard should be discussed with the Sponsor before initiation. 
Patients must have received a PD-1/PD-L1 inhibitor before receiving ATL001 unless contraindicated. 
In treatment Cohort A, patients will receive ATL001 as a monotherapy following standard of care 
therapies. It is expected that all patients will have received a PD-1/PD-L1 inhibitor as part of their 
standard therapy unless patients have contraindications to these agents.  
The option to open treatment Cohort B (combination with nivolumab) will allow an assessment of the 
potential therapeutic interaction of cNeTs and an immune checkpoint inhibitor. Since cNeTs express 
the effector cytokine IFN-γ, which is known to promote upregulation of PD-L1 in tumour cells, the 
concurrent use of nivolumab, an inhibitor of PD-1 interaction, may enhance the clinical anti-tumour 
activity of cNeTs.  
The option to open treatment Cohort C (higher dose IL-2) will allow an assessment of the potential 
therapeutic interaction of cNeTs and higher doses of IL-2 delivered intravenously. This higher dose 
regimen is closer in range to traditional IL-2 dosing in stage IV melanoma. Despite cNeTs requiring 
less IL-2 during their manufacture relative to other ACTs, higher doses of IL-2 may enhance their 
clinical anti-tumour activity.  
Since this is a single arm, Phase I/IIa study, there will be no formal hypothesis testing and as such, the 
study has not been formally powered. The cohort size has been selected based on historical response 
data for TILs and checkpoint inhibitors in patients with recurrent metastatic melanoma, to provide 


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adequate information about the safety and efficacy of ATL001, whilst exposing minimal numbers of 
patients to experimental therapy and procedures prior to an initial signal of efficacy. 
As the ATL001 product is patient specific, the cell dose will fall within a range. The lowest active cell 
dose to be infused is 5 x 107 CD3+ cells. The maximum active dose is 1000 x 107 CD3+ cells. This range 
has been selected based on prior reports of TIL-based adoptive cell therapy. A dose of cells may be 
comprised of one or more bags. Due to the manufacturing processes, it is unlikely that more than 1000 
x 107 CD3+ cells reactive to clonal neoantigens will be generated. However, should additional cells be 
generated, an additional dose may be prepared and stored for infusion at a future time point if clinically 
indicated. 
A variety of T cell dose regimens have been utilised in previous studies of adoptive cell therapy but, to 
date, there is no convincing evidence that the likelihood of efficacy correlates with administered cell 
dose, nor is increasing administered cell dose clearly associated with increased risk of toxicity. Early 
TIL trials used T cell doses exceeding 1011 cells with no apparent toxicity, but the cells were over 
expanded in vitro, with concomitant induction of senescence, down regulation of CD27 [Dudley et al, 
2005] and increased expression of CD57. Subsequent and current trials of conventional TIL therapies 
have generally investigated cell doses of 1010 cells with minimal ex vivo expansion, retention of CD27 
and CD28 expression and retention of proliferative capacity as determined by telomere length [Robbins 
et al, 2004]. In contrast with overall cell dose, the retention of proliferative capacity correlates with in 
vivo persistence of TIL therapy and with positive clinical outcome in the treatment of melanoma [Zhou 
et al, 2005]. 
The lack of correlation between administered dose and efficacy from previous studies supports the 
concept of a “threshold” dose; i.e. that which provides an immunological network of cells capable of 
sustaining in vivo proliferation. The data to support this hypothesis are from various clinical trials of 
adoptive T cell immunotherapy of viral infections where doses of 104-106 T cells reactive to viral 
neoantigens have been shown to be efficacious [Peggs et al, 2003; Peggs et al, 2011] and lead to 
substantial expansion in vivo and sustained immunity, in contrast to the transient immunity associated 
with infusion of doses of 1011 ex vivo expanded anti-viral T cells [Riddell et al, 1992].  
Given the lack of previous correlation between cell dose and efficacy or toxicity we plan to administer 
an active dose of TILs generated for each patient product within the target range of 5-1000 x 107 CD3+ 
cells. The lower end of the active dose range is set at 5 x 107 CD3+ cells to maximise the chance of 
observing clinical activity, if a cell dose-efficacy relationship exists. However, there is no data to 
suggest that this cell dose is the minimally clinically active dose.  
In the event that a product is manufactured for a patient but is considered to be “out of specification” 
because it does not meet the minimum cell doses and/or it contains higher than permitted autologous 
cell based impurities and/or it has not met the required potency, the Investigator may still consider it to 
be in the best interest of the patient to receive the product, based on a lack of alternative treatment and 
clinical trial options. In such cases, per applicable regulatory guidelines, the treating Investigator may 
make an exceptional request for the product to be released for use following a risk assessment. 
In up to 20 such cases, patients may receive an “out of specification” product within this study protocol, 
as long as all of the protocol requirements are met except product related attributes. All instances of 
patients receiving an “out of specification” product will be recorded. The safety and efficacy data from 
patients receiving an “out of specification” product will be presented separately to the data from patients 
receiving the intended cell dose range. Thus, the collection of data within this protocol from up to 20 
patients treated with “out of specification” products will allow flexibility to explore and understand 
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The supply of an ATL001 product that is considered “out of specification” with data to be captured in 
this protocol will be upon request from the treating Investigator, taking into account the alternative 
options for the subject and the consequences of not receiving the product. Refer to Appendix G for 
restrictions related to the use of “out of specification” products in Germany. 
2.2. 
Assessment of Benefit and Risk  
 
Unmet Medical Need 
The recent approval of checkpoint inhibitors for the first line treatment of metastatic and recurrent 
melanoma has significantly improved outcomes for patients, with some patients achieving long term 
responses. Despite this, some patients are refractory to checkpoint inhibitors or develop acquired 
resistance and in this situation treatment options are limited. There is an unmet need for new, more 
effective therapies for melanoma patients who have experienced disease progression on a PD-1/PD-L1 
inhibitor. 
 
Potential Benefit 
ATL001 is a novel, personalised treatment that is expected to target a patient’s tumour-specific clonal 
neoantigens and may have the potential for long term clinical benefit in melanoma as the target is 
present in every tumour cell. This concept is supported by the following observations: (1) First 
generation TILs have demonstrated clinically important responses in patients with metastatic 
melanoma; (2) Higher numbers of tumour infiltrating lymphocytes in melanomas are associated with 
improved outcomes (3) High TMB and high numbers of clonal mutations are associated with improved 
outcomes to immunotherapies in lung cancer and melanoma [McGranahan et al, 2016].  
 
Assessment and Management of Risk 
The principal anticipated safety risks anticipated for ATL001 therapy are associated with the 
procurement procedure, the infusion of cells and the administration of auxiliary medications 
(fludarabine, cyclophosphamide and IL-2). 
Monitoring and management plans for all potential safety risks are described in Section 7.  
Procurement Procedure Risks 
The protocol eligibility criteria require that the patient is considered medically fit enough to undergo 
procedures to procure blood and tumour tissue, including a general anaesthetic if required. 
The surgical procedures for tumour tissue procurement should be clinically relevant procedures which 
do not cause undue risk to patients, as determined by the Investigator, taking into consideration the 
risk/benefit for the patient. 
The precise risks of surgical procurement procedures will vary according to the specific surgical 
procedure required to procure at least 1.5 g (1.5 cm3) of tissue and/or the anaesthetic. Anticipated 
surgery-related events could include infection, bleeding and pain.  Procedure-related AEs and all SAEs 
from the time of the procurement to 28 days following procurement, or the start of anti-cancer therapy 
if sooner, will be collected. 
The requirement to provide 140 mL blood to make the ATL001 product should not pose a significant 
risk to patients in itself. UK national transfusion guidelines recommend that a maximum of 15% of total 
blood volume (i.e. 750 mL for men and 565 mL for women) can be safely donated without risk of 
hypovolaemia [Joint UK Blood Transfusion and Tissue Transplantation Services Professional Advisory 
Committee, 2018]. However, minimum pre-donation haemoglobin concentration requirements for 
blood donors are 125 g/L for females and 135 g/L for males, whereas patients with melanoma may have 


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lower haemoglobin levels. National guidelines for transfusion may vary. The prior donation of 140 ml 
of blood may modestly increase the likelihood of requiring a blood transfusion if there is any significant 
bleeding during the procedure. 
ATL001 Infusion Risks 
There may be a risk of an infusion reaction (e.g. fever, chills, headache). This risk will be reduced by 
the 
administration 
of 
standard 
prophylactic 
regimens 
(e.g. 
chlorphenamine 
and 
paracetamol/acetaminophen) before the infusion is given according to local SOPs. The use of 
corticosteroids for prophylaxis is prohibited. 
Very rarely, adverse reactions associated with the cryoprotectant agent 10% dimethyl sulphoxide 
(DMSO) have been reported, most commonly hypertension. Blood pressure (BP) and other vital signs 
will be monitored at the start and end of the infusion, and frequently post infusion. 
Cytokine release syndrome (CRS) and associated toxicities, including neurological toxicity, is 
considered a potential risk because of in vivo T cell proliferation and activation, although this is not 
anticipated to be as great with a TIL product as for patients receiving a CAR-T cell therapy due to the 
limited potential for on-target off-tumour toxicities, and physiological rather than supraphysiological 
stimulation of the T cell through its native receptor rather than the CAR (as described in Section 1). 
CRS usually occurs within one week of CAR-T cell therapy. In this study, patients should remain in the 
hospital facility for the time required by clinical consideration. A suggested management plan for CRS, 
based on European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation 
Committee of ISCT and EBMT (JACIE) guidelines, is provided in Section 7.7.4. 
Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS) is considered a potential risk as it 
is the second most common adverse event reported with CAR-T cell therapies and has been observed 
with other immunotherapies. It may occur at the same time as CRS or after CRS has resolved, and 
manifests as a variety of symptoms, including delirium, somnolescence, seizures, cognitive defects, 
ataxia, nerve palsies, dysphasia, encephalopathy, hallucinations and in severe cases, rapid onset of 
cerebral oedema. Symptoms generally resolve over a period of 2 to 9 days, with management. A 
suggested monitoring and management plan for ICANS, based on EBMT and JACIE guidelines, is 
provided in Section 7.7.5. 
It is noted that many patients receiving ATL001 infusion will have received prior checkpoint inhibitors 
and may have experienced immune-related adverse events related to these agents. For those with a 
history of primary or secondary hypoadrenalism who are receiving physiological glucocorticoid 
replacement for adrenal insufficiency, and for those with adrenal insufficiency who do not usually 
require maintenance, it is important to recognise the need for increased doses, or initiation of dosing of 
glucocorticoids to cover the “stress” period associated with the study intervention. Institutions may have 
their own standard approaches which should be followed, but general considerations include doubling 
of daily doses, switching to short-acting, more rapidly absorbed preparations for patients receiving long-
acting preparations, and consideration of switching from oral to parenteral routes of administration in 
patients who are unable to take oral medications or with significant gastro-intestinal symptoms 
(vomiting/severe diarrhoea). It is also important that patients remain aware of the potential need for 
increased dosing should they become unwell following discharge from hospital. 
The risk of administering a product that does not meet the IMP product release specifications for CD45+ 
or CD3+ cell dose, and/or includes increased levels of autologous cell based impurities and/or has not 
met the required potency, is that the product may be less likely to expand in vivo and lead to sustained 
immune response than an active product containing ≥ 5 x 107 CD3+ cells reactive to clonal neoantigens. 
To maximise the chances of observing a sustained response, an active dose range of 5-1000 x 107 CD3+ 
cells has been set, although it is acknowledged that this range has not been evaluated clinically and 


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there is no data to suggest that this is a minimal clinically active dose. However, if no other treatment 
or clinical trial options are considered to be beneficial and if the Investigator considers it to be in the 
best interest of the patient, administration of ATL001 that did not meet the set release criteria may be 
considered preferable to no treatment. In this case, the protocol makes provision for such patients to 
receive the product and be followed up within this protocol, per applicable regulatory guidelines, in 
order to ensure adequate safety monitoring, and to enable the collection of all safety and efficacy data 
from such patients. These data are pertinent to the study objectives and will contribute to the overall 
understanding of the safety profile and the association between cell dose and clinical endpoints.  
Risks of Auxiliary Medications 
The fludarabine and cyclophosphamide lymphodepletion regimen is expected to cause transient 
pancytopenia for up to 14 days, during which time patients will be susceptible to infections. Other 
common side effects associated with fludarabine and cyclophosphamide include poor appetite, nausea 
and vomiting, fatigue and diarrhoea. Cyclophosphamide at very high doses used in allogeneic transplant 
conditioning regimens can cause bladder irritation and fluid retention, but this is not anticipated with 
the doses to be used in this study. 
IL-2, at the doses used in the past to treat melanoma and renal cancer, is known to cause hypotension, 
diarrhoea, chills, nausea, vomiting, and rash. A very rare side effect is ‘capillary leak syndrome’ which 
can cause limb oedema, hypotension, arrhythmias, dyspnoea and hypoalbuminaemia. The daily doses 
of IL-2 that will be used in Cohorts A and B of this study are significantly lower than these doses, hence 
it is considered unlikely that capillary leak syndrome will occur as it has not generally been reported in 
previously published TIL studies using lower doses of IL-2. As additional precautions, in particular for 
patients in Cohort C, patients will need to be hospitalised for close monitoring during the IL-2 
administration period. 
Patients with a history of ≥ Grade 2 diarrhoea/colitis caused by previous immunotherapy, within 6 
months of screening, will not be eligible for any Cohort. However, patients that have been asymptomatic 
for at least 6 months or have had a normal colonoscopy post-immunotherapy (with uninflamed mucosa 
by visual assessment) are not excluded. Additionally, any patient with a history of neurological toxicity 
related to, or suspected to be related to, immunotherapy will also be excluded.  
These auxiliary medicines are discussed further in Section 5.2. 
Each of the first 3 patients enrolled in the study (from each treatment cohort) will be observed for 14 
days following ATL001 infusion before the next patient can undergo lymphodepletion. This 
observation period is considered sufficient to identify symptoms of immediate cytokine release 
syndrome and enable dose adjustment, if appropriate, for future patients. Following reviews of safety 
data from the initial patients, the observation period between patient administrations may be reduced 
(see Section 7.2 for the review procedure and decision criteria). 
Risks of Nivolumab (Cohort B Patients Only) 
Immune-related adverse reactions are common with nivolumab and most are reversible but some severe 
and fatal cases have occurred. Patients should be monitored continuously (at least up to 5 months after 
the last dose) as an adverse reaction with nivolumab may occur at any time during or after 
discontinuation of therapy. 
Immune related events include pneumonitis, colitis, endocrinopathies, hepatitis, nephritis, skin 
reactions, uveitis, arthritis, myositis, myocarditis, pancreatitis, Guillain-Barré syndrome, myelitis, 
myasthenia gravis, myasthenic syndrome, aseptic meningitis, autoimmune neuropathy (including facial 
and abducent nerve paresis), encephalitis, gastritis, duodenitis, sarcoidosis, rhabdomyolysis and cases 
of Vogt-Koyanagi-Harada syndrome. 


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Patients who receive nivolumab in Cohort B will have previously received a PD-1/PD-L1 inhibitor as 
part of standard of care treatments and will not be eligible for Cohort B if they have any 
contraindications for treatment, i.e. if they have experienced previously any recurrent Grade 3 immune-
related adverse events or any Grade 4 immune related adverse events attributed to a PD-1/PD-L1 
inhibitor.  
Refer to the latest available prescribing information (e.g. Summary of Product Characteristics 
(SmPC)/Package Insert) for further reference safety information for nivolumab.  
Potential Long-Term Risks 
Concerns about risks of tumorigenicity have been raised for genetically modified ACTs. Given that 
TILs undergo relatively modest expansion, and that CD3+ T-cells are diploid, differentiated cells with 
a finite proliferation potential, a very low risk of tumorigenicity is foreseen. Even in the setting of 
genetically modified T cell therapies, it has been demonstrated that mature T-cells exhibit resistance to 
oncogenic transformation [Newrzela et al, 2008]. In clinical trials involving gene transfer into mature 
T cells, leukaemia was never observed, despite follow-up assessments of more than 10 years. On this 
basis, neither in vitro nor in vivo evaluations of tumorigenic potential are planned as the risk is 
considered low. This approach is consistent with the development of sipuleucel-T (EPAR, 
EMA/440011/2013; STN, BL 125197) and Zalmoxis (EPAR, EMA/CHMP/589978/2016). The safety 
follow-up period of 2 years is considered appropriate to monitor this risk in patients with advanced or 
recurrent metastatic melanoma in whom the 5-year survival is still currently less than 20%. 
2.3. 
Overall Benefit-Risk and Ethical Assessment 
Advanced inoperable metastatic or recurrent melanoma remains an incurable disease for the vast 
majority of patients and there is a need for effective therapies to elicit deep and durable responses and 
to extend life without the cost of long-term tolerability burden. ATL001 represents a novel approach to 
melanoma therapy and may address this unmet need in patients with advanced disease who have been 
treated with a PD-1/PD-L1 inhibitor, for whom there are no approved curative therapies. It is considered 
appropriate to investigate ATL001 in patients with metastatic or recurrent melanoma following standard 
therapeutic interventions. 
3 
OBJECTIVES AND OUTCOME MEASURES 
3.1. 
Objectives 
 
Primary Objective 
To assess the safety and tolerability of ATL001 as a monotherapy and in combination with nivolumab. 
 
Secondary Objective 
To evaluate the clinical activity of ATL001 (using RECIST v1.1 and imRECIST) as a monotherapy and 
in combination with nivolumab. 
 
Exploratory Objectives 
1. To evaluate the persistence, phenotype and functionality of cNeT and to explore possible 
relationships with clinical outcomes. 
2. To evaluate potential biomarkers of clinical activity and factors affecting response. 
3. To evaluate the manufacturing rate and factors that may affect the quality of ATL001. 
4. To evaluate the utility of a bespoke plasma ctDNA assay. 


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3.2. 
Outcome Measures/Endpoints 
 
Primary Endpoint 
Frequency and severity of adverse events (AEs) and serious adverse events (SAEs) following tissue 
procurement and administration of lymphodepletion agents, ATL001 (monotherapy or in combination 
with nivolumab) and IL-2. 
 
Secondary Endpoints 
1. Percentage change from baseline in tumour size at 6 weeks and 12 weeks. 
2. Best percentage change from baseline in tumour size. 
3. Overall Response Rate (ORR).  
4. Time to response (TTR). 
5. Duration of response (DoR). 
6. Disease Control Rate (CR + PR + durable SD). 
7. Progression free survival (PFS). 
8. Overall survival (OS). 
 
Exploratory Endpoints 
1. Measures of numbers, phenotype and functionality of immune cells in starting materials, 
product intermediates, and ATL001 product. 
2. Measures of persistence, phenotype, functionality of infused T cells in the peripheral blood. 
3. Changes from baseline in bespoke clonal and subclonal mutation specific ctDNA panels. 
4. Number of products made from procured samples. 
5. Reasons for not manufacturing products. 
6. Potential factors affecting product quality to be explored, include but are not limited to: patient 
factors e.g. previous therapies; procurement sample quality; tumour biology factors e.g. PD-L1 
expression and TIL phenotype. 
7. Potential factors affecting clinical response to be explored include but are not limited to: patient 
factors e.g. previous therapies; tumour biology factors e.g. total tumour mutation burden at 
baseline, tumour T cell infiltrate, MHC expression and LOH-HLA, tumour expression of PD-
L1 and other immune checkpoint proteins and primary vs acquired resistance to a PD-1/PD-L1 
inhibitor; product factors e.g. cNeT dose; and cNeT engraftment.  
4 
PARTICIPANT ELIGIBILITY CRITERIA 
4.1. 
Inclusion Criteria 
To be eligible to participate in this study, eligibility criteria will apply at two timepoints: at study entry 
prior to procurement of tumour and blood for manufacture of ATL001, and then prior to 
lymphodepletion for treatment with ATL001. Participation in this clinical study should not preclude 
patients from receiving approved therapies that are considered likely to be beneficial for their condition. 
Inclusion Criteria: 


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1. Patient must be at least 18 years old at the screening visit. 
2. Patient must have given written informed consent to participate in the study. 
3. Patients must have histologically confirmed diagnosis of melanoma. 
4. Patients must have received a PD-1/PD-L1 inhibitor prior to treatment with ATL001 (unless 
contraindicated). 
5. Patients whose tumour is known to have a BRAF V600 mutation must have received BRAF 
targeted therapy (as well as a PD-1/PD-L1 inhibitor unless contraindicated) prior to treatment 
with ATL001. 
6. Patient is considered medically fit enough to undergo all study procedures and interventions: 
procedures to procure blood and tumour tissue, including a general anaesthetic if required, and 
to receive fludarabine, cyclophosphamide and IL-2 at protocol doses and schedules. 
7. Patient is considered, in the opinion of the Investigator, capable of adhering to the protocol. 
8. ECOG Performance Status 0-1. 
9. Adequate organ function, indicated by the following laboratory parameters: 
a. Haemoglobin ≥ 10.0 g/dL. 
b. White Blood Cell Count (WBC) ≥ 3.0 x10⁹/L. 
c. Absolute Neutrophil Count (ANC) ≥ 1.5 x10⁹/L. 
d. Platelets ≥ 100 x10⁹/L. 
e. INR/PT and APTR/APTT < 1.5x ULN, unless receiving therapeutic anticoagulation. 
Investigator discretion is required to ensure surgery is safe or that anticoagulants can 
be safely stopped. 
f. AST or ALT ≤ 2.5x ULN. 
g. Bilirubin < 1.5x ULN (or < 3x ULN in Gilbert’s Syndrome). 
h. Creatinine clearance/estimated GFR ≥ 50 mL/min. 
10. Female patients who are of childbearing potential must agree to use a highly effective method 
of contraception during the study and for at least 12 months after the ATL001 infusion. Non-
sterilised male participants who intend to be sexually active with a female partner of 
childbearing potential must use an acceptable method of contraception from the time of 
screening, throughout the duration of the study and for at least 6 months after the ATL001 
infusion. Refer to Appendix G for pregnancy testing requirements in Germany. See Section 4.3 
for details of acceptable methods of contraception. 
In addition to a re-evaluation of criteria 1-10, the following inclusion criteria must also be met 
prior to tissue procurement: 
11. To be eligible to enter this study for procurement a patient must fall into one of the following 
groups: 
a. Patients with metastatic or recurrent disease who have had no prior systemic therapy 
for advanced disease and who have accessible sites of disease suitable for collection of 
adequate tissue for ATL001 manufacture. 


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b. Patients with metastatic or recurrent disease who are on or have completed first line 
systemic therapy and have accessible sites of disease suitable for collection of adequate 
tissue for ATL001 manufacture. 
c. Other patients with advanced stage disease for whom no other alternative approved 
treatments are available, may be considered on a case-by-case basis and should be 
discussed with the Sponsor prior to enrolment. 
12. Anticipated life expectancy ≥ 6 months at the time of tissue procurement. 
In addition to a re-evaluation of criteria 1-10, the following inclusion criteria must also be met 
prior to lymphodepletion for treatment with ATL001: 
13. Patients must have metastatic melanoma and: 
a. Whose disease has progressed or recurred following standard of care. This includes 
patients who have received a component of standard of care therapy as part of a 
previous clinical trial in first line treatment; or 
b. Who are ineligible for, or who cannot tolerate, standard of care therapies. Patients who 
stop treatment due to immunotherapy toxicities do not need to progress in order to 
receive treatment with ATL001. 
14. Patients must have measurable disease according to RECIST v1.1 criteria prior to 
lymphodepletion. 
15. Patient is considered, in the opinion of the Investigator, well enough (i.e. ECOG Performance 
Status 0-1) to receive ATL001 treatment (This will be checked prior to lymphodepletion and 
again prior to receiving ATL001). 
In addition to 1-15, except inclusion 13a, the following inclusion criteria must be met for patients 
to be eligible for treatment in Cohort B: 
16. Prior to treatment with ATL001, the treatment regimen must have included a PD-1/PD-L1 
inhibitor and patients should have experienced: 
a. Radiological disease progression; or 
b. Stable disease following at least 4 doses of a PD-1/PD-L1 inhibitor. 
17. In addition to the need for highly effective contraception as outlined in Inclusion Criterion 10 
above, female patients in Cohort B of childbearing potential must agree to use effective 
contraception during treatment with nivolumab and for at least 5 months after the last dose of 
nivolumab. Patients must also agree to provide a serum or urine pregnancy test before each 
nivolumab administration during the treatment period in Cohort B. 
4.2. 
Exclusion Criteria 
Exclusion Criteria: 
1. Patients with known leptomeningeal disease or central nervous system (CNS) metastases that 
are untreated or symptomatic or progressing. Lesions should be clinically and radiologically 
stable for 2 months after treatment, as determined by MRI or CT evaluation, in line with 
accepted standard of care procedures, and should not require steroids. 
2. Patients with ocular, acral or mucosal melanoma. 


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3. Patients with hepatitis B or C, human immunodeficiency virus infection (HIV1/2), syphilis or 
HTLVI/II infection (see Section 6.1.1). 
4. Patients with active, known, or suspected, autoimmune disease requiring immunosuppressive 
treatments. 
5. Patients requiring regular treatment with steroids at a dose higher than prednisolone 10 mg/day 
(or equivalent). 
6. Patients with a current or recent history, as determined by the Investigator, of clinically 
significant, progressive, and/or uncontrolled renal, hepatic, haematological, endocrine, 
pulmonary, cardiac, gastroenterological or neurological disease. 
7. Patients with a history of immune mediated central nervous system toxicity that was caused by, 
or suspected to be caused by, immunotherapy. 
8. Patients with a history of ≥ Grade 2 diarrhoea/colitis caused by previous immunotherapy within 
6 months of screening. Patients that have been asymptomatic for at least 6 months or have had 
a normal colonoscopy post-immunotherapy (with uninflamed mucosa by visual assessment 
following discontinuation of immune suppression other than permitted modified release 
steroids) are not excluded. 
9. Patients who are pregnant or breastfeeding. 
10. Patients who have undergone major surgery in the previous 3 weeks. 
11. Patients with an active concurrent cancer or a history of cancer within the past 3 years (except 
for in situ carcinomas, early prostate cancer with normal PSA or non-melanomatous skin 
cancers). 
12. Patients with a history of organ transplantation. 
13. Patients who have previously received any investigational cell or gene therapies. 
14. Patients with contraindications for cyclophosphamide, fludarabine and IL-2 at per protocol 
doses (see Investigator’s Brochure for details).  
15. Patients with a confirmed history of allergic reactions to amphotericin b, penicillin and/or 
streptomycin.  
In addition to 1-15, the following exclusion criteria apply to patients who have received anti-
cancer therapy prior to study entry: 
16. Patients who have received any cytotoxic chemotherapy within the 3 weeks prior to tissue and 
blood procurement. 
In addition, the following exclusion criteria will apply for eligibility for Cohort B: 
17. Patients with a history of (non-infectious) pneumonitis that required systemic steroids, or 
current pneumonitis/interstitial lung disease. 
18. Patients with a history of severe hypersensitivity to a monoclonal antibody, allergy or 
hypersensitivity to nivolumab itself and/or its components. 
19. Patients who have received a live vaccination within the 28 days prior to the first dose of 
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20. Patients with any contraindications for nivolumab (Refer to the latest available prescribing 
information (e.g. SmPC/Package Insert) for reference safety information for nivolumab). 
In addition, the following exclusion criteria will apply prior to lymphodepletion for eligibility for 
Cohort C: 
21. Patients with a Left Ventricular Ejection Fraction (LVEF) < 45%. 
22. Patients with a forced expiratory volume in one second (FEV1) of less than or equal to 60% of 
their predicted normal.  
All exclusion criteria, except 3 and 16, will apply again prior to lymphodepletion for treatment 
with ATL001. 
In addition, the following criteria will apply: 
23. Patients who have received a live vaccination within the 28 days prior to lymphodepletion. 
24. Patients with an active infection requiring antibiotics. 
25. Patients who have received any cytotoxic chemotherapy within the 3 weeks prior to 
lymphodepletion. 
4.3. 
Restrictions, Contraception Requirements and Prohibited Medications during 
the Study 
Patients should not receive any live vaccinations for at least 3 months following lymphodepletion. 
Patients requiring blood product support at any time in the future should receive irradiated blood 
products. 
Patients should not receive steroids at a dose higher than prednisolone 10 mg/day (or equivalent) or 
other immunosuppressive agents post infusion during the study, unless necessary to manage toxicity 
(see Section 7). For participants in Cohort B receiving nivolumab, this remains the case during treatment 
and until 5 months after the last dose of nivolumab.  
No new anti-cancer agents should be given post infusion prior to documented disease progression. 
A list of prohibited and allowed concomitant medications is provided in Appendix C. 
The contraception requirements for the study comply with the latest available prescribing information 
(e.g. SmPC/Package Insert) for cyclophosphamide and fludarabine. Female patients of childbearing 
potential must agree to use adequate contraception during the study and for at least 12 months after 
administration of ATL001. Non-sterilised male participants who intend to be sexually active with a 
female partner of childbearing potential must use an acceptable method of contraception from the time 
of screening, throughout the duration of the study and for at least 6 months after the ATL001 infusion. 
Refer to Appendix G for pregnancy testing requirements in Germany. For participants in Cohort B 
receiving nivolumab, this remains the case during treatment and until 5 months after the last dose of 
nivolumab. 
The definition of a woman of childbearing potential is a woman who is between menarche and post-
menopausal (no menses for 12 months without an alternative medical cause) unless permanently sterile 
due to hysterectomy, bilateral salpingectomy and bilateral oophorectomy.  
Acceptable Highly Effective Methods of Contraception for women of childbearing potential include: 
a. Combined (oestrogen and progestogen containing) hormonal contraception associated 
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b. Progestogen-only hormonal contraception associated with inhibition of ovulation. 
c. Intrauterine device (IUD). 
d. Intrauterine hormone-releasing system (IUS). 
e. Bilateral tubal occlusion. 
f. Vasectomised partner (provided that partner is the sole sexual partner of the patient and 
that the vasectomised partner has received medical assessment of the surgical success). 
g. Sexual abstinence (defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments, i.e. from enrolment until 12 months 
post ATL001 infusion for women of childbearing potential and until 6 months post 
ATL001 infusion for patients with female partners of childbearing potential). Periodic 
abstinence is not acceptable. The reliability of sexual abstinence needs to be evaluated 
in relation to the preferred and usual lifestyle of the subject. 
Acceptable Methods of Contraception for non-sterilised male participants who intend to be sexually 
active with a female partner of childbearing potential include: 
a. Condom. 
b. Vasectomy/orchiectomy. 
Contraception used by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for patients participating in clinical trials.  
4.4. 
Criteria for Participant Discontinuation 
Patients may be discontinued from study treatment and/or assessments at any time, at the discretion of 
the Investigator(s). 
 
Discontinuation from Study Treatment 
As ATL001 is given as an intravenous infusion, the only reason to discontinue it is for a severe infusion 
reaction requiring i.v. corticosteroid or in case of voluntary discontinuation/withdrawal by the patient. 
See Section 7 for guidelines on management of infusion reactions. 
Specific reasons for discontinuing a patient from other components of protocol interventions 
(lymphodepletion agents or IL-2) may include: 
a. Severe infusion reaction requiring i.v. corticosteroid. 
b. Grade 3 or worse autoimmunity, cytokine release syndrome, capillary leak syndrome, that 
does not resolve to Grade 2 or below within 2 days. 
c. Grade 2 or worse neurological toxicity that does not resolve to Grade 1 or baseline within 
2 days. 
d. The omission of more than 2 doses of IL-2 due to an adverse event related to IL-2. 
e. Protocol non-compliance (e.g. patient refuses to remain in hospital facility for required 
time). 
f. Voluntary discontinuation/withdrawal by the patient. 
Patients who are found to be pregnant prior to lymphodepletion (i.e. at re-screening) or on planned day 
of administration of ATL001 (i.e. Day 0) (refer to Appendix G) should discontinue all study treatments. 


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Cohort B patients should discontinue treatment with nivolumab when they experience disease 
progression. If a patient in Cohort B becomes pregnant, they should discontinue treatment with 
nivolumab within this study (refer to Appendix G). 
Adverse events leading to discontinuation should be followed up until resolution. 
Patients who have discontinued treatment should wherever possible remain in the study and continue 
with follow up assessments for disease progression and survival. 
For participants in Cohort B who also receive nivolumab as part of the study, there are additional 
discontinuation criteria based on possible toxicities from checkpoint inhibitor (CPI) use. For guidance 
on treatment/dose modifications necessitated by immune-related AEs involving nivolumab, see Table 
2 extracted from the SmPC/Package Insert for nivolumab. Common immune-related toxicities 
associated with CPI use and criteria for discontinuation are further described in Section 7.6. 
 
 


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Table 2: Recommended Treatment/Dose Modifications for Nivolumab (Adapted from SmPC and 
Package Insert) 
Immune-related 
adverse reaction 
Severity 
Treatment modification 
Pneumonitis 
Grade 2 
 
 
 
 
Grades 3 or 4 
Withhold dose(s) until symptoms 
resolve, radiographic abnormalities 
improve, and management with 
corticosteroids is complete 
 
Permanently discontinue treatment 
Colitis 
Grades 2 or 3 
 
 
 
Grade 4 
Withhold dose(s) until symptoms 
resolve and management with 
corticosteroids, if needed, is complete 
 
Permanently discontinue treatment 
Hepatitis 
Grade 2 elevation in AST, 
ALT, or total 
bilirubin 
 
 
 
Grade 3 or 4 elevation in 
AST, ALT, or total 
bilirubin 
Withhold dose(s) until laboratory 
values return to baseline and 
management with corticosteroids, if needed, is 
complete 
 
 
Permanently discontinue treatment 
Nephritis 
Grade 2 with increased 
blood creatinine  
 
 
 
Grade ≥ 3 with increased 
blood creatinine 
Withhold dose(s) until creatinine 
returns to baseline and management with 
corticosteroids is complete 
 
 
Permanently discontinue treatment 
Endocrinopathies 
Symptomatic Grade 2 or 3 
hypothyroidism, 
hyperthyroidism, 
hypophysitis  
Grade 2 adrenal 
insufficiency 
Grade 3 diabetes 
 
 
 
 
 
Grade 4 hypothyroidism 
Grade 4 hyperthyroidism 
Grade 4 hypophysitis 
Grade 3 or 4 adrenal 
insufficiency 
Grade 4 diabetes 
Withhold dose(s) until symptoms 
resolve and management with 
corticosteroids (if needed for symptoms of acute 
inflammation) is complete. Treatment should be 
continued in the presence of hormone replacement 
therapy as long as no symptoms are 
present 
 
 
Permanently discontinue treatment 
Skin reactions 
Grade 3 rash 
 
 
 
Grade 4 rash 
 
SJS or TEN 
Withhold dose(s) until symptoms 
resolve and management with 
corticosteroids is complete 
 
Permanently discontinue treatment 
 
Permanently discontinue treatment 
Myocarditis 
Grades 2, 3 or 4 
Permanently discontinue treatment 
Neurological toxicities 
Grade 2 
 
Withhold dose(s) until symptoms 
resolve and management with 


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Grades 3 or 4 
corticosteroids is complete 
 
Permanently discontinue treatment 
Other immune-related 
adverse reactions 
Grade 3 (first occurrence) 
 
 
Grade 4 or recurrent Grade 
3; persistent Grade 2 or 3 
despite treatment 
modification; inability to 
reduce corticosteroid dose 
to 10 mg prednisone or 
equivalent per day 
Withhold dose(s) 
 
 
Permanently discontinue treatment 
Infusion-related 
reactions 
Grades 1 or 2 
 
Grades 3 or 4 
Interrupt or slow the rate of infusion 
 
Permanently discontinue treatment 
Note: Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events 
Version 4.0 (NCI-CTCAE v4). 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal 
necrolysis. 
 
Discontinuation from Study 
All patients who meet the eligibility criteria and receive study treatment are expected to remain “on-
study” for 24 months following ATL001 treatment, to enable the evaluation of the longer-term safety 
and efficacy.  
Specific reasons for discontinuing a patient from the study prior to 24 months may include: 
a. Inability to make ATL001. 
b. Patient does not meet pre-lymphodepletion eligibility criteria. 
c. Investigator decision. 
d. Voluntary discontinuation/withdrawal by the patient. 
e. Adverse event. 
f. Lost to follow up. 
g. Death. 
h. Study termination. 
A withdrawal/completion visit should be completed for all patients who discontinue from the study. 
See Section 6.4.10 for the requirements. 
5 
INVESTIGATIONAL AND AUXILIARY MEDICINAL 
PRODUCTS 
5.1. 
Investigational Medicinal Products 
 
ATL001 
5.1.1.1 
Composition 
The active moiety is clonal neoantigen reactive T cells (cNeT) formulated in a cryopreservation media. 
The final ATL001 is a cryopreserved cell therapy product. 


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5.1.1.2 
Manufacturing Summary 
The tumour and blood samples procured from the patient are shipped to the Sponsor’s manufacturing 
site for further processing. Tumour infiltrating lymphocytes (TILs) are isolated from the tumour tissue. 
The tumour is sequenced to identify the clonal neoantigen peptides which are subsequently 
manufactured. The blood sample is used to manufacture antigen presenting cells which can process and 
present the neoantigens to the TILs. In this way, clonal neoantigen reactive T cells are specifically 
isolated and expanded. The cNeT are harvested and formulated to form ATL001. 
5.1.1.3 
Shipping and Storage 
The Sponsor will ensure that the cell therapy product ATL001 is appropriately shipped from the 
manufacturing facility to the study site. ATL001 cryopreserved products are shipped at -135°C or below 
in a qualified dry shipper by a courier company experienced in handling such materials. 
Each ATL001 shipment will be temperature monitored across shipment and storage and accompanied 
by the appropriate documentation. Temperature monitoring logs and associated data are required be 
collected for verification of events and personnel handling related to ATL001. 
On receipt of ATL001 by the study site, the product should be stored at -135°C or below in a monitored 
vapour phase liquid nitrogen dewar or in a monitored and compliant cell therapy storage facility until 
the patient is ready for product administration. All medications must be stored in a safe and locked site 
with no access for unauthorised personnel. 
Clinical trial ATL001 supplies will be provided as a single dose in cryopreserved bags.  
All cryopreserved bags will have a label in an integrated sealed pocket with appropriate information for 
use in the clinical trial. The bags will be covered with a protective secondary outer bag in accordance 
with relevant competent regulatory authority requirements. 
Lymphodepletion should not commence until ATL001 is available. 
Thawing and Infusion 
No manipulation of the product is required at the clinical site prior to administration, apart from 
thawing. The cryopreserved cells should be thawed rapidly in a water bath at 37°C or alternative suitable 
thawing device for cell therapies (see Procurement and Cell Handling Manual) for immediate 
administration. 
Patients 
may 
be 
premedicated 
according 
to 
local 
SOPs 
(e.g. 
with 
paracetamol/acetaminophen (max 1 g) and chlorphenamine). 
ATL001 Cell Administration: Autologous cNeT as a single dose will be given. ATL001 will be 
administered by intravenous infusion within 30 minutes through either a peripheral or an existing central 
line. Do not filter with a leukoreduction filter. An infusion set with a standard blood filter (pore size no 
smaller than 170 microns) may be used, per institutional SOPs. To ensure all the product is infused, the 
bag may be flushed with a volume of sterile saline solution at the end of the infusion or as per 
institutional SOPs permit. See Investigator’s Brochure for detailed administration instructions. 
In addition to any protocol specific patient monitoring requirements, monitoring will follow the hospital 
standards for administration of blood products and an Investigator or Sub-Investigator should be 
available throughout the entire infusion. Patients should receive supportive care for acute or chronic 
toxicity or other supportive care if needed at the discretion of their physician, however prohibited 
medications and/or treatments will not be allowed except in the case of a medical emergency. Please 
see Section 4.3 for restricted medications and Section 7 for safety management guidelines. 
ATL001 will not be supplied by the Investigator to other Investigators not listed on the FDA Form 1572 
or equivalent, nor allow use of additional investigational products as instructed in this protocol. Due to 


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the autologous nature of this product, the Investigator will dispense ATL001 only from the designated 
study site and administer only to the patient for whom it was manufactured. 
Further details will be provided in the Procurement and Cell Handling Manual. 
Dose Adjustments 
No dose modifications are permitted for ATL001. Delays to dosing are not recommended however any 
delays should be communicated to the Sponsor medical monitor by the Investigator. 
5.1.1.4 
Destruction of ATL001 and Administration Components 
After the administration of ATL001 has been completed the empty infusion bag and used clinical 
supplies will be destroyed as clinical waste. If ATL001 is unused for any reason, the Sponsor should be 
notified to agree whether the product may be destroyed as clinical waste or may be returned to the 
Sponsor and used for research, quality control (QC) or training purposes. 
5.1.1.5 
Accountability 
It is mandatory for the Investigator at the study site to maintain appropriate records of the disposition 
of ATL001, including dates, quantity, and use by patients throughout the study to ensure full traceability 
is maintained. Records will be kept on product accountability and inventory forms. Product 
administration process will be documented on the administration record. The empty cryopreservation 
bag and disposables will be discarded in a biohazard container, witnessed and recorded by the research 
staff. 
In the case that ATL001 has been delivered to the site but cannot be administered, the site must notify 
the Sponsor to agree further steps for either the destruction or return of the ATL001 to Sponsor. 
Accountability of the investigational product will be verified by the study monitor during on-site 
monitoring visits. 
In the event, for any reason, the Sponsor instructs the study to be terminated, suspended, discontinued, 
or completed, the Investigator may return the unused supplies to the Sponsor. Final study agent 
accountability forms, which complete the accountability of the entire study, must be provided to 
Sponsor. 
 
Nivolumab (Cohort B Only) 
Nivolumab is a monoclonal antibody that targets and inhibits the immune checkpoint, PD-1. Activated 
cytotoxic T cells express PD-1, which recognises a ligand (PD-L1) that is expressed on a proportion of 
tumour cells and antigen presenting cells. When PD-1 binds to PD-L1, T cell anti-tumour activity is 
suppressed. Nivolumab prevents this interaction by binding PD-1 and in doing so it enhances the ability 
of TILs to recognise and kill tumour cells. 
Since cNeTs express the effector cytokine IFN-γ, which is known to promote upregulation of PD-L1 in 
tumour cells, the concurrent use of nivolumab, an inhibitor of PD-1 interaction, may enhance the clinical 
anti-tumour activity of cNeTs.  
Nivolumab is authorised for the treatment of patients with metastatic melanoma at a dose of 240 mg 
i.v. every 2 weeks thereafter, or at a dose of 480 mg i.v. every 4 weeks. 
Please consult the latest available version of the SmPC, package leaflet and/or other healthcare intended 
materials before taking any action relating to this agent. Please refer to the SmPC/Package Insert for 
nivolumab for reference safety information. 


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Patients who enrol in treatment Cohort B will receive a single dose of nivolumab 240 mg i.v. between 
days -13 and -7 prior to lymphodepletion dose. Following ATL001 infusion, 480 mg i.v. dose of 
nivolumab will be given on Day 14 and then every 4 weeks for up to 12 months, or up to 6 months 
following a CR or until RECIST v1.1 confirmed disease progression, whichever is sooner. Prior to 
nivolumab treatment administration, ECOG performance status and vital signs should be performed on 
the day of administration but physical examination (if applicable with the addition of a serum or urine 
pregnancy test prior to each nivolumab administration for female participants of childbearing potential) 
may be performed at the most recent clinic visit (if not on the same day, prior to administration) if ≤3 
days prior to administration (refer to Appendix G for additional pregnancy testing requirements in 
Germany). 
Further details will be provided in the Pharmacy Manual. 
5.2. 
Auxiliary Medicinal Products 
 
Lymphodepletion Agents: Fludarabine and Cyclophosphamide 
All current ACT trials employ some form of lymphodepletion, which is required to eliminate regulatory 
T cells and endogenous lymphocytes that compete with the transferred cells for homeostatic cytokines, 
effectively providing the infused T cells with the optimum environment to expand and re-populate the 
tumour microenvironment. Current trials most commonly use a combination of cyclophosphamide and 
fludarabine. The more intensive regimens cause 10-14 days of cytopenia but facilitate greater anti-
tumour activity. 
Fludarabine is a purine analogue antineoplastic agent which inhibits ribonucleotide reductase, DNA 
polymerase α/δ and ε, DNA primase and DNA ligase thereby inhibiting DNA synthesis. Furthermore, 
partial inhibition of RNA polymerase II and consequent reduction in protein synthesis occur. All of 
these contribute to inhibition of cell growth. Its effect is particularly marked in haematopoietic cells 
especially lymphocytes and it is indicated for the treatment of chronic lymphocytic leukaemia (CLL). 
For this reason, fludarabine is also commonly used as a lymphodepleting agent for ACT trials. 
The safety information for fludarabine refers to the recommended dose used for CLL, which is 25 
mg/m2 body surface area given daily for 5 consecutive days per 28-day cycle for up to 6 cycles. 
In ACT studies, fludarabine is generally given at doses of 25-30 mg/m2 for 3-5 days. The 
lymphodepletion dose of fludarabine to be used for this study is 30 mg/m2 body surface area for three 
doses in total. 
Refer to the latest available prescribing information (e.g. SmPC/Package Insert) for fludarabine safety 
information. Further safety information is available in the Investigator’s Brochure. 
Cyclophosphamide is an alkylating agent which has been demonstrated to have a cytostatic effect in 
many tumour types. Cyclophosphamide also has an immunosuppressive effect due largely to an 
inhibitory effect on B-cells, CD4+ T-cells and to a lesser extent CD8+ T-cells. It is approved for the 
treatment of a number of haematological and solid tumours at a range of doses. It is also used as a 
preparation for bone marrow transplantation when it is either given for 2 days at 60 mg/kg or 4 days at 
50 mg/kg. 
Doses of cyclophosphamide vary between ACT studies, ranging from 60 mg/kg for 2 days to 500 mg/m2 
for 2-3 days. The dose of cyclophosphamide to be used in this study is 300 mg/m2 for three days, which 
is towards the lower end of the dosing ranges commonly in use for ACT trials. 
Refer to the latest available prescribing information (e.g. SmPC/Package Insert) for cyclophosphamide 
safety information. Further safety information is available in the Investigator’s Brochure. 


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IL-2 
Interleukin-2 (IL-2) has essential roles in key functions of the immune system via direct effects on T 
cells. It promotes the differentiation of immature T cells to effector and memory T cells and has a role 
in the development of T cell immunologic memory. It is approved for the treatment of some solid 
tumours, notably melanoma and renal cell carcinoma. In the context of adoptive cell therapy, IL-2 is 
used to augment the clinical efficacy of TIL therapies by supporting in vivo proliferation and persistence 
of the infused cells. The high intravenous doses used in the early TIL studies enhanced clinical 
effectiveness but were also associated with significant toxicities. In more recent studies, lower i.v. doses 
resulted in a more gradual accumulation of toxicities, allowing for early adjustment of symptomatic and 
supportive care. In most cases this allowed 90% of the intended dose to be received. The Herlev group 
reported a small pilot study in which 6 melanoma patients received a low-dose subcutaneous IL-2 
regimen consisting of 2M IU/day for 14 days [Ellebaek et al, 2012]. Two of the patients achieved 
complete, long-lasting response, suggesting that low-dose IL-2 was effective, and it was also well 
tolerated; all planned injections were given without dose reduction. The most common adverse events 
were fever, chills, nausea and fatigue, none of these exceeding CTCAE Grade 2. Since then a number 
of studies have employed variable schedules of ‘low dose’ IL-2, with doses ranging from 0.5M 
IU/m2/day to 2M IU/kg/day, administered for between 5 and 14 days.  
Based on a review of the available literature and experience with cell therapies, the chosen regimens of 
IL-2 will include:  
For Cohorts A and B, IL-2 will be administered at a dose of 1M IU/m2 s.c. for 10 days, starting 3-12 
hours after the completion of the ATL001 infusion, as long as systolic BP ≥ 90 mmHg, pulse ≤ 100 
bpm and there is no infection requiring antibiotics.  
For Cohort C, IL-2 will be administered at a dose of 600,000 IU/kg i.v. (based on total body weight) 
for up to a maximum of six doses, as tolerated, starting 3-24 hours after the completion of the ATL001 
infusion at a frequency of 8-12 hourly, as long as systolic BP ≥ 90 mmHg, pulse ≤ 100 bpm and there 
is no infection requiring antibiotics. IL-2 dosing will be interrupted if patient experiences Grade 3 or 4 
toxicity related to IL-2 (with the exception of reversible Grade 3 toxicities attributable to IL-2, such as 
diarrhoea, nausea, vomiting, hypotension, rash/skin changes, anorexia, mucositis, dysphagia, or 
constitutional symptoms and laboratory changes. See Appendix F.). 
Refer to the latest available prescribing information (e.g. SmPC/Package Insert) for IL-2 safety 
information. Further safety information is available in the Investigator’s Brochure. 
5.3. 
Prior and Concomitant Medications 
All anti-cancer medications received by the patient will be recorded. All prescription, non-prescription, 
or over-the-counter medication given to, or taken by, the patient at entry and during the study must be 
clearly documented on the appropriate eCRF. 
Information on COVID-19 vaccination is provided in Appendix C. 
6 
STUDY PLAN AND PROCEDURES 
6.1. 
Tumour and Blood Procurement for Manufacture of ATL001 
 
Tumour Procurement for Manufacture of ATL001  
For patients with recurrent or metastatic disease who have accessible sites of disease suitable for 
surgical removal, attempts should be made to obtain at least 1.5 g (1.5 cm3) of tumour tissue for 


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assessment, sequencing and manufacturing of ATL001. A sample of archival tumour may be requested 
for analysis of the tumour microenvironment. 
The surgical procedures for tumour tissue procurement should be clinically relevant procedures which 
do not cause undue risk to patients, as determined by the Investigator, taking into consideration the 
risk/benefit for the patient. 
Access to the archival FFPE sample of primary tumour may be requested at any time during the study. 
When practical and safe to do so, surgery should be undertaken before the commencement of standard 
first line therapy. Alternatively, patients may be enrolled following initial therapy and surgery may be 
scheduled at a time that is clinically safe (i.e. after recovery from any chemotherapy-induced toxicity) 
and convenient, in which case the patient must meet the additional eligibility criteria prior to the 
procurement procedure.  
Patients should be considered to have 6 months life expectancy at the time of surgery to accommodate 
manufacturing time and a 12 week follow up period after therapy. 
Additional haematological and biochemical safety evaluations, ECGs, radiological investigations and 
urinalysis may be routinely required for surgical procedures at the study site and, if so, the site should 
follow its usual pre-operative practice. These additional evaluations should not be considered a 
requirement for this study protocol. 
Infectious disease screening within 30 days of surgery (IDM1) and a repeat screen on the day of surgery 
(IDM2) is required at any time that tumour tissue is procured. This screen will include the following 
tests: Anti-HIV 1 & 2, HBs Ag, Anti-HBc, Anti-HCV-Ab, Syphilis (Treponema pallidum) IgG/IgM 
and Anti-HTLV 1 & 2. Additional tests per local requirements, if required, should also be performed. 
Patients should have clearance for IDM1 within 30 days of the procurement of tumour tissue to allow 
material to be accepted into the manufacturing facility. 
Full instructions for tissue collection, labelling and transportation to the manufacturing facility is 
provided in the Procurement and Cell Handling Manual. 
 
Blood Procurement for Manufacture of ATL001 
The following blood samples will be collected: 
- 
A blood sample (target volume 140 mL whole blood) for ATL001 manufacture. 
- 
A blood sample for germline DNA which is needed for the identification of tumour-
specific clonal mutations (~10 mL). 
- 
A blood sample for ctDNA monitoring (~30 mL). 
- 
A blood sample for HLA testing (~4 mL). 
Patients will consent separately for germline DNA sequencing as part of the overall study consent 
process. 
In general, the 140 mL whole blood should be collected on the same day of tissue procurement unless 
otherwise agreed with the Sponsor. Tissues and blood procurement may be collected at different 
timepoints where same day collection is not clinically appropriate. 
UK and EU Only: For patients where tissue will be stored for potential future treatment on relapse, the 
140 mL blood sample for the manufacturing process, germline DNA, HLA and ctDNA blood samples 
will not be collected until the time of relapse when product manufacture is to be initiated. Where tissue 
has been previously stored and blood samples (140 mL whole blood, germline, ctDNA and HLA typing) 


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are to be collected at the time of relapse, IDM1 clearance is required within 30 days of blood sample 
collection. 
 
Situations Requiring Recollection of Blood or Tumour 
In the case that a blood sample does not yield enough antigen presenting cells to make ATL001 or for 
other reasons which are clinically relevant, additional blood sample(s) may be requested. 
If additional blood is requested, the following procedures must be performed: 
• 
Additional IDM1 (within 30 days of recollection) and IDM2 (day of recollection).  
Note: Additional IDM1 is not required if less than 30 days have elapsed since the last IDM 
screen.  
• 
Procedure-related AEs and all SAEs from the time of the recollection to 28 days following 
recollection, or the start of anti-cancer therapy if sooner, will be collected. 
In the case that the tumour sample does not yield enough tumour infiltrating lymphocytes or for other 
reasons which are clinically relevant, and if the patient has further subcutaneous, lymph node or soft 
tissue metastatic lesions that are planned to be removed for clinical reasons, a second tumour sample 
may be requested. The same procedures required for additional blood collection must be performed for 
additional tissue collection or the patient may need to be re-enrolled (see Section 6.4.1). 
All cases should be discussed with the Sponsor prior to any activities for recollection.  
6.2. 
Lymphodepletion and Administration of ATL001 and IL-2 
All patients will receive a lymphodepletion regimen of fludarabine 30 mg/m2 i.v. and 
cyclophosphamide 300 mg/m2 i.v. on each of Days -6, -5, and -4 prior to cell infusion. These can be 
administered according to local SOPs. 
Patients allocated to Cohort B will receive a single dose of nivolumab 240 mg i.v. on day -7. There is a 
window of 7 days prior to this to administer the nivolumab if more convenient for the patient. 
The ATL001 infusion is planned for day 0. A window of 5 days is considered acceptable to account for 
the case whereby a patient is not deemed clinically well enough to receive the cell infusion on the 
planned day. If any further delay is required, each case should be discussed with the Sponsor. Following 
a more prolonged delay, it is likely that a second course of lymphodepletion will be required. 
On the day of ATL001 infusion (Day 0), patients should be pre-medicated with a standard regimen to 
prevent infusion reactions (e.g. chlorphenamine and paracetamol/acetaminophen) according to local 
SOPs prior to the infusion of ATL001. This prophylactic regimen should not include corticosteroids. 
The infusion should be administered as soon as possible and within 30 minutes after thawing. The 
infusion should be administered via a giving set with the tap fully open i.e. rate controlled by gravity, 
and as per local SOPs. A saline flush should be used to ensure that all the contents of the bag and giving 
set are infused where possible and as permitted in local SOPs. Patients in Cohorts A and B will receive 
10 doses of IL-2 1M IU/m2 s.c daily from days 0-9 of the study, starting between 3 and 12 hours post 
infusion. Patients in Cohort C will receive up to 6 doses of 600,000 IU/kg i.v. at a frequency of 8-12 
hourly, starting between 3 and 24 hours post infusion. 
 
Possibility to Re-administer ATL001 
In a case where an additional ATL001 dose can be manufactured for a patient, this will be stored. If the 
Investigator considers it is clinically appropriate for a patient to receive an additional infusion of 


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ATL001 within the study protocol at the time of disease progression, this must be discussed with the 
Sponsor. In order to proceed, the following must be met: 
- 
The first infusion must have been adequately tolerated with no reports of infusion related 
serious adverse events or CTCAE Grade 4 adverse events.  
- 
Patient must have undergone at least one RECIST assessment following the initial ATL001 
administration which shows a clinical response or durable (> 12 weeks) stable disease. 
- 
Patient must be re-screened and confirmed eligible per protocol with the following exceptions: 
o Inclusion criteria 11 and 12 are not applicable. 
o Exclusion criteria 3 and 16 are not applicable. 
- 
The study must still be open to recruitment. 
- 
The product must be within its storage stability period. 
A repeat tumour biopsy will be requested, if safely accessible, to assess any changes in the neoantigen 
profile or tumour microenvironment. 
A further course of lymphodepletion may not be required in this case. Safety and efficacy data following 
a second administration will not contribute to the main study analysis and will be reported separately.


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6.3. 
Schedule of Assessments 
 
Schedule of Assessments for Cohorts A and C 
 
Screening 
Procurement 
Procurement 
Follow Up 
Pre-
Lymphodepletion 
Re-Screening 
Lymphodepletion 
ATL001 Treatment 
& IL-2 
Administration 
Period 
Follow up 
Withdrawal / 
Completion 
Survival Follow up a 
CSP section 
Visit No. 
1 
2 
3 
4 
5 – 7 
8 
9 
10 – 19 
20 – 22 
23 – 26 
27 – 32 
33 
Visit Schedule  
 
Up to 30 D to D7 
before 
procurement 
Procurement 
 D28 after 
procurement (± 7 
D) 
D -28 to D -7 
D -6 to D -4 
D -1 (within 48 
prior to ATL001 
Infusion) 
D0 (+5 D) 
D1 – D10 b 
D14, D21 (±3 D) 
and D28 (±7 D) 
W6, W12, W18 
and W24, (±7 D) 
W36, W48, W60, 
W72, W84, W96 
(±14 D) 
W104 / 
withdrawal c (±14 
D) 
Every 12 weeks 
(±14 days)  
until W364 d 
Informed 
Consent 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
6.4.1, 6.4.2, 
6.4.4.1 and 11.1 
Inclusion / 
Exclusion 
Criteria 
X 
 
 
X 
D -6 
pre-
infusi
on 
only 
X3F 
 
 
 
 
 
 
 
4.1 and 4.2 
Enrolment 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
6.4.1 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
6.4.2, 8.1.10 
Medical History 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
6.4.2, 6.4.4 
Melanoma 
History 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
6.4.2, 6.4.4 
Melanoma Risk 
Factors 
X 
 
 
 
 
 
 
 
 
 
 
 
 
6.4.2, 8.1.9 
ECOG PS 
X 
 
X 
X 
 
X 
 
 
X 
X 
X 
X 
 
6.4, 8.1.1 
Anti-cancer 
Therapies 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
6.4.2, 6.4.4 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
6.4 
Physical 
Examination 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
 
 
6.4, 8.1.2 
Vital Signs 
X 
 
 
X 
 
X 
X 
X 
 
 
 
 
 
6.4.2, 6.4.4, 6.4.5, 
6.4.6, 
8.1.3 
Body Weight 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
6.4, 8.1.6 
12-Lead ECG 
 
 
 
X 
 
X 
X 
 
 
 
 
 
 
6.4.2, 6.4.4, 6.4.5, 
8.1.5 


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Screening 
Procurement 
Procurement 
Follow Up 
Pre-
Lymphodepletion 
Re-Screening 
Lymphodepletion 
ATL001 Treatment 
& IL-2 
Administration 
Period 
Follow up 
Withdrawal / 
Completion 
Survival Follow up a 
CSP section 
Visit No. 
1 
2 
3 
4 
5 – 7 
8 
9 
10 – 19 
20 – 22 
23 – 26 
27 – 32 
33 
Visit Schedule  
 
Up to 30 D to D7 
before 
procurement 
Procurement 
 D28 after 
procurement (± 7 
D) 
D -28 to D -7 
D -6 to D -4 
D -1 (within 48 
prior to ATL001 
Infusion) 
D0 (+5 D) 
D1 – D10 b 
D14, D21 (±3 D) 
and D28 (±7 D) 
W6, W12, W18 
and W24, (±7 D) 
W36, W48, W60, 
W72, W84, W96 
(±14 D) 
W104 / 
withdrawal c (±14 
D) 
Every 12 weeks 
(±14 days)  
until W364 d 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
6.4.2 
Echocardiogra
m 
Xe 
 
 
Xf 
 
 
 
 
 
 
 
 
 
6.4.2, 6.4.4 
MRI/CT 
Tumour burden 
evaluation 
 
 
 
X 
 
 
 
 
 
W6, W12, W18, W24 and then 
every 12W, until confirmed 
radiological disease progression 
 
6.4, 6.4.12 
Pulmonary 
Function Tests 
(Cohort C only) 
 
 
 
Xg 
 
 
 
 
 
 
 
 
 
6.4.2, 6.4.4 
Colonoscopy 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
6.4.2 
Adverse Events 
i 
 
X 
Xi 
X 
X 
X 
X 
X 
X 
Xi 
Xi 
Xi 
Xi 
6.4, 8.2 
CRS Grading 
 
 
 
 
 
X 
 
X 
X 
 
 
 
 
6.4.5, 6.4.6, 6.4.7, 
7.7.4, 8.2.4 
ICANS Grading 
 
 
 
 
 
X 
 
X 
X 
W6 and 
W12j 
 
 
 
6.4.5, 6.4.6, 6.4.7, 
6.4.8, 7.7.5, 8.2.4 
Blood Sampling 
for: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infectious 
Disease Marker 
Screening 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
6.1.1, 6.4.2, 
6.4.3.1 
Haematology 
X 
 
X 
X 
X 
X 
X 
Xk 
X 
X 
X 
X 
 
6.4, 8.1.8 
HLA Typing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
6.1.2, 6.4.3.2 
Coagulation 
Screen 
Xl 
 
 
X 
 
X 
 
D1, D2, 
D3, D5, 
D7, D10l 
 
 
 
 
 
6.4.2, 6.4.4.1, 
8.1.8 
Clinical 
Chemistry 
X 
 
 
X 
X 
X 
X 
X k 
X 
X 
X 
X 
 
6.4, 8.1.8 
Thyroid 
Function Test 
 
 
 
X 
 
 
 
 
 
W12 and 
W24 
W48 and 
W72 
X 
 
6.4.4.1, 6.4.8, 
6.4.9, 6.4.1, 8.1.8 


ACHILLES THERAPEUTICS 
 
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Clinical Study Protocol 
 
Protocol Number: ATX-ME-001 
Confidential 
Page 62 of 129 
 
Screening 
Procurement 
Procurement 
Follow Up 
Pre-
Lymphodepletion 
Re-Screening 
Lymphodepletion 
ATL001 Treatment 
& IL-2 
Administration 
Period 
Follow up 
Withdrawal / 
Completion 
Survival Follow up a 
CSP section 
Visit No. 
1 
2 
3 
4 
5 – 7 
8 
9 
10 – 19 
20 – 22 
23 – 26 
27 – 32 
33 
Visit Schedule  
 
Up to 30 D to D7 
before 
procurement 
Procurement 
 D28 after 
procurement (± 7 
D) 
D -28 to D -7 
D -6 to D -4 
D -1 (within 48 
prior to ATL001 
Infusion) 
D0 (+5 D) 
D1 – D10 b 
D14, D21 (±3 D) 
and D28 (±7 D) 
W6, W12, W18 
and W24, (±7 D) 
W36, W48, W60, 
W72, W84, W96 
(±14 D) 
W104 / 
withdrawal c (±14 
D) 
Every 12 weeks 
(±14 days)  
until W364 d 
CRP 
 
 
 
X 
 
X 
 
D1, D2, 
D3, D5, 
D7, D10 
X 
X 
 
 
 
6.4.4.1, 6.4.5.1, 
6.4.7, 6.4.8, 8.1.8 
Immunomonitor
ing (PBMC and 
TBNK) 
 
 
 
X 
 
 
 
D3, D7, 
D10 
X 
X 
X 
X 
 
6.4, 8.4 
Immunomonitor
ing (Cytokines) 
 
 
 
X 
 
X 
 
D1, D2, 
D3, D5, 
D7, D10 
X 
X 
X 
X 
 
6.4, 8.4 
Immunological 
assay 
 
 
 
 
 
 
 
 
 
W6 only 
 
 
 
6.4.8, 8.4 
TCR RNA 
 
 
 
X 
 
 
 
D7 and 
D10 only 
X 
X 
X 
X 
 
6.4. 8.4 
ctDNA  
 
X 
 
X 
 
X 
 
D7 only 
X 
X 
X 
X 
 
6.4, 8.5.1 
Germline DNA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
6.1.2, 6.4.3.2 
Pulse Oximetry 
m 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
6.4.5, 8.1.4 
Pregnancy Test 
(Females) n 
X 
 
 
X 
 
 
Xo 
 
 
Xo 
Xo 
 
 
6.4, 8.1.7 
Tissue 
Procurement 
 
X 
 
 
 
 
 
 
 
 
 
 
 
6.1.1, 6.1.3, 
6.4.3.1 
Archival tissue  
(if available) 
X 
 
6.1.1, 6.4.3.1, 
8.1.11, 8.5.2 
Blood for 
Manufacturing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
6.1.2, 6.1.3, 
6.4.3.2 
Infusion 
Reaction 
Prophylaxis 
 
 
 
 
 
 
X 
 
 
 
 
 
 
6.2, 6.4.5.2 
ATL001 
Infusion 
 
 
 
 
 
 
X 
 
 
 
 
 
 
5.1.1 6.4.5.2 
Lymphodepleti
on (Flu/Cy) 
 
 
 
 
X 
 
 
 
 
 
 
 
 
6.2, 6.4.4.2 


ACHILLES THERAPEUTICS 
 
Version: 11.0 (Master), 02 October 2023 
Clinical Study Protocol 
 
Protocol Number: ATX-ME-001 
Confidential 
Page 63 of 129 
 
Screening 
Procurement 
Procurement 
Follow Up 
Pre-
Lymphodepletion 
Re-Screening 
Lymphodepletion 
ATL001 Treatment 
& IL-2 
Administration 
Period 
Follow up 
Withdrawal / 
Completion 
Survival Follow up a 
CSP section 
Visit No. 
1 
2 
3 
4 
5 – 7 
8 
9 
10 – 19 
20 – 22 
23 – 26 
27 – 32 
33 
Visit Schedule  
 
Up to 30 D to D7 
before 
procurement 
Procurement 
 D28 after 
procurement (± 7 
D) 
D -28 to D -7 
D -6 to D -4 
D -1 (within 48 
prior to ATL001 
Infusion) 
D0 (+5 D) 
D1 – D10 b 
D14, D21 (±3 D) 
and D28 (±7 D) 
W6, W12, W18 
and W24, (±7 D) 
W36, W48, W60, 
W72, W84, W96 
(±14 D) 
W104 / 
withdrawal c (±14 
D) 
Every 12 weeks 
(±14 days)  
until W364 d 
IL-2 
Administration 
 
 
 
 
 
 
Xp 
 
 
 
 
 
6.2, 6.4.5.2 
Optional 
Tumour Biopsy 
 
 
 
X 
 
 
 
 
 
W6 or W12, and at disease 
progressionq 
 
6.4.4.1, 6.4.8,  
8.5.2 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
X 
6.4.8, 6.4.9 
D = Day(s); W = Week(s) 
a. 
After confirmed disease progression, the patient would move to Survival Follow Up visits. These visits could be conducted by telephone if deemed clinically appropriate by the Investigator. 
b. 
For Immunomonitoring (PBMC and TBNK), Immunomonitoring (Cytokines), TCR RNA and ctDNA samples collected between Day 0 and Day 10, the following windows apply: Day 3 ± 1 day window; 
Day 5 and Day 7 ± 1 day window (if + 1 day visit window is used for Day 3 visit, then Day 5 visit will have + 1 day visit window; if + 1 day visit window is used for Day 5 visit, then Day 7 visit will have + 
1 day visit window); Day 10 ± 1 day window. 
c. 
If withdrawal is after ATL001 treatment and prior to week 104, the assessments should follow the previous visit, except undertaking RECIST scans if already performed. If withdrawal is prior to ATL001 
infusion, then the assessments required at procurement follow up visit should be completed. 
d. 
Patients may have Survival Follow Up visits until W104, or until W364, until such time as the Long Term Follow Up study is available at study site. 
e. 
Echocardiogram within 60 days prior to screening: Only for patients over 60 or with history or symptoms suggestive of ischaemic heart disease or clinically significant dysrhythmias. 
f. 
For patients being considered for Cohort C, an echocardiogram should be performed within 60 days prior to start of lymphodepletion. 
g. 
For patients being considered for Cohort C, pulmonary function test (spirometry) to include FEV1 within 90 days prior to start of lymphodepletion. 
h. 
Colonoscopy is only required for patients who have had a documented Grade 2 or greater diarrhoea or colitis due to previous immunotherapy within 6 months of screening. 
i. 
Adverse Events: Following tissue procurement, collect AEs related to procurement procedure and SAEs only for up to 28 days or until start of standard therapy for melanoma; After Week 36 or during 
Survival Follow Up visits, collect AEs of special interest only. 
j. 
If any abnormalities are detectable at Week 12, ICANs assessments should be repeated at Week 24. 
k. 
Haematology and clinical chemistry to be conducted daily post cell infusion until values return to normal or baseline, or as clinically indicated. 
l. 
Coagulation screen: At screening visits: INR/PT and APTR/APTT only. At visits Day-1 to day 10, screen includes Fibrinogen and D Dimer. 
m. 
Pulse Oximetry: Continuous monitoring during infusion with pre- and post-infusion measurements recorded and then with vital signs. 
n. 
Minimum requirements for protocol. National health authority requirements should be followed if additional testing is mandated. 
o. 
Refer to Appendix G for pregnancy testing requirements in Germany. 
p. 
IL-2 administration: Days 0-9 (Cohorts A and B); Days 0-3 (Cohort C). The first dose of IL-2 should be administered 3-12 hours post completion of ATL001 infusion in Cohorts A and B, and 3-24 hours 
post completion of ATL001 infusion in Cohort C. 
q. 
If a biopsy cannot be collected at Week 6 or Week 12, a tumour biopsy may be provided at a different timepoint. This will be agreed following a discussion with the Sponsor. 
 
 


ACHILLES THERAPEUTICS 
 
Version: 11.0 (Master), 02 October 2023 
Clinical Study Protocol 
 
Protocol Number: ATX-ME-001 
Confidential 
Page 64 of 129 
 
Schedule of Assessments for Cohort B 
 
Screening 
Procurement 
Procurement 
Follow Up 
Pre-
Lymphodepletion 
Re-Screening 
Nivolumab 
Administration 
Lymphodepletion 
ATL001 
Treatment & IL-2 
Administration 
Period 
Nivolumab 
Administration / 
Follow up 
Withdrawal / 
Completion 
Survival Follow up a 
CSP Section 
Visit No. 
1 
2 
3 
4 
N 
5 – 7 
8 
9 
10-19 
20 
/ N 
21-22 
N 
23-26 
27-32 
33 
Visit Schedule  
Up to 30 D to D7 
before 
procurement 
Procurement 
 D28 ± 7 D after 
procurement 
 
D -28 to D -7 
D -13 to D -7 
D -6 to D -4 
D -1 (within 48 
hours prior to 
ATL001 
D0 (+5 D) 
D1 – D10 b 
D14 (±3 D) 
D21 (±3 D) and 
D28 (±7 D) 
W6 + every 4 W 
(up to W54) 
(±3 D) 
W6, W12, W18 
and W24 (±7 D) 
W36, W48, W60, 
W72, W84, W96 
(±14 D) 
W104 / 
withdrawal ((±14 
D) c 
Every 12 weeks 
(±14 days)  
until W364 d 
Informed 
Consent 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
6.4.1, 6.4.2, 6.4.4.1 and 11.1 
Inclusion / 
Exclusion 
Criteria 
X 
 
 
X 
 
D -6 
pre-
infusi
on 
only 
X3F 
 
 
 
 
 
 
 
 
 
4.1 and 4.2 
Enrolment 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
6.4.1 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.4.2, 8.1.10 
Medical History 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
6.4.2, 6.4.4, 
Melanoma 
History 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
6.4.2, 6.4.4 
Melanoma Risk 
Factors 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.4.2, 8.1.9 
ECOG PS 
X 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
6.4, 8.1.1 
Anti-cancer 
Therapies 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
6.4.2, 6.4.4 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
6.4 
Physical 
Examination 
X 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
 
 
6.4, 8.1.2 
Vital Signs 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
6.4.2, 6.4.4, 6.4.5, 6.4.6, 8.1.3 
Body Weight 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
X 
X 
X 
 
6.4 
12-Lead ECG 
 
 
 
X 
 
 
X 
X5F 
 
 
 
 
 
 
 
 
6.4.2, 6.4.4, 6.4.5, 8.1.5 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.4.2 
Echocardiogra
m 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.4.2 


ACHILLES THERAPEUTICS 
 
Version: 11.0 (Master), 02 October 2023 
Clinical Study Protocol 
 
Protocol Number: ATX-ME-001 
Confidential 
Page 65 of 129 
 
Screening 
Procurement 
Procurement 
Follow Up 
Pre-
Lymphodepletion 
Re-Screening 
Nivolumab 
Administration 
Lymphodepletion 
ATL001 
Treatment & IL-2 
Administration 
Period 
Nivolumab 
Administration / 
Follow up 
Withdrawal / 
Completion 
Survival Follow up a 
CSP Section 
Visit No. 
1 
2 
3 
4 
N 
5 – 7 
8 
9 
10-19 
20 
/ N 
21-22 
N 
23-26 
27-32 
33 
Visit Schedule  
Up to 30 D to D7 
before 
procurement 
Procurement 
 D28 ± 7 D after 
procurement 
 
D -28 to D -7 
D -13 to D -7 
D -6 to D -4 
D -1 (within 48 
hours prior to 
ATL001 
D0 (+5 D) 
D1 – D10 b 
D14 (±3 D) 
D21 (±3 D) and 
D28 (±7 D) 
W6 + every 4 W 
(up to W54) 
(±3 D) 
W6, W12, W18 
and W24 (±7 D) 
W36, W48, W60, 
W72, W84, W96 
(±14 D) 
W104 / 
withdrawal ((±14 
D) c 
Every 12 weeks 
(±14 days)  
until W364 d 
MRI/CT 
Tumour burden 
evaluation 
 
 
 
X7F 
 
 
 
 
 
 
 
 
W6, W12, W18, W24 and then 
every 12 W, until confirmed 
radiological disease progression 
 
6.4, 6.4.12 
Colonoscopy 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.4.2 
Adverse Events 
g  
 
X 
Xg  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
Xg 
Xg 
Xg 
6.4, 8.2 
CRS Grading 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
 
 
 
 
6.4.5, 6.4.6, 6.4.7, 7.7.4, 8.2.4 
ICANS Grading 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
W6, 
W12h 
 
 
 
6.4.5, 6.4.6, 6.4.7, 7.7.5, 6.4.8, 
8.2.4 
Blood Sampling 
for: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infectious 
Disease Marker 
Screening 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.1, 
6.4.2, 6.4.3.1 
Haematology 
X 
 
X 
X 
 
X 
X 
X 
Xi 
X 
X 
 
X 
X 
X 
 
6.4, 8.1.8 
HLA Typing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.2 
6.4.3.2 
Coagulation 
Screen 
Xi 
 
 
X 
 
 
X 
 
D1, D2, 
D3, D5, 
D7, D10j 
 
 
 
 
 
 
 
6.4.2, 6.4.4.1, 8.1.8 
Clinical 
Chemistry 
X 
 
 
X 
 
X 
X 
X 
Xi 
X 
X 
 
X 
X 
X 
 
6.4, 8.1.8 
Thyroid 
Function Test 
 
 
 
X 
 
 
 
 
 
 
 
 
W12 and then 
every 12 W 
X 
 
 
CRP 
 
 
 
X 
 
 
X 
 
D1, D2, 
D3, D5, 
D7, D10 
X 
X 
 
X 
 
 
 
6.4.4.1, 6.4.5.1, 6.4.7, 6.4.8, 
8.1.8 
Immunomonitor
ing (PBMC and 
TBNK) 
 
 
 
X 
 
 
 
 
D3, D7, 
D10 
X 
X 
 
X 
X 
X 
 
6.4, 8.4 
Immunomonitor
ing (Cytokines) 
 
 
 
X 
 
 
X 
 
D1, D2, 
D3, D5, 
D7, D10 
X 
X 
 
X 
X 
X 
 
6.4, 8.4 


ACHILLES THERAPEUTICS 
 
Version: 11.0 (Master), 02 October 2023 
Clinical Study Protocol 
 
Protocol Number: ATX-ME-001 
Confidential 
Page 66 of 129 
 
Screening 
Procurement 
Procurement 
Follow Up 
Pre-
Lymphodepletion 
Re-Screening 
Nivolumab 
Administration 
Lymphodepletion 
ATL001 
Treatment & IL-2 
Administration 
Period 
Nivolumab 
Administration / 
Follow up 
Withdrawal / 
Completion 
Survival Follow up a 
CSP Section 
Visit No. 
1 
2 
3 
4 
N 
5 – 7 
8 
9 
10-19 
20 
/ N 
21-22 
N 
23-26 
27-32 
33 
Visit Schedule  
Up to 30 D to D7 
before 
procurement 
Procurement 
 D28 ± 7 D after 
procurement 
 
D -28 to D -7 
D -13 to D -7 
D -6 to D -4 
D -1 (within 48 
hours prior to 
ATL001 
D0 (+5 D) 
D1 – D10 b 
D14 (±3 D) 
D21 (±3 D) and 
D28 (±7 D) 
W6 + every 4 W 
(up to W54) 
(±3 D) 
W6, W12, W18 
and W24 (±7 D) 
W36, W48, W60, 
W72, W84, W96 
(±14 D) 
W104 / 
withdrawal ((±14 
D) c 
Every 12 weeks 
(±14 days)  
until W364 d 
Immunological 
assay 
 
 
 
 
 
 
 
 
 
 
 
 
W6 
only 
 
 
 
6.4.8, 8.4 
TCR RNA 
 
 
 
X 
 
 
 
 
D7 and 
D10 only 
X 
X 
 
X 
X 
X 
 
6.4. 8.4 
ctDNA 
 
X 
 
X 
 
 
X 
 
D7 only 
X 
X 
 
X 
X 
X 
 
6.4, 8.5.1 
Germline DNA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.2, 6.4.3.2 
Pulse Oximetry 
k  
 
 
 
 
 
 
X 
Xk 
X 
 
 
 
 
 
 
 
6.4.5, 8.1.4 
Pregnancy Test 
(Females) l 
X 
 
 
X 
X 
 
 
Xm 
 
X 
X 
X 
X 
X 
 
 
6.4, 8.1.7 
Tissue 
Procurement 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.1, 6.1.3, 6.4.3.1 
Archival tissue 
(if available) 
X 
 
6.1.1, 6.4.3.1, 8.5.2 
Blood for 
Manufacturing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.2, 6.1.3, 6.4.3.2 
Infusion 
Reaction 
Prophylaxis 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
6.2, 
6.4.5.2 
ATL001 
Infusion 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
5.1.1, 6.4.5.2 
Lymphodepleti
on (Flu/Cy) 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
6.2, 6.4.4.2 
IL-2 
Administration 
 
 
 
 
 
 
 
Xn 
 
 
 
 
 
 
 
6.2, 
6.4.5.2 
Optional 
Tumour Biopsy 
 
 
 
X 
 
 
 
 
 
 
 
 
W6 or W12, and at disease 
progressiono 
 
6.4.4.1, 
6.4.8, 8.5.2 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
6.4.8, 6.4.9 
Administration 
of Nivolumab  
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
 
 
5.1.2, 
6.4.13 
D = Day(s); W = Week(s); N = Standalone nivolumab dosing visit 
a. 
After confirmed disease progression, the patient would move to Survival Follow Up visits. These visits could be conducted by telephone if deemed clinically appropriate by the Investigator. 


ACHILLES THERAPEUTICS 
 
Version: 11.0 (Master), 02 October 2023 
Clinical Study Protocol 
 
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Confidential 
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b. 
For Immunomonitoring (PBMC and TBNK), Immunomonitoring (Cytokines), TCR RNA and ctDNA samples collected between Day 0 and Day 10, the following windows apply: Day 3 ± 1 day window; 
Day 5 and Day 7 ± 1 day window (if +1 day visit window is used for Day 3 visit, then Day 5 visit will have +1 day visit window; if +1 day visit window is used for Day 5 visit, then Day 7 visit will have +1 
day visit window); Day 10 ± 1 day window. 
c. 
If withdrawal is after ATL001 treatment and prior to week 104, the assessments should follow the previous visit, except undertaking RECIST scans if already performed. If withdrawal is prior to ATL001 
infusion, then the assessments required at procurement follow up visit should be completed. 
d. 
Patients may have Survival Follow Up visits until W104, or until W364, until such time as the Long Term Follow Up study is available at study site. 
e. 
Echocardiogram within 60 days prior to screening: Only for patients over 60 or with history or symptoms suggestive of ischaemic heart disease or clinically significant dysrhythmias. 
f. 
Colonoscopy is only required for patients who have had a documented Grade 2 or greater diarrhoea or colitis due to previous immunotherapy within 6 months of screening. 
g. 
Adverse Events: Following tissue procurement, collect AEs related to procurement procedure and SAEs only for up to 28 days or until start of standard therapy for melanoma; After Week 36 or during 
Survival Follow Up visits, collect AEs of special interest only. 
h. 
If any abnormalities are detectable at Week 12, ICANs assessments should be repeated at Week 24. 
i. 
Haematology and clinical chemistry to be conducted daily post cell infusion until values return to normal or baseline, or as clinically indicated. 
j. 
Coagulation screen: At screening visits: INR/PT and APTR/APTT only. At visits Day-1 to day 10, screen includes Fibrinogen and D Dimer. 
k. 
Pulse Oximetry: Continuous monitoring during infusion with pre- and post-infusion measurements recorded and then with vital signs. 
l. 
Minimum requirements for protocol. National health authority requirements should be followed if additional testing is mandated. 
m. 
Refer to Appendix G for pregnancy testing requirements in Germany. 
n. 
IL-2 administration: Days 0-9. The first dose of IL-2 should be administered 3-12 hours post completion of ATL001 infusion. 
o. 
If a biopsy cannot be collected at Week 6 or Week 12, a tumour biopsy may be provided at a different timepoint. This will be agreed following a discussion with the Sponsor. 


ACHILLES THERAPEUTICS 
 
Version: 11.0 (Master), 02 October 2023 
Clinical Study Protocol 
 
Protocol Number: ATX-ME-001 
Confidential 
Page 68 of 129 
6.4. 
Study Procedures by Visit 
The same visits and procedures would be followed by all patients regardless of whether they receive 
a target dose range product or an “out-of-specification" product.  
 
Consent and Enrolment Procedure 
A 2-part consent and enrolment procedure will apply for this study. 
Patients will consent for the whole study but will initially be enrolled only for the donation of 
materials required for the manufacturing of ATL001. Following the successful manufacture of 
ATL001, patients will provide additional consent for treatment with ATL001 prior to confirmation 
of patient eligibility and enrolment for treatment. Patients will be informed that the follow up period 
in this protocol is 2 years after treatment with ATL001, but that the total follow up period is 7 years 
after treatment with ATL001, and that after 2 years the follow up visits will be scheduled according 
to a separate Long Term Follow Up Protocol. 
At the time of the Screening Visit, patients who may be eligible for the study, will be informed 
about all treatment cohorts and will be asked to consider receiving ATL001 either as a monotherapy 
in treatment Cohort A and Cohort C, or in combination with nivolumab in treatment Cohort B, 
dependent upon which of the cohorts are open at the time of treatment. In centres where Cohort B 
and/or Cohort C are open, eligible patients will be asked, at the time of the Pre-Lymphodepletion 
Re-screening Visit, to confirm that they agree to receiving treatment within Cohort B and Cohort 
C. 
Patients will undergo all the procedures pertaining to the Screening Visit and Tissue/Blood 
Procurement Visit. Germline DNA sequencing is required as part of the manufacturing procedure 
as it is needed to identify the tumour-specific clonal mutations. Patients will consent for germline 
DNA sequencing as part of the overall study consent process. 
For some situations where additional tissue is requested (see Section 6.1.3), the patient may be 
required to re-enrol. Re-enrolment is dependent on the reason for re-procurement and will be guided 
by the Sponsor.  
 
Screening Visit (30 Days to 7 Days before Tissue Procurement) 
Procedures and assessments at this visit will be: 
a. Informed consent. 
b. Inclusion/exclusion criteria. 
c. Demographics (see Section 9.4.2). 
d. Relevant medical/surgical history (see Section 9.4.3). 
e. Prior therapies. 
f. Melanoma history (stage, subtype, molecular profile, treatment history). 
g. Melanoma risk factors (see Section 8.1.11). 
h. Physical examination. 
i. 
ECOG Performance status. 
j. 
Vital signs – BP, pulse rate, respiratory rate, and body temperature (oral or otic). 


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k. Body weight and height. 
l. 
Echocardiogram for all patients over 60 or with any history of cardiac pathology 
or symptoms within 60 days prior to screening. This is a baseline measurement and 
should contribute to assessment of exclusion criteria 6 and 21 (the latter for Cohort 
C only). 
m. Colonoscopy for patients who have had a documented Grade 2, or greater diarrhoea 
or colitis due to previous immunotherapy within six months of screening. Patients 
that have been asymptomatic for at least 6 months or have had a normal 
colonoscopy post-immunotherapy (with uninflamed mucosa by visual assessment) 
are not excluded. See Exclusion Criterion 8.  
n. Serum or urine pregnancy Test (for women of childbearing potential). 
o. Concomitant medications. 
p. Blood samples for: 
o IDM1: Including serology for Anti-HIV 1 & 2, HBs Ag, Anti-HBc, Anti-
HCV-Ab, Syphilis (Treponema pallidum) IgG/IgM and Anti-HTLV 1 & 
2. Additional tests per local requirements, if required, should also be 
performed. If performed, any positive test results must be reported to the 
study Sponsor.  
o Haematology. 
o Coagulation screen (INR/PT and APTR/APTT only).  
o Clinical chemistry. 
If it is not possible to perform all screening assessments 7 days prior to procurement, Sponsor 
approval may be granted to perform procedures within 7 days of procurement under exceptional 
circumstances.    
6.4.2.1 
Rescreening of Patients 
Patients may be rescreened under conditions such as the following: 
a. Marginally failed laboratory screening criteria for haemoglobin, neutrophil count, 
liver or kidney function tests. 
b. Transient or erroneous out of range safety laboratory values. 
c. Mild illness (e.g., a self-limiting viral illness) at the time of testing. 
If the repeat values for the laboratory screening criteria meet the pre-defined limits as outlined in 
the list of inclusion criteria and after the patient makes a complete recovery from the illness, the 
patient may be enrolled. 
 
Tissue and Blood Procurement for ATL001 Manufacture 
6.4.3.1 
Tumour Tissue Procurement 
Upon enrolment, a surgical procedure for tumour sample collection will be scheduled to enable 
manufacture ATL001. The surgical procedures for tumour tissue procurement should be clinically 
relevant procedures which do not cause undue risk to patients, as determined by the Investigator, 
taking into consideration the risk/benefit for the patient. 


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Access to the archival FFPE block of primary tumour may be requested for analysis of the tumour 
microenvironment, if available. 
Patients should have clearance of the first infectious disease marker screening sample (IDM1) 
within 30 days of the procurement of tumour tissue to allow material to be accepted into the 
manufacturing facility, and then a second infectious disease marker screening (IDM2) sample 
should be taken on the day of tumour tissue procurement. 
See Section 6.1.1 for full details of the procurement procedure. 
Further instructions for tissue collection, labelling and transportation to the manufacturing facility 
are provided in the Procurement and Cell Handling Manual. 
6.4.3.2 
Blood Sampling 
The following blood samples will be collected: 
a. A blood sample (target volume 140 mL whole blood) for ATL001 manufacture. 
b. A blood sample for germline DNA (~10 mL). 
c. A blood sample for ctDNA monitoring (~30 mL). 
d. A blood sample for HLA testing (~4 mL). 
See Section 6.1.2 for full details of the procurement procedure. 
Further instructions for tissue collection, labelling and transportation to the manufacturing facility 
are provided in the Procurement and Cell Handling Manual. 
Refer to Section 6.1.3 if additional blood or tumour is required.  
6.4.3.3 
Procurement Follow-up (Day 28 ± 7 days after tumour procurement) 
Procedures and assessments at this visit will be: 
a. Adverse Events (see Section 8.2). 
b. Concomitant medications. 
c. Physical examination. 
d. ECOG performance status. 
e. Haematology.  
 
Pre-Lymphodepletion Re-screening (Day -28 to Day -7) 
6.4.4.1 
Pre-Lymphodepletion Re-Screening Evaluations 
a. Informed consent, and assignment to Cohort A, Cohort B or Cohort C (if eligible). 
b. Physical Examination. 
c. Medical History. 
d. Prior therapies. 
e. Melanoma history (stage, subtype, molecular profile, treatment history). 
f. ECOG performance status. 
g. Check eligibility criteria – patients must meet all criteria. 


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h. Body Weight. 
i. 
Vital signs. 
j. 
For patients being considered for Cohort C, echocardiogram within 60 days prior 
to lymphodepletion. 
k. For patients being considered for Cohort C, pulmonary function test (spirometry) 
to include FEV1 within 90 days prior to lymphodepletion.  
l. 
Concomitant medications. 
m. 12-lead ECG. 
n. Blood draws for: 
o Haematology. 
o Coagulation screen (INR/PT and APTR/APTT only). 
o Clinical chemistry. 
o Thyroid Function Test.  
o CRP. 
o ctDNA (~10 mL). 
o Baseline samples for immunomonitoring – PBMC, TBNK and plasma 
cytokines- (as close to Day -6 as possible) (~30 mL and up to ~3 mL 
samples). 
o Baseline sample for TCR RNA (as close to Day -6 as possible) (~3 mL). 
o. Adverse Events. 
p. Serum or urine pregnancy test (for women of childbearing potential). 
q. MRI/CT tumour burden assessment must be after last cycle of previous systemic 
anti-cancer therapy and be within 3 weeks prior to lymphodepletion. 
r. Optional tumour biopsy [may be taken at any time between visit 3 and visit 5 if 
more convenient]. 
See Section 6.4.14 for Cohort B nivolumab treatment administration.  
6.4.4.2 
Lymphodepletion (Study Day -6, -5 and -4) 
Prior to receiving the ATL001 infusion, patients will undergo non-myeloablative lymphodepleting 
chemotherapy. Patients will receive fludarabine 30 mg/m2 i.v. and cyclophosphamide 300 mg/m2 
i.v. on each of Days -6, -5, and -4 prior to cell infusion with appropriate supportive care. These can 
be administered according to local SOPs. 
Lymphodepletion is contra-indicated in patients with active infections requiring antibiotics, so 
exclusion 18 should be re-checked prior to commencing lymphodepletion on Day -6, and this will 
be documented. 
Patients will be admitted to the hospital facility for close monitoring on day -4 (the final day of 
lymphodepletion) or as per institutional standard of care practises. 


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Patients in Cohort B will receive one dose of nivolumab 240 mg i.v. on day -7. There is an option 
to give this up to 7 days before day -6 if more convenient (i.e. any time from day -13 to day -7). 
Patients who enrol in treatment Cohort B will undergo the same assessments as those patients in 
Cohort A with the addition of a serum or urine pregnancy test which will be required prior to each 
nivolumab administration for female participants of childbearing potential. For assessments prior 
to nivolumab, ECOG performance status and vital signs should be performed on the day of 
administration but physical examination (and urine tests, if applicable) may be performed at most 
recent clinic visit (if not on the same day, prior to administration) if ≤3 days prior to administration. 
On each day of lymphodepletion, the following assessments should be conducted: 
a. Blood draws for: 
o Haematology. 
o Clinical chemistry. 
b. Adverse events. 
c. Concomitant medications. 
 
Pre-Treatment Evaluation and ATL001 Infusion (Study Days -1 to 0 [+5 Days]) 
6.4.5.1 
Baseline Pre-treatment Evaluations (Day -1) 
Day -1 visit can be performed within 48 hours prior to cell infusion. Prior to infusion, patients 
should be considered, in the opinion of the Investigator, well enough (i.e. ECOG Performance 
Status 0-1) to receive the infusion otherwise a delay should be considered (Section 6.2). 
a. Check Inclusion criteria 15 (Patient is well enough to receive ATL001). 
b. Adverse Events. 
c. Baseline CRS and ICANS Grading. 
d. Physical Examination. 
e. ECOG Performance Status. 
f. Concomitant medications. 
g. Body Weight. 
h. Vital signs.  
i. 
12-lead ECG.  
j. 
Pulse oximetry.  
k. Blood draws for: 
o Haematology. 
o Coagulation screen (INR/PT and APTR/APTT, fibrinogen and D-Dimer). 
o Clinical chemistry. 
o CRP. 
o Immunomonitoring: plasma cytokines only (e.g. IL-6, TNFα, IL-17, INF-
γ, IL-1b, IL-2, IL-8, IL-15, IL-10) (~3 mL). 


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o ctDNA (~10 mL). 
6.4.5.2 
ATL001 Infusion (Study Day 0 [+5 Days]) 
Patients should be pre-medicated with a standard regimen to prevent infusion reactions (e.g. 
chlorphenamine and paracetamol/acetaminophen) according to local SOPs prior to the infusion of 
ATL001. This prophylactic regimen should not contain corticosteroids. A single dose of ATL001 
cell dispersion will be infused within 30 minutes of thawing on Day 0. 
The following should be monitored on Day 0: 
a. Pulse oximetry – baseline measure (as close to the start of the infusion as possible) 
and continuous throughout the infusion and for as long as clinically indicated. The 
readings at the beginning and end of the infusion should be recorded in the eCRF. 
Post infusion measures at 30 minutes (± 5 minutes), 1 hour (± 10 minutes), 2 hours 
(± 15 minutes) and 4 hours (± 15 minutes) from the start of infusion, and as 
clinically indicated. 
b. Vital signs – baseline measure (as close to the start of the infusion as possible) and 
post infusion measures at 30 minutes (± 5 minutes), 1 hour (± 10 minutes), 2 hours 
(± 15 minutes) and 4 hours (± 15 minutes) from the start of infusion, and as 
clinically indicated. 
c. 12 lead ECG (within 30 minutes following end of infusion, and as clinically 
indicated). 
d. Blood draws for: 
o Haematology. 
o Clinical chemistry. 
e. Adverse events. 
f. Concomitant medications. 
Refer to Appendix G for additional testing requirements in Germany. 
Patients should receive a single dose of IL-2 1M IU/m2 s.c. at 3-12 hours post completion of infusion 
(Cohort A and Cohort B) or single dose of IL-2 600,000 IU/kg i.v. 3-24 hours post completion of 
infusion (Cohort C), as long as systolic BP ≥ 90 mmHg and pulse ≤ 100 bpm or pre-infusion levels. 
The injection can be delayed if needed to allow recovery to these levels. Time of administration 
should be recorded. 
 
Post Infusion Monitoring (Study Days 1 - 10) 
In Cohort A and Cohort B, patients will receive 9 further doses of IL-2 1M IU/m2 s.c. daily from 
days 1-9 of the study, as long as clinically stable and there is no evidence of severe infection, 
capillary leak syndrome or adverse events ≥ Grade 2 that are attributed to IL-2. 
Patients in Cohort A and Cohort B should remain in the hospital facility for the time required by 
clinical consideration, or until any signs/symptoms of treatment-related adverse events have 
resolved to Grade 1 or baseline levels, whichever is longer.  
In Cohort C, patients will receive up to 5 further doses of IL-2 600,000 IU/kg i.v. 8-12 hourly as 
long as clinically stable and there is no evidence of severe infection, capillary leak syndrome or 
adverse events ≥ Grade 3 that are attributed to IL-2.Patients in Cohort C should remain in the 


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hospital facility for the duration of IL-2 administration or until any signs/symptoms of treatment-
related adverse events have resolved to Grade 1 or baseline levels, whichever is longer.  
Assessments (every day will be a study visit day) 
a. Adverse events (daily). 
b. CRS and ICANS Grading. 
c. Physical examination (daily). 
d. Concomitant medications (daily). 
e. Vital signs and pulse oximetry (every day until day 10, and as clinically indicated). 
f. Body Weight (daily as an early indicator of fluid retention). 
g. Blood draws for: 
o Haematology (to be conducted daily post cell infusion until values return 
to normal or baseline, or as clinically indicated). 
o Coagulation screen (INR/PT and APTR/APTT, fibrinogen and D-Dimer) 
(Days 1, 2, 3, 5, 7 and 10 post infusion, and as clinically indicated. 
o Clinical chemistry evaluations (except TFTs) (to be conducted daily post 
cell infusion until values return to normal or baseline, or as clinically 
indicated). 
o CRP (Days 1, 2, 3, 5, 7 and 10 post infusion and as clinically indicated). 
o Immunomonitoring - Plasma cytokines (Days 1, 2, 3, 5, 7, and 10 post 
infusion, and repeated on day 12 if hospitalisation is prolonged due to CRS 
or ICANS for event assessment). 
o Immunomonitoring – PBMC and TBNK (~30 mL, Days 3, 7 and 10 post 
infusion). 
o ctDNA (~10 mL day 7). 
o TCR RNA (~3 mL, Days 7 and 10 post-infusion). 
See Section 6.3 for Immunomonitoring (PBMC and TBNK), Immunomonitoring (Cytokines), TCR 
RNA and ctDNA sample collection windows. 
 
Early Follow-Up Period (Day 14 - 28) 
Following discharge, all patients will attend clinic visits on days 14 (±3 days), 21 (±3 days), 28 (±7 
days), post ATL001 infusion. The following study-specific assessments will be performed at each 
visit for all patients. 
a. Adverse Events. 
b. CRS and ICANS Grading. 
c. Concomitant medications. 
d. Physical examination (Cohort A and C: anytime during the day; Cohort B: prior to 
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e. ECOG Performance Status (Cohort B only: Prior to nivolumab treatment 
administration). 
f. Blood draws for:  
o Haematology (not coagulation unless clinically indicated). 
o Clinical chemistry safety evaluations (including CRP but not TFTs unless 
clinically indicated).  
o Immunomonitoring – PBMC, TBNK and plasma cytokines (Plasma 
cytokines may be additionally performed on days 17 and 24 if 
hospitalisation is prolonged due to CRS or ICANS for event assessment). 
o TCR RNA. 
o ctDNA (~10 mL). 
Patients in treatment Cohort B will receive nivolumab on day 14 at a dose of 480 mg i.v. If patients 
have any toxicity that would prevent them from receiving nivolumab at the day 14 visit, the 
treatment should be delayed until they have resolved to Grade 1 or baseline. Refer to the latest 
available prescribing information (e.g. SmPC/Package Insert) and to local and national treatment 
guidelines for further reference safety information for nivolumab. 
 
Intermediate Follow-Up Period (Week 6 - Week 24) 
Patients will attend clinic visits every 6 weeks (weeks 6, 12, 18 and 24, all ±7 days) for the first 6 
months post ATL001 infusion. The following study-specific assessments will be performed at each 
visit prior to, and at the visit of, confirmed disease progression. 
a. Adverse Events. 
b. ICANS Grading until Week 12 (and at Week 24 if not Grade 0 at Week 12). 
c. Concomitant medications. 
d. Physical examinations (Cohort B only: Prior to nivolumab treatment 
administration, may be performed at most recent clinic visit if ≤ 3 days prior to 
administration). 
e. ECOG Performance status (Cohort B only: Prior to nivolumab treatment 
administration). 
f. Body Weight. 
g. Vital signs (Cohort B only: Prior to nivolumab treatment administration). 
h. Blood draws for: 
o Haematology (not coagulation unless clinically indicated). 
o Clinical chemistry safety evaluations including CRP (TFTs on weeks 12 
and 24 only unless more frequent assessment is clinically indicated). 
o Immunomonitoring – PBMC, TBNK and plasma cytokines (~33 mL each 
visit – see Section 8.4). 
o Immunomonitoring - for extended immunological assays, one 150 mL 
sample at week 6 only (unless the patient’s clinical condition precludes this 
sample) – see Section 8.4). 


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o TCR RNA (Week 6, 12 18 and 24). 
o ctDNA (~10 mL at all timepoints but ~30 mL at week 12). 
i. 
MRI/CT tumour burden evaluations (supplemented by documented caliper 
measurement of skin lesions if applicable) (Week 6, 12, 18 and 24 and then every 
12 weeks until the time of confirmed radiological disease progression – see Section 
6.4.13). 
j. 
Optional Tumour Biopsies: post treatment tumour biopsies will be requested (at 
week 6 or week 12 and/or at disease progression in patients whose tumour is safely 
accessible for biopsy. These samples will be used to assess the immune status of 
the tumour after ATL001 treatment and to explore changes related to 
efficacy/resistance to treatment). If a biopsy cannot be collected at week 6 or week 
12, a tumour biopsy may be provided at a different timepoint. This will be agreed 
following a discussion with Sponsor. 
For patients of childbearing potential:  
All Cohorts: Additional urine or serum pregnancy testing is required if the patient is being treated 
in Germany. This testing is required every 6 weeks for 12 months following ATL001 dose, study 
completion or withdrawal from study (refer to Appendix G).  
Cohort B: Urine or serum pregnancy testing is required prior to each nivolumab administration (i.e. 
every 4 weeks). For Cohort B patients being treated at sites in Germany, if nivolumab doses are 
delayed, omitted, or discontinued for any reason then the frequency of pregnancy testing should be 
adjusted accordingly but must satisfy the 6-weekly requirement seen in Cohorts A and C (refer to 
Appendix G). 
Patients in treatment Cohort B will attend for additional visits to receive nivolumab at dose of 480 
mg i.v. every 4 weeks, if tolerated, for up to 12 months, up to 6 months following a CR or until 
RECIST v1.1 confirmed disease progression, whichever is sooner.  
If a patient has disease progression during this study period, refer to Section 6.4.10.  
 
Long Term Follow-Up Period (Week 36 - Week 104) 
Patients will attend clinic visits every 12 weeks (weeks 36, 48, 60, 72, 84, 96 and 104) (all ±14 
days), post ATL001 infusion. The following limited study-specific assessments will be performed 
at each visit prior to, and at the visit of, confirmed disease progression. 
a. Adverse Events of Special Interest (see Section 8.2.4). 
b. Concomitant medications. 
c. Physical examinations (Cohort B only: Prior to nivolumab treatment 
administration, may be performed at most recent clinic visit if ≤ 3 days prior to 
administration). 
d. ECOG Performance status (Cohort B only: Prior to nivolumab treatment 
administration). 
e. Body Weight. 
f. Vital signs (Cohort B only: Prior to nivolumab treatment administration). 
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o Haematology (not coagulation unless clinically indicated). 
o Clinical chemistry safety evaluations, except CRP (In Cohort A and Cohort 
C, TFTs are required on weeks 48, 72 and 104 only, unless more frequent 
assessment is clinically indicated. However, in Cohort B, TFTs are 
required at every 12-weekly visit). 
o Immunomonitoring – PBMC, TBNK and plasma cytokines. 
o TCR RNA. 
o ctDNA (~10 mL). 
h. MRI/CT tumour burden evaluations (supplemented by documented caliper 
measurement of skin lesions if applicable) (until the time of confirmed radiological 
disease progression, see Section 6.4.13). 
Patients in treatment Cohort B will attend for additional visits to receive nivolumab at dose of 
480mg i.v. every 4 weeks, if tolerated, for up to 12 months, up to 6 months following a CR or until 
RECIST v1.1 confirmed disease progression, whichever is sooner. 
If a patient has disease progression, during this study period, refer to Section 6.4.10.  
For patients of childbearing potential:  
All Cohorts: Additional urine or serum pregnancy testing is required if the patient is being treated 
in Germany. This testing is required every 6 weeks for 12 months following ATL001 dose, study 
completion or withdrawal from study (refer to Appendix G).  
Cohort B: Urine or serum pregnancy testing is required prior to each nivolumab administration (i.e. 
every 4 weeks). For Cohort B patients being treated at sites in Germany, if nivolumab doses are 
delayed, omitted, or discontinued for any reason then the frequency of pregnancy testing should be 
adjusted accordingly but must satisfy the 6-weekly requirement seen in Cohorts A and C (refer to 
Appendix G). 
 
Survival Follow Up Visits 
If a patient has disease progression prior to week 104, patients will move into Survival Follow Up. 
These study visits will be scheduled every 12 weeks (± 14 days), until week 104 (or Week 364, 
until such time as the Long Term Follow Up study is available at study site), and assessments will 
consist only of the assessments listed below. These visits could be conducted by phone if deemed 
clinically appropriate by the Investigator: 
a. Anti-cancer treatments. 
b. Survival Status. 
c. Adverse Events of Special Interest (see Section 8.2.4). 
 
Withdrawal/Completion Visit 
After week 104 (2 years ±14 days) following ATL001 infusion, no further follow up visits will be 
performed in this protocol, and the patient will have completed the study. Patients will continue to 
be followed up for a further 5 years in a separate Long Term Follow Up Protocol. The assessments 
will be the same as described in Section 6.4.10 with a reduced frequency. 
Patients who complete the study or who withdraw from the study for any reason prior to the week 
104 visit will be asked to complete a Withdrawal/Completion Visit.  


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For patients who withdraw from the study within 28 days of procurement, the 
withdrawal/completion visit should be completed at Visit 3. If patients are withdrawn after Visit 3 
and before lymphodepletion, no further follow up investigations are required provided that the Visit 
3 assessments were performed after procurement and any ongoing procurement-related adverse 
events have resolved. For patients who withdraw from the study after commencing 
lymphodepletion but before receiving ATL001, the withdrawal/completion visit will require 
information about toxicities related to study treatments, which should be followed up until 
resolution. 
For patients who withdraw from the study after receiving ATL001, the withdrawal/completion visit 
assessments will be completed (except MRI or CT scan if performed at the preceding visit). 
Patients who have received ATL001 and who withdraw from the study prior to the week 104 visit 
will be asked consent to the collection of survival status information and adverse events of special 
interest at 3-monthly periods until week 104 (or Week 364, until such time as the Long Term Follow 
Up study is available at study site) after dosing. After this period, patients will be asked to consent 
to the collection of survival status as part of the separate Long Term Follow Up Protocol. Overall, 
each patient will continue to be followed up for a minimum period of 5 years, as part of the separate 
Long Term Follow Up Protocol.  
If the Long Term Follow Up protocol is not yet available at the study site, patients will continue to 
be followed up in the original study protocol until such time as the Long Term Follow Up is 
available at study site.   
 
Unscheduled Visit 
At the Investigators’ discretion, an Unscheduled Visit may be completed at any time during the 
study, if deemed necessary for the patients’ safety and wellbeing. Unscheduled visits may also be 
completed in the cases of re-collection of blood or re-administration of ATL001 or the collection 
of excess biological material from standard of care procedures. 
 
Efficacy Monitoring  
6.4.13.1 
Assessment Modalities 
Anti-tumour activity will be assessed at scheduled timepoints by CT scans of chest, abdomen and 
pelvis, and other locations if indicated. If CT scanning is not acceptable, MRI may be an alternative. 
The same modality should be used per patient throughout the study to assess lesion responses. If 
necessary, CT measurements may be supplemented by caliper measurement of measurable skin 
lesions. Skin lesions are only considered measurable when they are ≥ 10 mm in diameter as assessed 
using calipers. Caliper measurements, if used, must be documented by colour photography, 
including a ruler to confirm the size of the lesion. 
Access to the scan most recently preceding procurement and any CT scans conducted as part of 
standard clinical practice to assess the patient’s response to the most recent therapy, may be needed 
to retrospectively evaluate response to the immediately preceding therapy, in order to aid the 
assessment and interpretation of clinical activity.  
6.4.13.2 
imRECIST Considerations 
In this study protocol, both RECIST 1.1 and imRECIST tumour responses will be recorded. 
ATL001 may induce an inflammatory reaction within tumours due to the infiltration and activation 
of T cells, and as a result, the phenomenon of pseudo-progression may be observed at the initial 
scan, as has been documented when treatment is initiated with checkpoint inhibitors. The immune 


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modified RECIST (imRECIST) guidelines [Hodi et al, 2018] have been developed to take this into 
account and there are some important considerations to be aware of which have implications for the 
conduct of the study. 
According to RECIST v1.1 criteria [Eisenhauer et al, 2009] an observation of disease progression 
(PD) at the first scan should be recorded as a best response of PD whereas imRECIST criteria 
recognise responses that are observed following an initial radiological PD, provided that a minimum 
time-period of at least 4 weeks has elapsed following the initial PD and the subsequent scan. 
Secondly, unlike RECIST v1.1, the imRECIST criteria do not consider non-target lesions in the 
definition of disease progression and the appearance of new lesions per se is also not considered to 
be evidence of disease progression, unless the dimension of the new lesion when added to the target 
lesions would result in an increase in tumour burden ≥ 20% relative to the nadir. 
The implications for efficacy monitoring are: 
1. All patients should have at least two post-baseline scans, regardless of whether a RECIST 
v1.1 progression or imRECIST progression was observed at the first post-baseline scan. 
2. Investigators should use imRECIST criteria in determining whether disease progression 
has been detected and whether further radiological imaging is required in the study. 
a. As per imRECIST guidelines, all imRECIST progression events should be 
confirmed by scanning at two consecutive timepoints at least 28 days apart. 
Further details are provided in Section 15, Appendix B and the study Statistical Analysis Plan 
(SAP). 
 
Cohort B: Nivolumab Treatment Administration 
6.4.14.1 
Day -13 to Day -7 
A single dose of nivolumab 240 mg i.v. between Day -13 and Day -7 will be administered prior to 
lymphodepletion dose. 
6.4.14.2 
Day 14 and then Every 4 Weeks (Up to 12 months) 
A dose of nivolumab 480 mg i.v. will be administered on Day 14 (+3 days). If patients have any 
toxicity that would prevent them from receiving nivolumab at the Day 14 visit, the treatment should 
be delayed until toxicity resolved to Grade 1 or baseline.  
Patients will attend additional visits to receive nivolumab at dose of 480 mg i.v. at Week 6 (± 3 
days) and then every 4 weeks (± 3 days), if tolerated, for up to 12 months, up to 6 months following 
a CR or until RECIST v1.1 confirmed disease progression, whichever is sooner.  
Refer to the latest available prescribing information (e.g. SmPC/Package Insert) and to local and 
national treatment guidelines for further reference safety information for nivolumab. 
7 
SAFETY MONITORING AND MANAGEMENT GUIDELINES 
7.1. 
Anticipated Safety Risks 
The principal anticipated safety risks, as summarised in Section 2.2, are associated with the 
procurement procedures, transient pancytopenia due to the lymphodepletion regimen, adverse 
events related to the administration of IL-2, and to the cell infusion itself, including infusion 
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Syndrome (ICANS). CRS is considered a potential risk because of in vivo T cell proliferation and 
activation, although this is not anticipated to be as great with a TIL product as for patients receiving 
a CAR-T cell therapy. CRS is a result of excessive IL-6 production from activated T cells, and 
treatment with the anti-IL-6 receptor antibody, tocilizumab, has been shown to be an effective 
strategy in patients receiving CAR-T therapies for other cancers and will need to be available on 
site. Due to shortages of tocilizumab caused by the COVID-19 pandemic, siltuximab (anti-IL-6 
antibody) may be used in first line treatment of CRS, rather than in second line (See Table 5).  
7.2. 
General Precautions 
Patients will be admitted to hospital for close monitoring on Day -4 (or as per institutional standard 
of care practices) and should remain in the hospital facility for the time required by clinical 
consideration, or until any signs/symptoms of treatment-related adverse events have resolved to 
Grade 1 or baseline levels, whichever is longer. Patients in Cohort C must remain in the hospital 
facility for the duration of IL-2 administration or until any signs/symptoms of treatment-related 
adverse events have resolved to Grade 1 or baseline levels, whichever is longer. 
Following discharge from hospital patients should be advised to remain within close distance of the 
Investigational Site or an alternative local cell therapy treatment centre for 4 weeks in case any new 
adverse events arise between scheduled visits. Patients should be advised not to drive for 8 weeks 
following the cell infusion. 
ATL001 is being studied in two clinical trials for solid tumours which are recruiting concurrently 
(one is this study and the second is a study in patients with advanced NSCLC, ATX-NS-001). Safety 
of the IMP will be evaluated in all patients to whom the IMP has been administered. The first 3 
patients to receive ATL001 (across both ATX-ME-001 and ATX-NS-001) had been observed for 
14 days following ATL001 infusion before the next patient underwent lymphodepletion. This is 
considered sufficient to identify symptoms of immediate cytokine release syndrome or severe 
infusion reactions.  
Providing none of the following events are observed in any of the first three patients to receive 
ATL001 across both studies, the observation period between patient administrations (inter- and 
intra-study) may be reduced to 7 days: 
• 
Severe infusion reaction requiring i.v. corticosteroid. 
• 
Grade 3 or worse autoimmunity, cytokine release syndrome or capillary leak syndrome, 
that does not resolve to Grade 2 or below within 2 days. 
• 
Grade 2 or worse neurological toxicity that does not resolve to Grade 1 or baseline 
within 2 days. 
• 
The omission of more than 2 doses of IL-2 due to an adverse event related to IL-2. 
• 
Any other clinically significant adverse event considered to be related to ATL001 
infusion. 
The IDSMC will review all safety data from the first 6 patients to whom ATL001 is administered 
across both studies and if ≤1 of these events have been observed in 6 patients, the requirement for 
an observation period between patient administrations will be discontinued. This decision will be 
documented in the IDSMC meeting minutes. 


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7.3. 
Adverse Events Related to Tissue Procurement Procedures 
Patients should be managed according to local standard surgical and anaesthetic guidelines. 
Procedure-related AEs and all SAEs will be collected for 28 days post tumour tissue procurement 
or until the patient starts systemic therapy for melanoma, whichever is sooner. 
7.4. 
Management of Adverse Events Related to Lymphodepletion Regimen 
The fludarabine and cyclophosphamide lymphodepletion regimen is expected to cause transient 
pancytopenia for up to 14 days, during which time patients will be susceptible to infections. Other 
common side effects associated with fludarabine and cyclophosphamide include poor appetite, 
nausea, vomiting, fatigue and diarrhoea. Cyclophosphamide at high doses can cause bladder 
irritation and fluid retention but this is not anticipated with the doses to be used in this study. 
Patients should receive prophylactic treatment with cotrimoxazole, acyclovir and fluconazole if 
required according to local SOPs following fludarabine and cyclophosphamide, for the prevention 
of infections in neutropenic patients. 
Patients may receive supportive care with growth factors and irradiated blood products as required 
to treat neutropenia and anaemia. The routine use of prophylactic G-CSF is not recommended as it 
may induce myeloid derived suppressor cells which could impair the immune response to ATL001.  
Patients requiring blood product support at any time in the future after receiving fludarabine should 
receive irradiated blood products. 
Patients should not receive any live vaccinations for at least 3 months following lymphodepletion, 
per fludarabine Summary of Product Characteristics (SmPC). 
Please consult the latest available version of the SmPC, package leaflet and/or other healthcare 
intended materials before taking any action relating to fludarabine and cyclophosphamide. 
7.5. 
Management of Adverse Events Related to IL-2 
IL-2 is known to cause hypotension, diarrhoea, chills, nausea, vomiting, and rash. A very rare side 
effect is ‘capillary leak syndrome’ which can cause limb oedema, hypotension, arrhythmias, 
dyspnoea and hypoalbuminaemia. The daily doses of IL-2 in Cohorts A and B are 18 times lower 
than the doses used to treat melanoma and renal cancer, so it is considered unlikely that capillary 
leak syndrome will occur. In Cohort C, IL-2 dosing will be 600,000 IU/kg and administered by 
intravenous infusion at a frequency of 8-12 hourly for up to a maximum of six doses as tolerated. 
Toxicities are more likely at higher doses over shorter periods of time. In Cohort C, if toxicities can 
be reversed within 24 hours by supportive measures, then additional doses may continue. If greater 
than two doses of IL-2 are skipped, IL-2 administration will be ceased. In addition, dosing may be 
held or stopped at the discretion of the treating Investigator.  
Vital signs, pulse oximetry, weight and adverse events will be monitored daily while patients are 
receiving IL-2 so that adverse reactions can be detected early and dose modifications may be made 
accordingly. IL-2 dosing will be interrupted if patient experiences Grade 3 or 4 toxicity related to 
IL-2 (with the exception of reversible Grade 3 toxicities attributable to IL-2, such as diarrhoea, 
nausea, vomiting, hypotension, rash/skin changes, anorexia, mucositis, dysphagia, or constitutional 
symptoms and laboratory changes. See Appendix F.). Management of IL-2 toxicity is detailed in 
Appendix F. 
Please consult the latest available version of the SmPC, package leaflet and/or other healthcare 
intended materials before taking any action relating to IL-2. 


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7.6. 
Management of Adverse Events Related to Nivolumab (Cohort B Patients 
Only)  
For those receiving nivolumab in Cohort B, there is the risk of autoimmune related toxicities as a 
result of CPI treatment, e.g. endocrinopathies, pneumonitis, colitis, nephritis, hepatitis and skin 
reactions.  
For guidance based on common immune-related toxicities associated with CPI use, refer to Table 
3. 
 
 


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Table 3: Recommendations for Immune-related Toxicities with Immune Checkpoint Inhibitors 
(Adapted from Haanen et al, 2017) 
Immune-related 
adverse reaction 
Treatment modification 
Immune-related 
skin toxicity 
For grade 1–2 skin AEs, continue (at least 1 week) with ICPis. Start topical 
emollients, antihistamines in the case of pruritus and/or topical (mild strength) 
corticosteroid creams. Reinitiate ICPi when <grade 1. 
 
For grade 3 skin AEs, interrupt ICPi and start immediate treatment with topical 
emollients, antihistamines and high strength corticosteroid creams.  
 
For grade 4 skin AEs, discontinue ICPi (permanently), consider admitting patient 
and always consult dermatologist immediately. Start i.v. corticosteroids [1–2mg/kg 
(methyl)prednisone] and taper based on response of AE. 
Immune-related 
endocrinopathies 
In symptomatic hyperthyroism patients, usually grade 1 or 2, interrupt ICPi, start 
beta-blocker therapy (propranolol or atenolol/metoprolol). Restart ICPi when 
asymptomatic. 
 
In the case of hypothyroidism, rarely>grade 2, start thyroxine depending on the 
severity (0.5-1.5 μg/kg/day). Increase the dose until TSH is normal. In the case of 
inﬂammation of the thyroid gland, start prednisone orally 1mg/kg. Taper based on 
recovery of clinical symptoms. Consider interruption of ICPi treatment when 
symptomatic.  
 
In the case of hypophysitis (rarely>grade 2), when headache, diplopia or other 
neurological symptoms are present, start (methyl)prednisone 1mg/kg orally and 
taper over 2–4 weeks. Start HRT depending on the affected hormonal axis 
(levothyroxine, hydrocortisol, testosterone).  
 
In patients with type I DM grade 3 to 4 [ketoacidotic (sub)coma], admit to hospital 
immediately and start treatment of newly onset type I DM. Role of corticosteroids 
in preventing complete loss of insulin producing cells is unknown and not 
recommended. 
Immune-related 
hepatotoxicity 
For grade 2 hepatitis, withhold ICPi and monitor AST/ALT levels closely (1–2 
times/week). When no improvement over 1 week, start (methyl)prednisone (0.5–
1mg/kg). Taper over several weeks under close monitoring of AST/ALT and 
bilirubin. 
 
For grade 3 hepatitis, discontinue ICPi and immediately start with 
(methyl)prednisone 1–2mg/kg. When no improvement in 2–3 days, add MMF 
(1000mg b.d.). Taper immunosuppression over 4–6 weeks under close monitoring 
of AST/ALT and bilirubin. 
 
For grade 4 hepatitis, permanently discontinue ICPi, admit patient to the hospital 
and initiate (methyl)prednisone 2mg/kg i.v. Add MMF if no improvement is 
observed within 2–3 days. Consult hepatologist if no improvement under double 
immunosuppression. Other immunosuppressive drugs to consider are ATG and 
tacrolimus. Consult or refer patient to an experienced centre. Taper over 6 weeks 
under close monitoring of liver tests. 
Gastrointestinal 
toxicity 
In patients with non-severe diarrhoea (grade 1), ICPi can be continued. Treatment 
with antidiarrhoeal medication (e.g. loperamide) should be prescribed.  
 
In grade 2 diarrhoea, ICPi should be interrupted and the patient should start with 
corticosteroids depending on the severity and other symptoms (either budesonide 
or oral corticosteroids 1mg/kg). In the case of no improvement within 3–5 days, 
colonoscopy should be carried out and, in the case of colitis, inﬂiximab 5mg/kg 
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In patients with severe diarrhoea (grade 3 to 4), permanently discontinue ICPi. 
Admit patient to the hospital and initiate (methyl)prednisone 2mg/kg i.v. Add 
MMF if improvement is observed within 2–3 days. Consult a 
hepatologist/gastroenterologist if no improvement under double 
immunosuppression. Other immunosuppressive drugs to consider are ATG and 
tacrolimus. Consult or refer patient to an experienced centre. Taper over 6weeks 
under close monitoring of liver tests 
Immune-related 
pneumonitis 
In grade 1 and 2 pneumonitis, interrupt ICPi therapy, try to rule out infection and 
start with prednisone 1–2mg/kg orally. Taper over 4–6 weeks.  
 
In grade 3 and 4 pneumonitis, discontinue ICPi permanently, admit the patient to 
the hospital, even ICU if necessary and immediately start high-dose 
(methyl)prednisone 2–4mg/kg i.v. Add inﬂiximab, MMF or cyclophosphamide in 
the case of deterioration under steroids. Taper over a period of 4–6 weeks. 
Neurological 
toxicity 
In the case of mild neurological AEs, withhold ICPi and perform work-up (MRI 
scan, lumbar puncture) to deﬁne nature of neurotoxicity. In the case of 
deterioration or severe neurological symptoms, admit the patient and start 
(methyl)prednisone 1–2mg/kg orally or i.v. In the case of Guillain-Barre´ or 
myasthenia-like symptoms, consider adding plasmapheresis or i.v. Ig. 
Cardiac toxicity 
When a myocarditis is suspected, admit the patient and immediately start high-
dose (methyl)prednisone (1–2mg/kg). In the case of deterioration, consider adding 
another immunosuppressive drug (MMF or tacrolimus). 
Rheumatological 
toxicity 
For mild arthralgia, start NSAIDs, and in the case of no improvement, consider 
low dose steroids (10–20mg prednisone). In the case of severe polyarthritis, refer 
patient to or consult a rheumatologist and start prednisone 1mg/kg. Sometimes 
inﬂiximab or another anti-TNFa drug is required for improvement of arthritis. 
Renal toxicity 
In case of nephritis, rule out other causes of renal failure ﬁrst. Interrupt or 
permanently discontinue ICPi depending on the severity of the renal insufﬁciency. 
Stop other nephrotoxic drugs. Start (methyl)prednisone 1–2mg/kg. Consider renal 
biopsy to conﬁrm diagnosis. 
AE, adverse event; ALT, alanine transaminase; AST, aspartate transaminase; ATG, anti-thymocyte globulin; DM, 
diabetes mellitus; HRT, hormone replacement therapy; ICPi, immune checkpoint inhibitor; ICU, intensive care unit; Ig, 
immunoglobulin; i.v. intravenous; MMF, mycophenolate mofetil; MRI, magnetic resonance imaging; NSAID, 
nonsteroidal anti-inflammatory drug; TNFa, tumour necrosis factor alpha; TSH, thyroid-stimulating hormone. 
Based on the severity of the adverse reaction, nivolumab should be withheld and corticosteroids 
administered. If immunosuppression with corticosteroids is used to treat an adverse reaction, a taper 
of at least 1 month duration should be initiated upon improvement. Rapid tapering may lead to 
worsening or recurrence of the adverse reaction. Non-corticosteroid immunosuppressive therapy 
should be added if there is worsening or no improvement despite corticosteroid use.  
Patients should not receive any live vaccinations for at least 5 months following last nivolumab 
dose, per the nivolumab SmPC. 
Nivolumab should not be resumed while the patient is receiving immunosuppressive doses of 
corticosteroids (i.e. greater than 10 mg prednisolone equivalent) or other immunosuppressive 
therapy. Prophylactic antibiotics should be used to prevent opportunistic infections (i.e. 
pneumocystis carinii pneumonia) in patients receiving immunosuppressive therapy. 
Nivolumab must be permanently discontinued for any severe immune-related adverse reaction that 
recurs and for any life-threatening immune-related adverse reaction. 
Patients should be monitored continuously (at least up to 5 months after the last dose) as an adverse 
reaction with nivolumab may occur at any time during or after discontinuation of therapy.  
Please consult the latest available version of the SmPC, package leaflet and/or other healthcare 
intended materials before taking any action relating to this agent. Please also refer to local, regional 


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and national guidelines for management of nivolumab toxicity and to the SmPC/Package Insert for 
nivolumab for reference safety information.  
7.7. 
Management of Adverse Events Related to ATL001 Infusion 
 
Infusion Reactions  
There may be a risk of an infusion reaction (e.g. fever, chills, headache). This risk may be reduced 
by the administration of a standard prophylactic regimen (e.g. chlorphenamine and 
paracetamol/acetaminophen) according to local SOPs before the infusion is given. However, 
prophylactic corticosteroids must be avoided. 
If a patient develops an infusion reaction during the infusion, the following procedures should be 
followed: 
- 
Mild to moderate reactions (e.g. low-grade fever (< 38.5°C); hypotension (< 30 
mmHg decrease from baseline)) 
o Slow down the infusion rate. 
o Consider giving PRN antipyretic/antihistamine medication. 
o Avoid corticosteroids where possible. 
- 
Moderate to severe reactions (e.g. fever > 38.5°C; chills; mucosal swelling; 
shortness of breath; hypotension (> 30 mmHg from baseline)) 
o Stop the infusion and treat the symptoms with antihistamine/antipyretic 
medication and supportive care. 
o Consider need for i.v. hydrocortisone. 
o If cytokine release syndrome is suspected, tocilizumab or siltuximab 
therapy may be beneficial. See Section 7.7.4.  
In the event of an infusion reaction which does not require corticosteroid treatment, the infusion 
may be restarted once the symptoms have resolved and completed, provided this is not more than 
30 minutes from thawing and the symptoms/signs do not recur. The Sponsor (or representative) 
should be contacted to inform them of any patient that does not receive the full infusion and the 
remaining infusate should be retained at 2-8°C pending instructions from the Sponsor. 
In the event of an infusion reaction severe enough to require i.v. corticosteroid, the infusion should 
be permanently discontinued, and the Sponsor should be informed. 
 
DMSO Toxicities 
These are very rare but may include: raised or lowered blood pressure, seizure or respiratory arrest. 
The most common reaction is hypertension, in which case giving anti-hypertensive medication and 
diuretics is recommended. 
 
Autoimmune Related Toxicity 
It is considered unlikely that ATL001 infusion will trigger autoimmune related toxicity as there is 
no genetic modification of the T-cell receptor, the product is derived from TILs that have undergone 
selection for self-tolerance, and clonal neoantigens are tumour-specific rather than tumour-
associated antigens so cross reaction with naturally occurring proteins should not occur. However, 
as this is a first-in-human study, patients will undergo monitoring for development of autoimmune 


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conditions. Patients in Cohort B may be at greater risk of developing autoimmune related toxicity 
than patients in Cohort A and Cohort C, as a result of more prolonged exposure to the immune 
checkpoint inhibitor nivolumab, which is associated with this adverse effect.  
In addition to sequential measurements of thyroid function for two years, neurological toxicity and 
autoimmune conditions are defined as Adverse Events of Special Interest for ATL001, to ensure 
they will be monitored, and their relatedness to ATL001 will be considered, throughout the study 
and the long term follow up period. 
 
Cytokine Release Syndrome 
Cytokine release syndrome (CRS) and associated toxicities is considered a potential risk because 
of in vivo T cell proliferation and activation. Cytokine release syndrome may develop within 
minutes or hours following a CAR-T cell infusion but can have a later onset during the first 2 weeks. 
Patients should be monitored for clinical symptoms/signs of cytokine release syndrome during the 
first 10 days after the infusion (and for longer if any evidence of CRS on day 10).  
Appendix D provides an example CRS Monitoring Chart which can be used by investigational sites 
for these assessments. 
Patients should be treated according to the severity grade as initially recommended by Lee et al, 
2014 and updated in the American Society for Transplantation and Cellular Therapies (ASTCT) 
Consensus Grading, which recognised fever, hypotension and hypoxia as the principal 
determinants of CRS severity [Lee et al, 2019]. Patients who develop fever or other symptoms/signs 
of CRS during this period must remain in hospital until symptoms have resolved. For the purposes 
of recording events of CRS, the ASTCT Consensus Grading System (see Table 4) should be used 
rather than the common terminology criteria for adverse events (CTCAE) system. 
Table 4: ASTCT Consensus Grading of CRS (Taken from Lee et al, 2019) 
 
Multiple treatment algorithms for CRS have been developed since the approvals of CAR-T cell 
therapies [reviewed by Riegler et al, 2019], with a common goal of preventing irreversible organ 
damage without compromising clinical activity. All recommend the early use of the IL-6 receptor 
inhibitor, tocilizumab in patients with Grade 2 CRS that is not responding to conservative 
management and in patients who are developing severe CRS (Grade 3 or 4). High dose 
corticosteroids are recommended in severe and life-threatening conditions. The best practice 
recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the 
Joint Accreditation Committee of ISCT and EBMT (JACIE) for the management of CRS aligned 
to the ASTCT Grading System 2019 [Yakoub-Agha, 2020] are presented here as a suggested 
management plan, although it is expected that sites will also follow their local SOPs. 


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Table 5: Suggested CRS Treatment Algorithm (Adapted from Lee et al, 2019 and Yakoub-Agha, 
2020) 
CRS Grade 
Treatment 
Grade 1 
Fever ≥ 38°C without hypotension or hypoxia 
 
Corticosteroids should be avoided 
Investigate potential sources of infection, then 
commence supportive care according to 
institutional standards including analgesics, 
antipyretics, and broad-spectrum antibiotics. 
If no improvement after 3 days, consider 
tocilizumab 8mg/kg/i.v. 
Grade 2 
Fever ≥ 38°C  
Hypotension not requiring vasopressors 
Hypoxia requiring low flow nasal cannula or 
blow-by 
 
Corticosteroids should be avoided unless 
condition deteriorates 
Alert the ICU and Sponsor Medical Monitor. 
Investigate potential sources of infection, then 
commence supportive care (as above) including 
fluid substitution for hypotension and low-flow 
oxygen. 
Use tocilizumab* 8mg/kg/i.v. early if symptoms do 
not improve soon or worsen and repeat if required*. 
If condition deteriorates consider adding i.v. 
dexamethasone 10mg q.d.s. for 1 to 3 days. 
[Corticosteroids should be tapered as soon as 
possible, as clinical condition permits]. 
Grade 3 
Fever ≥ 38°C   
WITH 
Hypotension requiring a vasopressor with or 
without vasopressin 
AND/OR 
Hypoxia requiring high flow nasal cannula, face 
mask, nonrebreather mask, venturi mask  
 
 
Intensive care. 
Single vasopressor with or without vasopressin. 
High flow oxygen.  
Tocilizumab 8mg/kg/i.v. (repeated as necessary*) 
and dexamethasone 10mg i.v. q.d.s. for 1 to 3 days. 
[Corticosteroids should be tapered as soon as 
possible, as clinical condition permits]. 
If condition deteriorates consider increasing i.v. 
dexamethasone to 20mg q.d.s. for 1 to 3 days. 
Grade 4 Fever ≥ 38°C 
WITH 
Hypotension requiring multiple vasopressors 
(excluding vasopressin) 
AND/OR 
Intensive care. 
Positive Pressure Oxygen e.g. CPAP, BiPAP, 
intubation and mechanical ventilation. 
Tocilizumab 8mg/kg/i.v. (repeated as necessary*) 
and dexamethasone 20mg i.v. q.d.s. for 3 days, 
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CRS Grade 
Treatment 
Hypoxia requiring positive pressure  
If condition deteriorates consider changing 
dexamethasone to methylprednisolone 1000mg/day 
for 3 days, then 250mg b.d. for 2 days, then 125mg 
b.d. for 2 days and then 60mg b.d. for 2 days. 
*The initial dose of tocilizumab given should be 8 mg/kg administered over 60 minutes as an i.v. infusion. If no clinical 
improvement in the signs and symptoms of CRS occurs after the first dose, up to 3 additional doses may be administered. 
The interval between consecutive doses should be at least 8 hours. Doses exceeding 800 mg per infusion are not 
recommended in CRS patients. Siltuximab 11mg/kg for 1 day may be considered as a second line option if unresponsive 
to tocilizumab. 
Adapted from: Lee et al, 2019 and Yakoub-Agha, 2020. 
*https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125276s114lbl.pdf 
 
Immune Effector Cell-Associated Neurotoxicity Syndrome 
Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS) is defined by ASTCT as ‘a 
disorder characterized by a pathologic process involving the central nervous system (CNS) 
following any immune therapy that results in the activation or engagement of endogenous or infused 
T cells and/or other immune effector cells. Symptoms or signs can be progressive and may include 
aphasia, altered level of consciousness, impairment of cognitive skills, motor weakness, seizures, 
and cerebral edema.’ It may occur at the same time as CRS or after CRS has resolved and symptoms 
generally resolve over a period of 2 to 9 days with management.  
The earliest manifestations of ICANS are tremor, dysgraphia, mild difficulty with expressive 
speech (especially in naming objects), impaired attention, apraxia and mild lethargy, so it is 
important that patients are closely monitored for these symptoms during the early period of 
hospitalisation. The Immune effector Cell-associated Encephalopathy (ICE) score is recommended 
for these assessments (see Table 6). ICANS assessments should be documented at baseline (pre-
infusion) and should be assessed at least once daily from the day of cell infusion, and at each visit 
until week 12 as part of the general assessment of the patient’s neurological condition. If any 
abnormalities are detectable at week 12, the assessments should be repeated at week 24. From the 
first sign of any neurological or behavioural disturbance, these assessments should be performed at 
least twice daily. These assessments, along with the level of consciousness and signs of seizure, 
motor weakness or raised intracranial pressure give the overall ICANS Grade (see Table 7).  
Appendix E provides an example Neurotoxicity Monitoring Chart which can be used by 
investigational sites for these assessments. 
Table 6: ICE Score (Adapted from Lee et al, 2019) 
Domain 
Score 
Orientation: To year, month, city, hospital 
4 
Naming: Ability to name 3 objects  
3 
Following commands: Ability to follow simple 
1 
Writing: Ability to write a standard sentence  
1 
Attention: Ability to count back from 100 by 10 
1 
 
 
 


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Table 7: ASTCT Consensus Grading of ICANS (Taken from Lee et al, 2019) 
 
Patients should be managed according to the overall severity grade of ICANS, as defined in the 
ASTCT Consensus Grading System [Lee et al, 2019] (see Table 7). For the purposes of recording 
events of ICANS, the ASTCT Grading System should be used rather than the CTCAE system. 
The best practice recommendations of the EBMT and JACIE for the management of ICANS aligned 
to the ASTCT Grading System [Yakoub-Agha, 2020] are presented here as a suggested 
management plan, although it is expected that sites will also follow their local SOPs. 
As a further precaution, prophylactic treatment with the non-sedating anti-seizure medication 
levetiracetam (Keppra) at a dose of 500 mg b.d. should be commenced at the earliest sign of 
neurological or behavioural abnormality, even if the ICANS Grade at the time is normal. This 
recommendation will be reviewed by the IDSMC at scheduled safety reviews. 
Table 8: Suggested ICANS Treatment Algorithm (Adapted from Lee et al, 2019 and Yakoub-Agha, 
2020) 
ICANS Grade 
Treatment 
Commence Levetiracetam seizure prophylaxis 500 mg b.d. at the earliest sign of neurological or 
behavioural disturbance even if ICANS assessment is normal 
Grade 1 
ICE Score 7-9, decreased level of consciousness 
but spontaneously awakes 
 
Alert neurologist and ICU 
Alert Sponsor Medical Monitor. 
Close monitoring and supportive care. ICANS 
Grade assessment at least twice daily. Avoid 
medications that cause CNS depression. 
Daily EEG and Fundoscopy. MRI scan or CT if not 
available. Lumbar Puncture (LP) as clinically 
indicated. 
Commence Levetiracetam seizure prophylaxis 500 
mg b.d. if not already started. 


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ICANS Grade 
Treatment 
Consider low doses of haloperidol (0.5mg i.v. every 
6 hrs) or lorazepam (0.25-0.5mg i.v. every 8 hrs) to 
manage agitation. 
Grade 2 
ICE Score 3-6, decreased level of consciousness 
but awakes to voice 
 
Alert neurologist and move to ICU Close 
monitoring including EEG, Fundoscopy, MRI and 
then LP if no suggestion of raised intracranial 
pressure (ICP). 
Commence Levetiracetam seizure prophylaxis 500 
mg b.d. if not already started. 
Commence i.v. dexamethasone 10mg q.d.s. for 1 to 
3 days.  
 [Corticosteroids should be tapered as soon as 
possible when symptoms resolve to Grade 1, as 
clinical condition permits]. 
Tocilizumab not indicated unless concurrent CRS. 
Grade 3 
ICE Score 0-2, very decreased level of 
consciousness and only awakes to tactile stimulus 
Any seizures 
Evidence of focal or local cerebral oedema 
 
Intensive care.  
Manage seizures with benzodiazepine and 
levetiracetam (Keppra).  
Commence dexamethasone 10mg i.v. q.d.s. or 
20mg i.v. b.d. for 1 to 3 days. 
[Corticosteroids should be tapered as soon as 
possible when symptoms resolve to Grade 1, as 
clinical condition permits]. 
Tocilizumab not indicated unless concurrent CRS. 
If Grade 3 ICANS persists, consider repeating 
neuroimaging every 2 to 3 days. 
Grade 4  
ICE Score impossible 
Unrousable or only awakens to vigorous 
repetitive stimulation 
Life threatening prolonged or repetitive seizures 
Deep focal motor weakness 
Generalised cerebral oedema 
Papilloedema, Cushing’s triad or Cranial nerve VI 
palsy 
Decorticate or Decerebrate posturing 
Intensive care.  
Methylprednisolone 1000mg/day for 3 days, then 
250mg b.d. for 2 days, then 125mg b.d. for 2 days 
and then 60mg b.d. for 2 days. 
Consider alternatives e.g high dose 
cyclophosphamide, Siltuximab, Anakinra (IL-1R 
antagonist).  


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7.8. 
Study Safety Stopping Criteria and Procedures 
An Independent Data Safety Monitoring Committee will be formed to monitor patient safety during 
the study (see Section 9.5 for description and meeting schedule).  
An initial formal review of safety by the IDSMC will take place after the first 6 evaluable patients 
have received ATL001 treatment in all studies of ATL001 running concurrently and all these 
patients have been followed up for a minimum of 28 days. For the purpose of the IDSMC review, 
an evaluable patient is a patient who has received lymphodepletion and ATL001. All safety data 
from any patients treated in the study during this period will be considered in the review. 
A second IDSMC safety review will take place when 6 evaluable patients have received ATL001 
treatment within this study and followed up for a minimum of 28 days. This safety review will 
determine whether enrolment into Cohort B can commence at centres. These two reviews may be 
combined depending on recruitment timings.  IDSMC will be informed about other study related 
activities as deemed relevant to the ongoing oversight of patient safety including the initiation of 
additional cohorts or procedures. 
An IDSMC safety review of the first 6 patients treated in each treatment Cohort will also be 
scheduled. Reviews of safety will take place when the first 3 patients have been treated and followed 
up for a minimum of 28 days in each additional treatment Cohort, with similar reductions in 
observation period(s) if there are no unexpected toxicities associated with these Cohorts. 
At any of the 6-patient safety reviews, if 2 or more patients out of 6 exhibit any of the following 
toxicities, within 28 days after receiving ATL001, enrolment may be paused if these are considered 
to be a result of study interventions. The IDSMC will be asked to review eligibility criteria, doses 
of all study treatments and all available safety data, and to make recommendations as to the further 
conduct of the study: 
- 
Grade 3 or worse non-haematological toxicity that does not resolve to Grade 2 or less within 
7 days. 
- 
Grade 2 or worse neurological toxicity that does not resolve to Grade 1 or baseline within 7 
days.  
- 
Grade 3 or worse haematological toxicity (excluding lymphopenia) that does not resolve to 
Grade 1 or baseline within 14 days.  
The committee will also be convened in the event of any patient developing a serious infusion 
reaction or Grade ≥ 3 CRS. In addition, any death within 30 days of ATL001 infusion (other than 
as a result of the underlying disease for which the patient is being treated) and any Grade 4 ICANS 
event will trigger a study pause and IDSMC review. 
An additional IDSMC safety review may take place when 20 patients in this study have been treated 
and followed up for a minimum of 14 days post-infusion. This will be scheduled if 6 or more 
patients experience the above toxicities as a result of study treatments. 
The IDSMC will make recommendations for continuation, modification, suspension or 
discontinuation of the study conduct in accordance with their review of all data available to them, 
taking into consideration the clinical significance of the events and the likelihood of relatedness to 
ATL001 or other study medications. If the decision is to suspend enrolment it may be restarted, 
after appropriate preventative or management guidelines have been established, in a protocol 
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Patients may also be discontinued from study treatment and/or assessments at any time, at the 
discretion of the Investigator(s). Specific reasons for discontinuing a patient are summarised in 
Section 4. 
Patients who have discontinued treatment should wherever possible remain in the study and 
continue with follow up assessments for disease progression and survival. 
The study may be terminated at any time and for any reason at the discretion of the Sponsor relating 
to observed safety or clinical efficacy parameters. 
8 
MEASUREMENT OF STUDY VARIABLES 
8.1. 
Screening and On Study Measurements 
 
Performance Status 
Performance Status (PS) will be assessed according to the ECOG Performance Status Scale (See 
Appendix A). 
 
Physical Examination 
The physical examination should include medical assessments according to clinical relevance. 
Findings considered as clinically significant changes since the physical examination at Screening 
will be recorded as adverse events. 
 
Vital Signs  
Vital signs (BP [systolic and diastolic], pulse rate, respiratory rate, and body temperature [oral or 
otic]) will be recorded with the patient resting in the supine position for at least at 10 minutes. 
 
Pulse Oximetry 
Pulse oximetry to measure the oxygen level (oxygen saturation) of the blood. Continuous 
monitoring during ATL001 infusion with pre- and post-infusion measurements recorded. 
 
Electrocardiogram 
12-lead electrocardiogram (ECG) recordings will be made at the time points designated. The 
Investigator should review all ECG recordings and record as normal or abnormal. Clinically 
significant abnormalities should be recorded as adverse events. 
 
Echocardiogram 
At screening, an echocardiogram will be performed for patients over 60 or with history or symptoms 
suggestive of ischaemic heart disease or clinically significant dysrhythmias, unless results are 
available from within 60 days prior to the screening visit. For patients being considered for Cohort 
C, an echocardiogram will be performed at re-screening unless results from scans within 60 days 
prior to start of lymphodepletion are available. 
 
Colonoscopy  
Colonoscopy is only required for patients who have had a documented Grade 2 or greater 
diarrhoea or colitis due to previous immunotherapy within 6 months of screening. 
 
Body Weight 
Body weight will be determined at the scheduled timepoints.  


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Pregnancy Test (Female Patients) 
For female participants of childbearing potential, serum or urine pregnancy tests are required. In 
Cohort B, additional serum or urine pregnancy test prior to each nivolumab administration for 
female participants of childbearing potential is required. Refer to Appendix G for pregnancy testing 
requirements in Germany. 
 
Safety Laboratory Measurements 
See Table 9 for clinical laboratory safety assessments to be performed. 
Clinically significant derangements should be reported as adverse events per Section 8.2, and tests 
repeated as appropriate. 
Table 9: Clinical Laboratory Safety Assessments 
Laboratory 
Assessments 
Parameters 
Haematology 
Haemoglobin (Hb)  
White cell count and differential 
(neutrophils/lymphocytes/monocytes/eosinophils/basophils) 
Platelet count 
Chemistry  
Alanine transaminase (ALT/SGPT), OR 
Aspartate transaminase (AST/SGOT) 
Albumin 
Alkaline phosphatase (ALP) 
Bilirubin 
Lactate dehydrogenase (LDH) 
Total Protein 
Urea or Blood Urea Nitrogen (BUN) 
Calcium 
Creatinine 
Phosphate  
Potassium  
Sodium 
Estimated GFR (by Cockcroft-Gault equation*) 
Glucose (non-fasting) 
Thyroid Function 
Tests 
Thyroid Function Tests (baseline and selected timepoints in Cohort A and 
Cohort C, and every 12 weeks for patients in Cohort B; these are to include T4 
and TSH ± T3) – see Schedule of Assessments, withdrawal/completion and as 
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Coagulation 
International normalised ratio (INR) or Prothrombin time (PT) 
Activated partial thromboplastin ratio (APTR) or Activated partial 
thromboplastin time (APTT) 
D-Dimer  
Fibrinogen  
Other 
CRP (C-reactive protein) 
Pregnancy test (serum or urine) 
Infection screening (anti-HIV 1&2, HBs Ag, Anti-HBc, Anti-HCV-Ab, syphilis 
(treponema pallidum) IgG/IgM, and Anti-HTLV 1&2) 
*The Cockcroft-Gault equation may be used to estimate GFR: 
Creatinine clearance = (((140 – age in years) x (weight in kg)) x 1.23) / (serum creatinine in micromole/L). 
For women, multiply the result of the calculation by 0.85. 
 
Melanoma Risk Factors 
Melanoma risk factors, including but not limited to ultraviolet light exposure, history of moles, 
family history of melanoma, previous skin cancer, immune suppression and skin colour, will be 
assessed at a screening visit. 
 
Demographics 
Demographic data, including but not limited to age, gender, weight, height, race and ethnicity, will 
be collected at baseline. 
 
Archival Tumour Tissue (if available) 
Archival FFPE block or slides of primary tumour may be requested for analysis of the tumour 
microenvironment, if available anytime from screening to study withdrawal. 
8.2. 
Adverse Events 
 
Definitions per ICH E2A 
Table 10: Adverse Event Definitions 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. 
Adverse Drug Reaction 
(ADR) 
 
All noxious and unintended responses to a medicinal product related 
to any dose should be considered adverse drug reactions. The criteria 
‘responses to a medicinal product’ applies if there are facts (evidence) 
or arguments to suggest a causal relationship. 
Serious Adverse Event 
(SAE) 
A serious adverse event is any untoward medical occurrence that: 
• Results in death. 
• Is life-threatening. 


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Term 
Definition 
• Requires inpatient hospitalisation or prolongation of existing 
hospitalisation. 
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly or birth defect 
Other ‘important medical events’ may also be considered serious if 
they jeopardise the participant or require an intervention to prevent 
one of the above outcomes. 
NOTE: The term "life-threatening" in the definition of "serious" refers 
to an event in which the participant was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe. 
Serious Adverse 
Reaction (SAR) 
An adverse event that is both serious and, in the opinion of the 
reporting Investigator or Achilles Therapeutics (or representative), 
believed with reasonable probability to be due to one of the trial 
treatments, based on the information provided. 
Suspected Unexpected 
Serious Adverse 
Reaction (SUSAR) 
A serious adverse reaction, the nature and severity of which is not 
consistent with the information about the medicinal product in 
question set out in the reference safety information: 
• In the case of a product with a marketing authorisation, this could be in 
the Summary of Product Characteristics (SmPC)/Package Insert for that 
product, so long as it is being used within its license. If it is being used 
off label an assessment of the SmPC/Package Insert suitability will 
need to be undertaken. 
• In the case of any other investigational medicinal product, the 
Reference Safety Information (RSI) for assessment of expectedness of 
serious adverse reactions is located in the section of the Investigator’s 
Brochure relating to the product in question. 
 
Reporting and Recording of Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation patient administered 
a pharmaceutical product that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether related to the medicinal (investigational) product or not. For patients in the US, 
adverse events will be reported as specified in 21 CFR 312.32. 
The protocol requirements for reporting of AEs and SAEs are as follows: 
• 
Procedure-related AEs and all SAEs (including non-procedure-related) from the time of the 
procurement to 28 days following procurement, or the start of anti-cancer therapy if sooner, 
will be collected. 
• 
Cohort A and Cohort C: All AEs and SAEs from Pre-Lymphodepletion Re-screening Visit 
until Week 36 or until confirmed disease progression (whichever is sooner), and then only 
AESIs until Week 104 (or Week 364, until such time as the Long Term Follow Up study is 
available at study site). 


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• 
Cohort B: All AEs and SAEs from Pre-Lymphodepletion Re-screening Visit until 5 months 
after the last dose of nivolumab (but with a minimum reporting period of up to Week 36) 
or until confirmed disease progression (whichever is sooner), and then only AESIs until 
Week 104 (or Week 364, until such time as the Long Term Follow Up study is available at 
study site). 
Signs or symptoms of the condition/disease for which the investigational product is being studied 
should be recorded as AEs only if their nature changes or their frequency or intensity increases in 
a clinically significant manner as compared to the clinical profile known to the Investigator from 
the patients’ history or from screening to IMP administration. 
The patient will be given an opportunity to report AEs spontaneously at each study visit. A general 
prompt will also be given to detect AEs, e.g. ‘Did you notice anything unusual about your health 
since your last visit?’  
When recording an AE, the Investigator should use the overall diagnosis or syndrome using 
standard medical terminology, rather than recording individual symptoms or signs. The eCRF and 
source documents should be consistent. Any discrepancies between the patient’s own words on 
his/her own records (e.g. diary card) and the corresponding medical terminology should be clarified 
in the source documentation. Details for completion of the AE eCRF (including judgment of 
relationship to study drug) are described in the eCRF Completion Guidelines. 
AEs should be followed until it resolved, has a stable sequela, the Investigator determines that it is 
no longer clinically significant, or the patient is lost to follow up. If an AE is still ongoing at the 
end of the study for any patient, follow up should be provided in the separate Long Term Follow 
Up study. If no follow up is provided, the Investigator must provide a justification. 
 
Reporting and Recording of Serious Adverse Events 
Once it is determined that a patient experienced an AE, the seriousness of the AE must be 
determined. An SAE is any untoward medical occurrence that at any dose: 
a. Results in Death. 
b. Is life-threatening. 
c. Results in significant or persistent disability/incapacity. 
d. Is a congenital anomaly/birth defect. 
e. Requires inpatient hospitalisation or prolongation of existing hospitalisation. 
Admission to hospital for reasons not associated with the occurrence of an AE (e.g. pre-planned 
surgery or elective surgery for a pre-existing condition that has not worsened or manifested in an 
unusual or uncharacteristic manner) do not qualify for reporting. Additionally, SAEs deemed to be 
caused exclusively by disease progression do not qualify for reporting. 
If a pre-existing condition has worsened or manifested in an unusual or uncharacteristic manner, 
this should be reflected in a change of AE grade if necessary and the possible seriousness of the 
event would need to be determined. 
All Investigators will be thoroughly instructed and trained on all relevant aspects of the 
Investigator’s reporting obligations for SAEs. This information, including all relevant contact 
details, is summarised in the instructions for SAE reporting included in the Investigator Site File. 
This information will be updated as needed. 


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If an SAE is reported, the Sponsor or its representative must be informed within 24 hours of 
knowledge of this information by the site. The Investigator must forward to the Sponsor (or its 
representative) a duly completed SAE Report Form, even if the data are incomplete, or if it is 
obvious that more data will be needed to draw any conclusions. It is important for the Investigator, 
when completing the SAE report form, to include the assessment as to the causal relationship 
between the SAE and the ATIMP administration. This insight from the Investigator is very 
important for the Sponsor to consider in assessing the safety of the ATIMP and in determining 
whether the SAE requires reporting to the regulatory authorities in an expedited manner. 
Additional information (e.g. autopsy or laboratory reports) received by the Investigator must be 
provided within 24 hours of the Investigator’s awareness. For this, an AE page in the CRF as well 
as the SAE form must be completed for each SAE. Information not available at the time of the 
initial report must be documented on a follow-up SAE form. The Investigator is specifically 
requested to collect and report to the Sponsor (or its representative) any SAEs (even if the 
Investigator is certain that they are in no way associated with the ATIMP), up to 90 days from the 
end of the study for each patient, and to also inform participating patients of the need to inform the 
Investigator of any SAE within this period. Serious AEs that the Investigator thinks may be 
associated with the ATIMP must be reported to the Sponsor (or its representative) regardless of the 
time between the event and the end of the study. 
An SAE should be followed until it has resolved, has stable sequelae, the Investigator determines 
that it is no longer clinically significant, or until the end of the study. Information on SAEs obtained 
after clinical database lock will be captured. In addition, an Investigator may be requested by the 
Sponsor (or its representative) to obtain specific information in an expedited manner. 
The grading scale used to assess the severity of AEs will be the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. CRS and ICANS will 
be assessed using American Society for Transplantation and Cellular Therapy (ASTCT) criteria 
(see Section 7.7.4 and Section 7.7.5). For patients in Cohort B, AEs related to nivolumab will be 
assessed against NCI CTCAE Version 4.0, as per the SmPC/Package Insert, and treatment modified 
accordingly (see Section 7.6). 
 
Adverse Events of Special Interest 
An AE of special interest is any AE that the Sponsor, or a regulatory authority, has mandated be 
reported on an expedited basis, regardless of the seriousness, expectedness, or relatedness of the 
AE to the administration of study medication. The following events are considered AEs of special 
interest and must be informed to the Sponsor (or its representative) using the same process as for 
SAEs: 
a. Grade 3 and higher cytokine release syndrome (CRS). 
b. Second documented malignancies. 
c. Grade 2 and higher neurological adverse events. 
d. Autoimmune conditions. 
An AE of special interest should be followed until it has resolved, has stable sequelae, the 
Investigator determines that it is no longer clinically significant, or until the end of the study. In 
addition, an Investigator may be requested by the Sponsor (or its representative) to obtain specific 
information in an expedited manner. 


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Pregnancy Reporting 
Should a patient become pregnant after ATL001 administration, the Sponsor (or its representative) 
should be informed immediately.  
The Investigator must inform the patient of information currently known about potential risks and 
about available treatment alternatives. 
The pregnancy will be documented on the Pregnancy Initial Report Form provided to the 
Investigator. The progression of the pregnancy and the eventual birth (if applicable) must be 
followed up using the Pregnancy Follow-up Report Form in which the Investigator must report on 
the health of the mother and of the child. The health of the child must be followed for 1 year after 
birth for any significant medical issues and until stabilisation of any post-natal conditions. In certain 
circumstances, the Sponsor (or its representative) may request that follow up is continued for a 
longer period. 
In cases where the partner of a male patient enrolled in a clinical study becomes pregnant, the 
Sponsor (or its representative) will ask the Investigator or designee to contact the patient and his 
partner to request consent via a Pregnant Partner Consent Form. If the partner consents to provide 
additional information, this will be collected on the Pregnancy Initial Report Form and Pregnancy 
Follow-up Report Form. 
A pregnancy becomes an SAE in the following circumstances: miscarriage, abortion, or 
anomaly/birth defect of the child. Those SAEs must be additionally reported using the SAE/AESI 
Report Form in accordance with Section 8.2.3. 
 
Expedited Safety Reporting 
The Sponsor (or its representative) will notify Investigators of all reportable SAEs. This notification 
will be in the form of an expedited safety report. Upon receiving such notices, the Investigator must 
review and retain the notice with other study-related documentation. 
The Sponsor (or its representative) will ensure that SAEs are reported to the Ethics Committees and 
regulatory authority(ies) according to local requirements.  
Suspected Unexpected Serious Adverse Reactions and other significant safety issues reported from 
ATX-ME-001 shall be reported to the relevant competent health authorities in all concerned 
countries according to local regulations (either as expedited safety reports and/or in aggregate 
reports), by the Sponsor (or its representative). 
8.3. 
Clinical Efficacy Measurements 
Anti-tumour activity will be assessed at scheduled timepoints by CT scans of chest, abdomen and 
pelvis, and other locations if indicated. If CT scanning is not acceptable, MRI may be an alternative. 
The same modality should be used per patient throughout the study to assess lesion response. MRI 
scans may be used for scheduled brain imaging in patients with stable brain metastases at baseline, 
and if clinically indicated. If necessary, CT measurements may be supplemented by caliper 
measurement of measurable skin lesions. Skin lesions are only considered measurable when they 
are ≥ 10 mm in diameter as assessed using calipers. Caliper measurements, if used, must be 
documented by colour photography, including a ruler to confirm the size of the lesion.  
Efficacy assessments will be recorded by the Investigator and confirmed by an Independent Central 
Reviewer. 


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Efficacy will be evaluated by MRI/CT scans every 6 weeks to week 24 and then every 12 weeks 
according to RECIST v1.1 and Immune modified RECIST (imRECIST) criteria as described in 
Section 9. 
See Appendix B for a summary of the differences between RECIST v1.1 and imRECIST 
assessment criteria. 
8.4. 
Immunomonitoring Measurements 
Immunomonitoring samples for cellular assays (30 mL samples in heparin tubes for peripheral 
blood mononuclear cells (PBMC) and basic T cell, B cell and NK cell phenotyping (TBNK)) will 
be taken at baseline (pre-lymphodepletion) and on days 3, 7, 10, 14, 21 and 28, weeks 6, 12, 18, 24 
and every 12 weeks thereafter until the visit of confirmed disease progression. Samples should be, 
handled and transported as specified in the site laboratory manual. 
Persistence, phenotype and functionality of T cells will be assessed by multiple assays including 
but not limited to multi-parametric flow cytometry, cytokine assessment, T cell receptor repertoire 
diversity, ELISpot and intracellular cytokine staining. 
Additional immunomonitoring samples are: up to 3 mL samples for plasma cytokines, which will 
be taken at baseline (pre-lymphodepletion) and on days -1, 1, 2, 3, 5, 7, 10, 14, 21 and 28, then 
weeks 6, 12, 18, 24 and every 12 weeks thereafter until the visit of confirmed disease progression, 
and 3 mL samples for TCR-RNA sequencing which will be taken baseline (pre-lymphodepletion) 
and on days 7, 10, 14, 21 and 28, then weeks 6, 12, 18, 24 and every 12 weeks thereafter until the 
visit of confirmed disease progression. 
At the week 6 visit, an extra 150 mL blood sample is required for extended immunological assays, 
as long as the patient’s clinical condition does not preclude it. This will facilitate the evaluation of 
T cell reactivities using professional antigen presenting cells. The extra blood is needed to generate 
enough antigen presenting cells to determine if cNeT therapy promotes spreading of T cell 
responses to neoantigenic epitopes different from those in the original product (epitope spreading) 
and will facilitate single cell analysis of cNeTs circulating in the blood of patients post therapeutic 
intervention. 
8.5. 
Exploratory Measurements 
 
Circulating Tumour DNA (ctDNA) 
Plasma samples (derived from 10 mL of blood) for ctDNA assessment will be monitored at time of 
tumour procurement, pre-lymphodepletion, pre-infusion and on Days 7, 14, 21, 28, weeks 6, 12, 
18, 24 and every 12 weeks thereafter until disease progression. These samples are all 10 mL samples 
except on the procurement visit and the week 12 visit when they will be 30 mL samples. The extra 
20 mL volume at both timepoints is needed to profile how the patient tumour heterogeneity changes 
in response to ATL001 treatment. 
A bespoke ctDNA assay will be created based on the specific truncal (clonal) and branched 
(subclonal) mutations/predicted neoantigens detected in the patient’s tumour at baseline. These 
samples will be analysed retrospectively to assess the potential value of the assay as a biomarker of 
response. 


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Optional Tumour Biopsies 
If a patient has a tumour that can be safely accessed, optional pre- and post-treatment tumour 
biopsies will be requested to assess changes in the tumour microenvironment at one or more of the 
following times: 
• 
Between procurement and treatment with ATL001. 
• 
Following treatment with ATL001. 
• 
At the time of disease progression. 
 
Optional Samples to be Acquired from Standard of Care Procedures 
If a patient undergoes any standard of care procedures that involve the collection of biological 
material deemed relevant to ATL001 treatment, at any time during the period that they are enrolled 
in the study, a sample may be requested for research purposes if one can be provided at no additional 
risk to the patient.  
9 
STATISTICAL METHODS 
9.1. 
Sample Size Calculation 
Since this is a first-in-human study, there will be no formal hypothesis testing and as such, the study 
has not been formally powered. The sample size has been selected to provide adequate information 
about the safety and efficacy of ATL001, whilst also exposing minimal numbers of patients to 
experimental therapy and procedures prior to an initial signal of efficacy. 
In treatment Cohort A, a minimum of 20 patients will receive ATL001 following standard of care 
therapies with an active cell dose of 5-1000 x 107 CD3+ cells. It is expected that most patients will 
have received a PD-1/PD-L1 inhibitor as part of their standard therapy unless patients have 
contraindications to these agents. 
The expectation is that ATL001 could achieve a response in at least 30% of patients, based on a 
response rate of 35% in studies of first generation TIL in patients with metastatic melanoma that 
has recurred following treatment with PD-1 inhibitors.  
Based on a sample size of 20 evaluable patients treated with a product with an active cell dose range 
of 5-1000 x 107 CD3+ cells, if the true ORR were 30%, there would be approximately a 90% 
probability of observing 4 or more responders out of 20 patients. Conversely, if the true response 
rate were only 10% there would be only a 13% probability of observing 4 or more responses by 
chance.  
The collection of data within this protocol from up to 20 patients treated with “out of specification” 
products will allow flexibility to explore and understand possible dose-efficacy relationships and 
to inform the target dosing range for future studies.  
In treatment Cohort B, up to 20 patients will be offered ATL001 followed by continuation of 
nivolumab. The sample size of 20 patients has been selected in order to establish the safety, 
tolerability and clinical activity of ATL001 followed by nivolumab, in the context of the overall 
safety and efficacy profile of ATL001 from treatment Cohort A.  
In Cohort C, up to 20 patients will receive ATL001 followed by higher dose IL-2 (600,000 IU/kg) 
administered by intravenous infusion, after standard of care therapies. The sample size of 20 
patients has been selected to establish the safety, tolerability, and clinical activity of ATL001 


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followed by higher doses of IL-2, in the context of the overall safety and efficacy profile of ATL001 
from Cohort A. 
The Sponsor will also have the ability to stratify patient data across Cohort A, Cohort B and Cohort 
C according to disease status at dosing. 
The totality of the safety and tolerability data from the study will contribute to decisions regarding 
the continuation of the combination to the next stage of development. Unless otherwise stated, data 
from treatment Cohorts A, B and C (if B and/or C performed) will be presented separately. The 
data from any patients receiving an “out of specification” product will be presented separately to 
data from patients receiving the target cell dose. 
One or more interim analyses may be performed in this study (see Section 9.6). Following one of 
these analyses, and dependent on the emerging data, the protocol may be amended to increase the 
sample size or an expansion cohort. The sample size will be decided following interactions with 
regulatory authorities. 
9.2. 
Analysis Populations 
 
All Patients  
Population Disposition, screen failures and reasons for screen failures, will be reported for this 
population. 
 
Surgical Population 
The Surgical Population (SP) will include all patients in whom tumour procurement procedures 
were performed, regardless of whether the patient later went on to receive ATL001 treatment. The 
SP will be used only to evaluate the safety of the tumour procurement procedure. The safety of the 
tumour procurement procedure will be presented separately to the safety of the ATL001 treatment. 
 
Full Analysis Set (FAS) 
The Full Analysis Set (FAS) is based on the intention-to-treat principle and is defined as all patients 
who initiated lymphodepletion treatment, regardless of whether they subsequently received 
treatment with ATL001 or IL-2. 
The FAS data will used to understand the tolerability of lymphodepletion and evaluate the likely 
attrition rates prior to receiving ATL001. Note, the FAS will not be the primary analysis set used 
for the evaluation of safety and tolerability, since it is possible that not all patients in the FAS may 
have received the investigational product (ATL001). 
 
Treated Patient Population 
The Treated Patient population (TP) is a subset of the FAS and is defined as all patients who 
received treatment with ATL001, regardless of whether they completed the planned infusion and/or 
nivolumab and/or subsequent IL-2 injections. The TP population will be the primary analysis 
population used to evaluate the safety and tolerability of ATL001. The TP population will also be 
used to assess the secondary endpoint, Overall Survival. 
 
Evaluable for Response (EFR) Population 
The evaluable for response (EFR) population is defined as the subset of the TP population with the 
intended disease and indication, and measurable disease at baseline.  


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The EFR population will be the primary analysis population used to assess all RECIST and 
imRECIST-based efficacy endpoints (ORR, imORR, DOR, imDOR, TTR, imTTR, DCR, PFS and 
imPFS). Since measurable disease is an entry criterion for the study, the EFR should be identical to 
the TP, unless there are any patients who did not meet this entry criterion.  
 
Per Protocol Evaluable for Response (PPEFR) Population 
The PPEFR population is defined as the subset of the EFR without a major deviation. In addition 
to the absence of measurable disease, major deviations that would lead to the exclusion of a patient 
from the PPEFR population include: 
a. Patients who did not have the intended disease or indication.  
b. Patients with baseline radiological scan performed before the start of protocol 
specified interval prior to study enrolment.  
c. Patients who did not receive the intended doses of fludarabine, cyclophosphamide 
or IL-2. 
d. Patients whose ATL001 infusion is not completed within 30 minutes of thawing. 
e. Patients who did not have at least two post-baseline radiological assessments, for 
reasons other than death. 
f. Patients whose baseline radiological scan did not cover all protocol-specified 
anatomical areas (i.e. chest, abdomen, pelvis) and were determined to have lesions 
at the next scan in one of these areas. 
In addition to the above criteria, if there are any patients whose product contained an active dose of 
5-1000 x 107 CD3+ cells, but who received less than 5 x 107 CD3+ cells for any reason, their data, 
for the purpose of the PPEFR outputs, will be presented alongside data for the patients that received 
"out of specification" products. The cell dose received will be estimated based on the residual 
volume and total cell content of the bag. 
The PPEFR will be used to assess the sensitivity of efficacy analyses based on the EFR to major 
deviations. 
9.3. 
Study Endpoints 
 
Safety and Tolerability 
Safety and tolerability will be assessed based on adverse events, safety assessments (including vital 
signs, ECG, clinical laboratory tests) and physical examination. 
 
Efficacy Endpoints 
9.3.2.1 
Tumour Size 
The percentage change from baseline in tumour size (TS) is a secondary endpoint and will be 
evaluated at three time points: 
1. The percentage change from baseline at week 6 (%ΔTSWk6). 
2. The percentage change from baseline at week 12 (%ΔTSWk12). 
3. The best percentage change from baseline in TS (%ΔTSbest), at any time point. 
%ΔTSWk6 and %ΔTSWk12 will be defined as follows: 


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Baseline TS: defined as the sum of longest diameters of target lesions at baseline. 
- 
Week X TS: defined as the sum of longest diameters of target lesions at Week X 
(where X is either 6 or 12). 
%ΔTSWkX = 100 × (Week X TS – Baseline TS)/Baseline TS 
Patients who do not have Week X TS will be handled as follows: 
1. Patients who die by any cause other than an accident before Week X (+ 7 days) TS 
measurement without radiographic evidence of progression, an increase from 
baseline of 20% will be imputed.  
2. Patients with missing data at Week X (+ 7 days) due to prior radiological disease 
progression will be included in the analysis and will be assigned a percentage 
change from baseline of 20%, or the value that was observed at the time of disease 
progression (whichever is larger). 
Note: Allowing for the protocol-permitted visit window of 7 days, any data collected up to week X 
+ 7 days will be considered evaluable when calculating %ΔTSWkX. 
The best percentage change from baseline in TS (%ΔTSbest), at any time point will be defined as 
follows: 
• 
Baseline TS: defined as the sum of longest diameters of target lesions at baseline. 
• 
Best TS: defined as the smallest sum of longest diameters of target lesions at observed 
at any time point following the start of study treatment up to disease progression (regardless 
of whether it was a scheduled assessment). 
%ΔTSbest = 100 × (Best TS – Baseline TS)/Baseline TS 
Patients in the Evaluable for Response (EFR) set without any evaluable post-baseline target lesion 
data will be excluded from the waterfall plot of %ΔTSbest, except if the patient is known to have 
died (other than an accident), or if non-target lesion or new lesion data is available prior to Week 
12 (+7 days) which is indicative of disease progression. In such cases, the patient will have an 
increase from baseline of 20% imputed. 
9.3.2.2 
Objective Response Rate 
The RECIST ORR is defined as the number (%) of patients with confirmed Best Overall Response 
(BOR) of CR or PR. Data obtained up until progression, or last evaluable assessment in the absence 
of progression, will be included in the assessment of ORR. Any responses with an onset date after 
the start of a subsequent anti-cancer treatment will not be counted as responses in the ORR. Further 
details of the derivation of the BOR, and the criteria for response are provided in Appendix B and 
will be further expanded in the study Statistical Analysis Plan. 
The imRECIST ORR (imORR) is defined as the number (%) of patients with confirmed imRECIST 
Best Overall Response (imBOR) of CR or PR. The key difference between the ORR and imORR 
is that the imORR may include responses observed following an initial disease progression (PD), 
provided that minimum time-period has elapsed following the initial PD and the subsequent 
response (PR and CR). Furthermore, the imRECIST criteria does not necessarily consider the 
appearance of new lesions as evidence of progression, unless the dimension of the new lesion when 
added to the target lesions would result in an increase in tumour burden ≥ 20% relative to the nadir. 
Similarly, non-target lesion (NTL) evaluations do not contribute to the evaluation of the imORR, 
other than to preclude an imBOR of CR if the NTLs have not completely disappeared. A summary 


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of the differences between RECIST v1.1 and the imRECIST criteria is provided in Appendix B and 
details on the derivation of imBOR and imORR will be further expanded in the study Statistical 
Analysis Plan. 
9.3.2.3 
Time to Response 
Time to Response (TTR) is defined as the time (days) from the start of treatment with ATL001 to 
the onset of response (partial response (PR) or complete response (CR)) in the subset of patients 
who were categorised as confirmed responders for ORR. 
The imTTR, is defined as the time (days) from the start of treatment with ATL001 to the onset of 
response (PR or CR) in the subset of patients who were categorised as confirmed responders for 
imORR.  
9.3.2.4 
Duration of Response 
The duration of response (DoR) is defined as the time from the date of first documented response 
until the date of documented disease progression or death in the absence of disease progression, in 
the subset of patients classified as responders for ORR (based on RECIST v1.1). The end of 
response should coincide with the date of disease progression or death from any cause used for the 
PFS endpoint. DoR will be calculated programmatically. 
The time of the initial response will be defined as the latest of the dates contributing towards the 
first visit response of PR or CR. For example, if the patient was first noted to have a PR at week 6, 
and the target and non-target lesions were assessed on different dates at this visit, then the later of 
the two assessment dates would be used as the start date of the response. 
If a patient does not progress following a response, then their DoR will use the PFS censoring date. 
Duration of response will not be defined for those patients who do not have a documented response. 
The immune-modified duration of response (imDOR) will be calculated analogously, i.e. it is 
defined as the time from the date of first documented response until the date of documented disease 
progression or death in the absence of disease progression, in the subset of patients classified as 
responders for imORR (based on imRECIST). The end of response should coincide with the date 
of disease progression or death from any cause used for the imPFS endpoint. 
The time of the initial response will be defined as the latest of the dates contributing towards the 
first visit response of PR or CR. For example, if the patient was first noted to have a PR at week 6, 
and the target and non-target lesions were assessed on different dates at this visit, then the later of 
the two assessment dates would be used as the start date of the response. 
If a patient does not progress following a response, then their imDoR will use the imPFS censoring 
date. The imDOR will not be defined for those patients who do not have a documented imRECIST 
response. 
9.3.2.5 
Progression Free Survival 
Progression free survival (PFS) is a secondary endpoint in the study. 
The RECIST PFS is defined as the time from starting treatment until the date of objective disease 
progression or death (by any cause in the absence of disease progression) regardless of whether the 
patient completes the scheduled study treatment or receives another anti-tumour therapy prior to 
disease progression. Patients who have not experienced disease progression or died at the time of 
the data cut-off will be censored at the time of the latest date of assessment from their last evaluable 
RECIST assessment. However, if a patient progresses or dies following missed RECIST 


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assessments, with an interval of > 12 weeks + 14 days from the previous assessment (to 
accommodate the 7 day window surrounding the preceding and subsequent assessments), the 
patient will be censored at the time of the latest evaluable RECIST v1.1 assessment. 
The PFS time will always be derived based on the scan/assessment dates rather than visit dates and 
the following rules will be applied: 
- 
Date of disease progression will be determined based on the earliest of the dates 
of the component that triggered the disease progression, i.e. if both the target 
lesions and the non-target lesions indicate disease progression but were scanned on 
different days, the earlier of the 2 dates would be applied. 
- 
When censoring a patient for PFS the patient will be censored at the latest of the 
dates contributing to a particular overall visit assessment. 
Immune-modified RECIST PFS (imPFS) will be defined in accordance with the imRECIST criteria. 
The key differences between the imRECIST criteria and RECIST v1.1, with respect to the 
determination of progression, are below: 
1. Non-target lesions will not be taken into account when determining when a patient 
has had an imPFS event. 
2. New lesions will only be taken into account if the new lesion is measurable, and 
the longest diameter of the new lesion, when added to the sum of longest diameters 
of target lesions at the same visit results in an increase in tumour burden relative to 
the nadir ≥ 20%. 
3. An imRECIST PD will not be considered an imPFS event if a subsequent scan (≥ 
4 weeks later) shows an imSD/PR or CR. 
To aid interpretation of the study results, the proportions of patients alive and progression-free at 6, 
12 and 18 months will be presented for both PFS and imPFS. 
Both PFS and imPFS will be derived programmatically. Further details will be provided in the SAP. 
9.3.2.6 
Disease Control Rate 
Disease control rate (DCR) is defined as the proportion of patients with a confirmed response of 
PR or CR (confirmed at least two consecutive assessments at least 28 days apart), or with a BOR 
of stable disease (SD) or better sustained for at least 12 weeks (-7 days to allow for the visit window) 
after starting treatment based on the RECIST v1.1 definitions of PR, CR and SD. 
9.3.2.7 
Overall Survival 
Overall survival is defined as the time from starting treatment until death due to any cause. Any 
patient not known to have died at the time of the data cut-off will be censored based on the last 
recorded date on which the patient was known to be alive. OS will be assessed based on the Treated 
Patient population (TP) (see Section 9.2.4). 
Note: Survival calls may be made following the date of data cut-off (DCO) for the analysis, and if 
patients are confirmed to be alive or if the death date is after the DCO these patients will be censored 
at the date of DCO. 
 
Exploratory Endpoints 
The exploratory objectives will be assessed by a number of assays in the starting material, product 
intermediates and final ATL001 product. These may include but not limited to: 


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Tumour Mutational Burden and the Tumour Immune Checkpoint Landscape 
(whole exome sequencing, effector/regulatory T cell balance, PD-L1 expression 
and MHC Class I and II expression). 
- 
cNeT phenotype, functionality and persistence (Multi-parametric Flow cytometry, 
Cytokine assessment, T cell receptor repertoire diversity from RNA analysis, 
Neoantigen reactivity by ELISpot and intracellular cytokine staining, and ctDNA). 
- 
The manufacturing rate will be defined as the number of products made from the 
number of patients undergoing tumour and blood procurement. 
- 
Reasons for not manufacturing a product may include sample not acceptable, 
patient death before product manufactured, patient withdrew consent, failure of in-
process control, QC release failure. 
- 
Factors affecting the manufacturing rate and product quality will be explored 
including clinical, tumour and sample characteristics. 
9.4. 
Methods of Statistical Analysis 
All statistical analyses will be performed by, or under the direct auspices of, Achilles Therapeutics 
UK Limited. 
Unless stated otherwise, data from treatment Cohorts A, B and C will be presented separately. The 
data from any patients receiving an “out of specification” product will be presented separately from 
treatment Cohorts A, B and C. 
The data cut-off for primary analysis for each treatment Cohort will be a minimum of 12 weeks 
after the last patient is recruited in the Cohort of Interest. Following the primary analysis, the study 
will continue for further evaluation of the longer-term efficacy endpoints such as DoR, PFS and 
OS. End of study is defined as the last visit of the last patient undergoing the study. 
 
Assessment of Safety and Tolerability 
9.4.1.1 
Safety and Tolerability of the Procurement Procedures and Lymphodepletion 
The safety and tolerability of the procurement procedures (tumour and blood) will be assessed in 
the Surgical Population (SP). All SAEs, collected from the date of the procurement procedure, until 
28 days after the tissue procurement procedure (or commencement of systemic anti-cancer therapy, 
if sooner), will be listed. Additionally, all AEs considered related to the procurement procedures, 
with an onset date and time following the start of the first procurement procedure until 28 days after 
the tissue procurement procedure (or commencement of first line therapy, if sooner), will be 
summarised in order of descending frequency (i.e. most frequent event will be shown first). 
In the unlikely event that any patients commence lymphodepletion, but do not commence study 
treatment (ATL001) as planned, a listing of adverse event data from the subset of the FAS, who are 
not also in the TP population, will also be provided. 
9.4.1.2 
Safety and Tolerability of the Study Treatment 
The safety and tolerability of the study treatment will be assessed using the TP population. 
All AE data will be listed along with information regarding onset time (study day), duration, 
severity, and relationship to study treatment. Adverse events will be tabulated and summarised 
according to the current version of the Medical Dictionary for Regulatory Activities (MedDRA) by 


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system organ class and preferred term. Serious AEs will be tabulated and listed separately with 
CRS and ICANS Grades listed. Full details will be provided in the study SAP. 
All clinical laboratory data (clinical chemistry, haematology data), and vital signs data will be listed 
and, where appropriate, summarised. In addition, all data measured on a continuous scale (except 
pulse oximetry, respiration rate and pulse) will be displayed graphically as described below: 
- 
Profile plots over time, including reference lines at the lower limit of normal (LLN) 
and upper limit of normal (ULN). 
- 
Profile plots of the change from baseline over time, including a horizontal reference 
line at zero. 
Furthermore, to understand the feasibility of intended treatment regimen, the proportion of patients 
receiving the completing the full treatment regimen will be presented, taking as a denominator the 
number of patients in the TP population. Patients will be considered to have completed the full 
treatment regimen if they received: 
- 
A lymphodepletion regimen of fludarabine 30 mg/m2 i.v. and cyclophosphamide 
300 mg/m2 i.v. on each of Days -6, -5, and -4 prior to cell infusion. These can be 
administered according to local SOPs. 
- 
A complete ATL001 infusion. 
- 
In Cohorts A and B: 10 doses of IL-2 1M IU/m2 s.c. daily from days 0-9 of the 
study, starting between 3 and 12 hours post-infusion. 
- 
In Cohort C: 6 doses of IL-2 600,000 IU/kg i.v. every 8-12 hours, starting between 
3 and 24 hours post-infusion. 
Further details will be provided in the study SAP. 
 
Demographics and Baseline Characteristics 
Patient disposition, including but not limited to, the date of informed consent, date of first dose and 
reasons for discontinuation from study treatment will be listed and summarised. 
Baseline demographic data, which may include but is not limited to the following will be listed and 
summarised using appropriate descriptive statistics, based on the SP and the TP: 
Table 11: Descriptive Statistics for Baseline Demographic Data 
Demographic Data 
Baseline Characteristics 
Age 
Gender 
Weight 
Height 
Race 
Ethnicity 
Disease stage at study entry 
ECOG PS (0 or 1) 
LDH 
Presence of Driver Mutations 
PD-L1 Tumour Proportion Score 
TIL infiltrate in primary tumour (absent/non-
brisk/brisk)  
Number of distant metastases 


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Number of prior lines of therapy before tissue 
procurement 
Number of prior lines of therapy before ATL001 
infusion 
Origin of tumour starting material (e.g. 
primary/metastasis/lymph node) 
 
Medical History and Medications 
Relevant medical history and prior treatment for melanoma will be listed. 
All medications received following the start of treatment (including those that were ongoing prior 
to first dose) will be listed. 
 
Efficacy Data 
All RECIST and imRECIST-based data will be listed, and the BOR, ORR and DCR will be 
summarised (n and %). For those patients with a BOR of PD, the summary will include 
sub-categories to distinguish between PD as defined by the RECIST criteria, and early deaths that 
have been assigned to the PD category. A listing of early deaths will also be provided. 
Dependent on the number of responders, DOR (based on both RECIST and imRECIST) may also 
be summarised using Kaplan-Meier (KM) statistics. PFS and imPFS will be listed and will be 
summarised based on KM estimates. To aid interpretation, the proportion of patients’ 
progression-free at 6, 12 and 18 months will also be presented. PFS and imPFS will be displayed 
graphically using Kaplan-Meier curves, if there are sufficient PFS events. 
The percentage change from baseline in tumour size at week 6 (%ΔTSWk6), week 12 (%ΔTSWk12) 
and the best percentage change from baseline in tumour size (%ΔTSbest), will be presented 
graphically using waterfall plots. The waterfall plots will present each patient’s %ΔTS as a separate 
bar with the bars ordered from the largest increase to the largest decrease. Reference lines at the 
+20% and –30% change in tumour size levels will be added to the plots, which correspond with the 
definitions of disease progression and PR, respectively. Data imputation rules, to account for 
missing data are provided in Section 9.3.2.1. 
Each patient’s percentage change from baseline in tumour size, over time, will also be displayed 
graphically using patient profile plots (spider plots). 
The primary analysis of all RECIST and imRECIST-based will be performed using the EFR set. In 
order to assess the sensitivity of the primary endpoint to major deviations, a sensitivity analysis will 
also be performed using the PPEFR set.  
Overall survival data will be listed and summarised using the TP based on KM descriptive statistics. 
To aid interpretation, the proportion of patients’ event-free at 6, 12 and 18 months will also be 
presented. OS will be displayed graphically using Kaplan-Meier curves, if there are sufficient OS 
events. 
 
Exploratory Endpoint Data 
Not all Exploratory Endpoint data will be presented in the Clinical Study Report. A separate 
Translational Research Report will be produced. Full details will be provided in the Translational 
Science Statistical Analysis Plan. 


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Data to be presented in the CSR will be listed, summarised and displayed graphically according to 
the nature of the data. 
9.5. 
Independent Data Safety Monitoring Committee Reviews 
An Independent Data Safety Monitoring Committee will be formed to monitor patient safety during 
the study. The IDSMC will also oversee the ATX-NS-001 clinical study of ATL001 in patients with 
advanced NSCLC, and potentially additional future clinical studies in other cancers. The members 
will include an independent statistician and three independent physicians, one of whom is an expert 
in melanoma, one is an expert in lung cancer and one an expert in adoptive cell therapies. The 
members of the IDSMC serve in an individual capacity and provide their expertise, including 
recommendations regarding the continuation, modification, or termination of the studies in the 
clinical programme. The IDSMC will review cumulative study data to evaluate safety, study 
conduct, scientific validity and data integrity of the studies. Pertinent data from all ongoing clinical 
studies will be shared with the IDSMC. 
An initial formal review of safety by the IDSMC will take place after the first 6 evaluable patients 
across ATX-NS-001 and ATX-ME-001 have all been treated and followed up for a minimum of 28 
days post infusion. All safety data recorded during this period will be reviewed.  
A subsequent IDSMC safety review will take place when 6 patients in ATX-ME-001 have all been 
treated and followed up for a minimum of 28 days. This safety review will determine whether 
enrolment into Cohort B can commence at centres. The IDSMC will be informed about other study 
related activities as deemed relevant to the ongoing oversight of patient safety including the 
initiation of additional cohorts or procedures. 
Provided that the IDSMC agrees that the study can proceed without modification, the study will be 
considered to have proceeded from Phase I to Phase II following this IDSMC review. These two 
reviews may be combined depending on recruitment timings. 
Similarly, an IDSMC safety review will be triggered when 6 evaluable patients have received 
ATL001 within the ATX-NS-001 study protocol and followed up for a minimum of 28 days. All 
safety data from any patients treated in ATX-ME-001 will be considered in the review. 
An additional IDSMC safety review will take place when 20 patients in this study have all been 
treated and followed up for a minimum of 28 days post infusion. 
An IDSMC safety review of the first 6 patients treated in each treatment Cohort will also be 
scheduled when the 6th patient has been followed up for a minimum of 28 days post-infusion. 
Additional safety reviews may be performed at other times as deemed appropriate by the Sponsor 
or IDSMC. 
An evaluable patient for the IDSMC safety review will be defined as a patient who has received 
lymphodepletion and ATL001 infusion, at the target dose. 
The committee will meet at regular intervals commensurate with the recruitment rate during the 
recruitment period to review progress and safety.  
The committee will also be convened in the event of any patient developing a serious infusion 
reaction or Grade ≥ 3.CRS. In addition, any death within 30 days of ATL001 infusion (other than 
as a result of the underlying disease for which the patient is being treated) and any Grade 4 ICANS 
event will trigger a study pause and IDSMC review. 
The committee will meet at least twice a year during the 2 year follow up phase after completion of 
recruitment. Further details will be provided in an IDSMC charter. 


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9.6. 
Interim Analyses 
The following interim analyses of efficacy may be performed: 
1. Optional interim analyses when approximately 10 evaluable patients have been followed up 
for 6 and 12 weeks. 
2. An interim analysis of each treatment cohort separately when all patients in a cohort have been 
followed up for 12 weeks. 
3. A final analysis when all patients have either died or have been followed up for 2 years. 
Additional interim analyses may be performed at other times during the study. Based on the 
emerging data, Cohort A may be terminated for futility following an internal data review or interim 
analysis if it is felt that sufficient data have already been generated to address the study objectives 
for ATL001 as a monotherapy. No cohort will be terminated early as a result of a positive efficacy 
signal. 
Since the study is open-label, there are no blinding issues associated with performing interim 
analyses. Similarly, since the study is not formally powered and there are no planned hypothesis 
tests, no multiplicity adjustments are required to be accounted for in the interim analyses. 
10 
ETHICAL AND REGULATORY REQUIREMENTS 
10.1. 
Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with the International Conference on Harmonisation 
(ICH)/Good Clinical Practice (GCP) guidelines and applicable regulatory requirements. 
10.2. 
Independent Ethics Committee (IEC) / Institutional Review Board (IRB) 
Review & Reports 
The final study protocol and the final version of the Written Informed Consent Form(s) will be 
approved or given a favourable opinion in writing by the IEC or IRB as appropriate. The 
Investigator will provide the Sponsor with a copy of the communication from the IRB or IEC to the 
Investigator indicating approval of the protocol and consent form, referring to the study by date, 
title, protocol number and the documents reviewed. 
The Investigator must receive written approval from the Sponsor before he or she can enrol any 
patient into the study. 
All changes to the protocol and consent form must be reviewed and approved prior to 
implementation, except where necessary to eliminate apparent immediate hazards to human 
subjects. The Principal Investigator is responsible for informing the IEC or IRB of any amendment 
to the protocol in accordance with local requirements. In addition, the IEC or IRB must approve all 
advertising used to recruit patient for the study. 
Under no circumstances will the investigation be extended beyond the limitations defined in this 
protocol or any subsequent amendments. 
The protocol must be re-approved by the IEC or IRB annually, as local regulations require. The 
Investigator must report to the IRB or IEC, at least annually, on the progress of the investigation. 
Continuing IRB/IEC review should be documented by a letter from the IRB. Notification to the 
IRB/IEC by the Investigator within 3 months after completion, termination, or discontinuation of 


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the study at the specific site must be documented or in an appropriate timeframe as required by the 
relevant IRB or ethics committee. 
10.3. 
Peer Review 
The final study protocol and the final version of the Written Informed Consent Form(s) will undergo 
a process of Peer Review by a representation of the study Investigators and any other internal 
research or scientific committee per institution standards. 
10.4. 
Regulatory Compliance 
The final study protocol must be approved or given a favourable opinion in writing by the national 
regulatory authority prior to initiation of the study. 
10.5. 
Notification of Serious Breaches to GCP and/or the Protocol 
The Sponsor will notify the Regulatory Authorities in writing of any serious breaches without undue 
delay and in accordance with local regulatory requirements. 
A “serious breach” is a breach which is likely to effect to a significant degree: 
a. The safety or physical or mental integrity of the subjects of the trial; or 
b. The scientific value of the trial. 
11 
STUDY MANAGEMENT 
11.1. 
Patient Information and Consent 
The Principal Investigator at the centre will ensure that the patient is given full and adequate oral 
and written information about the nature, purpose, possible risk and benefit of the study. Patients 
must also be notified that they are free to discontinue from the study at any time. The patient should 
be given the opportunity to ask questions and allowed time (at least 24 hours) to consider the 
information provided. 
The consent form that is used must comply with the requirements of ICH E6 and local regulatory 
authorities, be the current version, and must be approved by both the reviewing IRB/IEC and by 
the Sponsor prior to use. The patient’s signed and dated informed consent(s) must be obtained 
before conducting any procedure specifically for the study. 
The original, signed copy of the informed consent must be maintained in the institution’s records, 
and is subject to inspection by a Sponsor representative. 
A copy of the written Informed Consent Form must be given to the patient. If modifications are 
made according to local requirements, the new version has to be approved by the Sponsor. 
11.2. 
Data Protection and Patient Confidentiality  
The written Informed Consent Form (ICF) will explain that study data will be stored in a database, 
maintaining confidentiality in accordance with national data protection legislation. All data will be 
pseudonymised and patients will be identified by a Sponsor-assigned patient number/study code. 
The Written Informed Consent Form will also explain that for data verification purposes, authorised 
representatives of the Sponsor, a regulatory authority, an IEC or IRB may require direct access to 
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All collected patient data will be treated confidentially. As required for autologous cellular 
products, 100% traceability and identification have to be maintained from the procurement of 
materials required for manufacturing through product manufacture to the administration and 
disposal of ATL001. Each autologous product will be identified with a combination of four patient 
identifiers to ensure absolute identification. The four pseudo-anonymised identifiers used in this 
study will be the patient’s unique study number, initials, gender and date of birth. 
In compliance with ICH, E6 guidelines regarding the monitoring of clinical studies, and in 
fulfilment of the Investigator’s obligation to the Sponsor, it is required that the Investigator must 
permit the study monitor or competent regulatory authority representative direct access to review 
that portion of the patient’s medical record that is directly related to the study. This includes all 
study relevant documentation (including signed inform consent, medical histories to verify 
eligibility, laboratory test results to verify transcription accuracy, treatment and diagnostic reports, 
admission/discharge summaries for hospital admissions occurring while the patient is on study and 
autopsy reports for deaths occurring during or in temporal proximity to the study). 
It is the Investigator’s responsibility to obtain patient signatures on any locally required 
confidentiality documents. As part of the required content of informed consent, the patient must be 
informed that his/her records will be reviewed by Sponsor, the study monitor, or a representative 
of the relevant competent regulatory authority. Should access to the medical record require a 
separate waiver or authorisation, it is the Investigator’s responsibility to obtain such permission 
from the patient in writing before the patient is entered into the study. 
All information provided to the Investigator by Sponsor, including nonclinical data, protocols, 
eCRFs, and verbal and written information, will be kept strictly confidential and confined to the 
clinical personnel involved in conducting this study, and no disclosure shall be made except in 
accordance with any right of publication granted to the Investigator. 
11.3. 
Case Report Form Completion 
Case Report Form (CRF) completion will be via an electronic data capture (EDC) and will be 
reviewed for completeness and accuracy by the Sponsor or designee. The eCRFs per patient will be 
created by designee for use by the Investigator or site coordinator during data collection. Once the 
eCRF screens are programmed and tested, the site will be given access to the application and will 
be responsible for entering all applicable patient data directly into the database. The Sponsor 
designee will review all patient data for completeness and accuracy. Only the Investigator may sign 
eCRFs. If no other issues or questions arise from the final data revisions, the data will be locked by 
the Sponsor to preserve the “clean and complete” status of the eCRF data until the final locking of 
the database. All forms must be entered into the electronic data capture system in a timely manner. 
Data will be entered into the eCRF as information becomes available on a visit-by-visit basis. The 
Study Completion Information page of the eCRF must be signed by the Principal Investigator. 
All eCRF corrections are to be made by an Investigator or other designated study site personnel. 
The Principal Investigator or Sub-Investigator must authorise changes to the recorded safety and 
efficacy data. 
11.4. 
Monitoring and Data Verification 
The monitoring of this study will be performed in accordance with the principles of Good Clinical 
Practice (GCP) as laid out in the International Conference on Harmonisation (ICH) document 
“Good Clinical Practice: Consolidated Guideline”. 


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Study monitors designated by the Sponsor will visit the study site periodically to monitor 
compliance with the protocol, applicable regulatory regulations/requirements, and to ensure the 
maintenance of adequate and accurate clinical records. Monitoring functions will be performed in 
compliance with recognised Good Clinical Practices (GCP). The Investigator agrees to allow these 
study monitors, and other authorised Sponsor personnel, access to the clinical supplies, the 
investigational agent dispensing and storage area, patient medical records, laboratory data, and 
other source documentation of the study patients.  
Source data verification will be conducted in the review of all CRFs. During this detailed review 
by the study monitor, the decision will be made as to their acceptability. Missing or incorrect or 
further clarification of data will be handled by data Clarification or Query Forms. Data queries will 
be generated either automatically, by programmed edit checks, or manually by the Sponsor 
designee. Data queries are then presented to study site staff (coordinators and/or Investigators) for 
resolution. Data clarifications or query forms are to be completed by the site staff in a timely 
manner. At the conclusion of the study, the completed CRFs and data queries will be reviewed and 
approved by the Investigator’s signature, in the appropriate space of the CRF. 
The dates of monitoring visits will be recorded on the monitoring sign-in log kept at the site. 
Sponsor expects that, during monitoring visits, the study coordinator, study personnel and 
Investigator will be available, the source documentation will be available, and a suitable 
environment will be provided for review of study-related documents. The Investigator agrees to 
assist Sponsor personnel in their duties, if requested. 
11.5. 
Data Management 
Data will be entered onto the clinical study database and validated. Any missing, impossible or 
inconsistent recordings in the eCRFs will be referred back to the Investigator and be documented 
for each individual patient before clean file status is declared. Source data should be made available 
to the monitor for review. 
All entries to the study database will be available in an audit trail. 
The study monitor will check data at the monitoring visits to the investigational site. The 
Investigator, together with delegates and the study monitor, will ensure that the data in the eCRFs 
are accurate and complete. 
11.6. 
Management and Archiving of Study Documents 
It is the responsibility of the Investigator and study staff to maintain a comprehensive and 
centralised filing system of all study-related documentation that is suitable for inspection at any 
time by the study monitor and the relevant competent regulatory authority. Elements must include, 
but are not limited to: 
- 
All essential regulatory documents as required by ICH E6, Good Clinical Practices. 
- 
Patient files containing the signed informed consent(s) and supporting source documentation 
(e.g. laboratory reports, progress notes, medical histories, physical and diagnostic findings, 
diagnoses and dates of treatment prior to and during this study) that support data entered on the 
eCRFs. 
- 
Pharmacy or Investigator files, containing the investigational agent accountability records or 
dispensation logs and all study agent-related correspondence. 
These documents should be updated as needed during the course of the study. In addition to the 
documents required prior to the study, other documentation may be required during the course of 


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the study. A copy of the completed eCRFs for each patient will be provided to the site at the end of 
the study and must be stored with the site’s study files. 
The Sponsor will retain all documentation pertaining to this study. 
The FDA requires that the Investigator must retain study files for a period of at least 5 years after 
study completion or 2 years following the date that a marketing application is approved for the 
indication in which the study agent is being investigated (whichever is later). 
The hospital in which ATL001 is used will be required to establish and maintain a system for patient 
and product traceability containing sufficient detail to enable traceability between the donated 
tissues and cells used for manufacture and receipt by the patient of the final product. 
The Investigator/institution where ATL001 is used, should keep their parts of the traceability 
records for a minimum of 30 years, or longer if required by the terms of the clinical trial 
authorisation or by the agreement with the Sponsor. 
If no marketing application or license is to be filed, or if the application or license is not approved 
for such an indication, the files must be stored until 2 years after the Sponsor notifies the FDA and 
the Investigator that the indication has been discontinued. 
If the Investigator for any reason desires to dispose of the study files/records, they may be 
transferred to another institution, another Investigator, or to Sponsor upon written agreement 
between the Investigator and Sponsor. 
11.7. 
Audits and Inspections 
Authorised representatives of the Sponsor, a regulatory authority, an Independent Ethics Committee 
(IEC) or an Institutional Review Board (IRB) may visit the centre to perform audits or inspections, 
including source data verification. The purpose of an audit or inspection is to systematically and 
independently examine all study related activities and documents to determine whether these 
activities were conducted, and data were recorded, analysed, and accurately reported according to 
the protocol, GCP guidelines of the ICH and any applicable regulatory requirements. The 
Investigator should contact the Sponsor immediately if contacted by a regulatory agency about an 
inspection at his or her centre. 
11.8. 
Training of Staff 
Before the first patient is entered into the study, a Sponsor representative will review and discuss 
the requirements of the Clinical Study Protocol and related documents with the investigational staff 
and also train them in any study specific procedures including collection of samples and EDC 
system used. 
The Principal Investigator will maintain a record of all individuals involved in the study (medical, 
nursing and other staff). He or she will ensure that appropriate training relevant to the study is given 
to all of these staff, and that any new information of relevance to the performance of this study is 
forwarded to the staff involved. 
11.9. 
Amendments to the Protocol 
Through the course of the study amendments to the protocol may be required as identified by the 
Sponsor and/or study site. 
Amendments to the protocol will originate from the Sponsor and will be provided to the Investigator 
for submission to his/her IRB or IEC for their review and approval prior to implementation. It 
should be noted that when an amendment to a protocol substantially alters the study design or 


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increases potential risk to the study patient, the informed consent should be revised and re-submitted 
to the IRB or IEC for approval, and, if applicable, the patient’s consent to continue participation 
should be obtained. Local requirements must be followed. 
The Sponsor will distribute amendments and new versions of the protocol to the Principal 
Investigator who in turn is responsible for the distribution of these documents to his or her IEC or 
IRB, and to the staff at his or her centre. The distribution of these documents to the regulatory 
authority will be handled according to local practice by the Sponsor. 
11.10. Study Agreements 
The Principal Investigator at the centre must comply with all the terms, conditions, and obligations 
of the study agreement for this study. In the event of any inconsistency between this protocol and 
the study agreement, this protocol shall prevail. 
11.11. Financial Disclosure 
All Investigators are required to declare in writing any conflict of interest with their ability to 
perform the functions of an Investigator in an independent manner. This includes any financial 
interest that are either held by the Investigator or his/her Sub-Investigators themselves, their spouse 
or dependent children, and any other relationships with employees of the Sponsor that could affect 
the Investigator’s objectivity. 
In accordance with US 21 CFR, Part 54.4, Investigators are required to provide information on 
financial interest and arrangements during the course of the study and for one year after the 
completion of the study. 
11.12. Study Timetable and Termination 
The timelines for the study will be as per the study agreement with the study site. The start of the 
study is defined as the first patient signing informed consent. The end of the study is defined as the 
last visit of the last patient undergoing the study. 
The study may be terminated at individual centres if the study procedures are not being performed 
according to GCP, or if recruitment is slow. The Sponsor may also terminate the entire study 
prematurely based on business decisions, efficacy, safety, or other reasons. 
11.13. Sample Management 
Biological samples will be used up, disposed of after analyses or retained for further use for a 
maximum of 15 years following the patient’s last visit in the study. 
Biological samples remaining after planned analyses will be retained will be retained for future and 
optional research for a maximum of 15 years following the last patient’s last visit in the study. 
A full chain of custody will be maintained for all samples throughout their lifecycle. 
The Principal Investigator at each centre will maintain a full traceability of collected biological 
samples from the patients while in storage at the centre until shipment or disposal. 
The sample receiver will maintain a full traceability of the samples while in storage and during use 
until used or disposed of or until further shipment and keeps documentation of receipt of arrival. 
Samples will be stored by Achilles Therapeutics UK Limited in a biobank and provided for research 
purposes in order to further understand the disease and therapy.  


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This biomaterial may be shared with Achilles Therapeutics UK Limited authorised representatives. 
Samples shipped to external vendors for analysis will be returned to the Sponsor upon completion 
of analysis, where available. These return shipments may be planned in batches. 
Biomaterial ownership will be transferred to Achilles Therapeutics UK Limited. 
12 
USE OF INFORMATION AND PUBLICATION POLICY 
The information provided in support of or generated as a result of this study is confidential. Any 
use or reproduction thereof, including but not limited to publications or presentations by the 
Investigator or his/her associates, must be submitted to the Sponsor for review and the opportunity 
to make comments prior to publication or presentation in any form. All publications must 
acknowledge the Sponsorship. 
All information not previously published concerning information such as patent applications, 
formulas, manufacturing processes, basic scientific data, and formulation information supplied by 
the Sponsor to the Investigator is considered confidential and shall remain the sole property of the 
Sponsor. The Investigator agrees to use this information only to accomplish this study and will not 
use it for other purposes without the Sponsor’s written consent. 
13 
EMERGENCY PROCEDURES 
13.1. 
Medical Emergency Contact Procedure 
In the case of a medical emergency, contact personnel shown below. 
 
 
13.2. 
Overdose 
It is not possible for a patient to receive an overdose of ATL001 due to the fixed volume in a Product 
Infusion Bag. 
Investigators should be advised that any patient who receives a higher dose than that intended of 
any other component of study medication should be monitored closely, managed with appropriate 
supportive care and followed up expectantly. 
Such overdoses should be recorded as AEs/SAEs as follows: 
- 
An overdose with associated AEs/SAEs is recorded as the AE diagnosis/symptoms 
on the relevant AE/SAE modules in the CRF and on the overdose CRF module. 
- 
An overdose with no associated symptoms is only reported on the overdose CRF 
module. 
If an overdose occurs in the course of the study, then Investigators or other site personnel must 
inform Achilles Therapeutics (or its representative) immediately, or no later than 24 hours of 
when he or she becomes aware of it. 
 
 


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15 
APPENDICES 
Appendix A: ECOG Performance Status Score 
 
Developed by the Eastern Cooperative Oncology Group 
GRADE ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Dead 
 
Source: Oken et al, 1982 Am J Clin Oncol 5(6):649-655 
 
 


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Appendix B: Summary of Differences Between RECIST v1.1 and imRECIST 
 
 
Source: Hodi et al, 2018 J Clin Oncol 36(9):850-858 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix C: Prohibited and Concomitant Medications 
 
Prohibited Medications: 
• 
Prior to procurement:  
o Regular, ongoing immunosuppressive treatments for active autoimmune 
disease – including but not limited to: azathioprine, abatacept, 
adalimumab, anakinra, basiliximab, certolizumab, cyclosporin, 
daclizumab, etanercept, golimumab, infliximab, ixekizumab, 
leflunomide, methotrexate, mycophenolate, natalizumab, rituximab, 
sarilumab, secukinumab, tacrolimus, tocilizumab, tofacitinib, 
ustekinumab, vedolizumab. 
o Regular, ongoing treatment with steroids at a dose higher than 
prednisolone 10 mg/day (or equivalent – i.e. prednisone 5 mg, 
triamcinolone 8 mg, dexamethasone 1.6 mg, betamethasone 1.2 mg, 
methylprednisolone 8 mg, hydrocortisone 40 mg). Patients receiving 
modified-release, oral preparations of steroids with low systemic 
availability (e.g. beclomethasone dipropionate, budesonide) should be 
discussed with the Sponsor.  
o Any investigational cell or gene therapies.  
o Any cytotoxic chemotherapy or anti-angiogenesis agent (e.g. 
bevacizumab) within the 3 weeks prior to procurement.  
• 
Between re-screening and Lymphodepletion:  
o Regular, ongoing immunosuppressive treatments for active autoimmune 
disease. 
o Regular, ongoing treatment with steroids at a dose higher than 
prednisolone 10 mg/day or equivalent. 
o Any live vaccination within the 28 days prior to lymphodepletion.  
o Any cytotoxic chemotherapy agent within the 3 weeks prior to 
lymphodepletion.  
o Any investigational cell or gene therapies.  
• 
From Lymphodepletion through follow up period: 
o Non-Steroidal Anti-Inflammatory agents (e.g. ibuprofen), aspirin or any 
other drug with an anti-platelet effect should not be used from 
lymphodepletion until recovery of normal platelet counts. 
o G-CSF is not recommended as a routine prophylaxis in all patients 
following lymphodepletion as it can stimulate myeloid derived 
suppressor cells (however, its use is at the discretion of the Investigator 
dependent on the clinical situation and it should be used to manage 
cytopenia). 
o Corticosteroids as anti-emesis prophylaxis or infusion reaction 
prophylaxis. 


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o Any immunosuppressive treatments, unless needed to treat emerging 
toxicity (e.g. tocilizumab or siltuximab for CRS).  
o Treatment with steroids at a dose higher than prednisolone 10 mg/day (or 
equivalent), unless needed to treat emerging toxicity.  
o Any investigational cell or gene therapies. 
o Any live vaccination within 3 months of last dose fludarabine (or 5 
months after last dose nivolumab for Cohort B participants). 
o Non-irradiated blood products.  
 
Permitted Concomitant Medications: 
• 
Procurement:  
o Any standard pre-medication agents and anaesthetic agents. 
• 
Lymphodepletion:  
o Fludarabine and cyclophosphamide per protocol.  
o Any anti-emetic prophylaxis (per local SOPs) except corticosteroids. 
o Anti-infective prophylaxis, per local SOPs (e.g. cotrimoxazole, acyclovir, 
fluconazole). 
o G-CSF to manage prolonged neutropenia, per local SOPs. 
• 
Prior to ATL001 infusion or during follow up period: 
o Chlorphenamine and paracetamol/acetaminophen to prevent infusion 
reactions, per local SOPs. 
o Tocilizumab or siltuximab to treat cytokine release syndrome, per 
protocol guidelines.  
o IL-2 (aldesleukin) per protocol. 
• 
COVID-19 vaccination: 
o Currently authorised COVID-19 vaccines do not use mechanisms or 
vectors that would classify them as “live vaccinations”. As such, 
Exclusion Criterion 23 does not apply to the use of these vaccines in 
study participants; nor does the SmPC/Package Insert guidance for live 
vaccination following fludarabine or nivolumab administration (i.e. 
avoidance of live vaccination for 3 and 4 months, respectively).  
o There is a risk that immunosuppressed individuals may have a 
suboptimal immunological response to COVID-19 vaccines. As such, 
COVID-19 vaccine doses should ideally be given to trial participants at 
least two weeks pre-lymphodepletion and two weeks post-ATL001 
infusion (or as per local SOPs, if already in place). 
 


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Appendix D: CRS Monitoring Chart 
 
Date 
Baseline   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Temperature 
≥ 38°C  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypotension 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoxia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRS grade 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Temperature 
≥ 38°C  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypotension 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoxia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRS grade 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Temperature 
≥ 38°C  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypotension 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoxia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRS grade 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Temperature 
≥ 38°C  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypotension 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoxia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRS grade 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Temperature 
≥ 38°C  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypotension 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoxia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRS grade 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix E: Neurotoxicity Monitoring Charts 
 
Date 
Baseline 
 
 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
 
 
 
Year (1p) 
 
 
 
 
 
 
 
 
 
 
Month (1p) 
 
 
 
 
 
 
 
 
 
 
City (1p) 
 
 
 
 
 
 
 
 
 
 
Hospital (1p) 
 
 
 
 
 
 
 
 
 
 
Follow commands (1p) 
 
 
 
 
 
 
 
 
 
 
Naming three nearby 
objects (max 3p) 
 
 
 
 
 
 
 
 
 
 
Writing a standard sentence 
(1p) 
 
 
 
 
 
 
 
 
 
 
Count backwards  
from 100 in tens (1p) 
 
 
 
 
 
 
 
 
 
 
ICE Score 
 
 
 
 
 
 
 
 
 
 
Depression level of 
consciousness 
 
 
 
 
 
 
 
 
 
 
Seizures 
 
 
 
 
 
 
 
 
 
 
Motor findings 
 
 
 
 
 
 
 
 
 
 
Elevated ICP/cerebral 
oedema 
 
 
 
 
 
 
 
 
 
 
ICANS Grade 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
Time 
Short sentence 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix F: Expected IL-2 Toxicities and Their Management  
 
Expected toxicity  
Expected 
Grade  
Supportive Measures  
Stop Treatment*  
Chills/rigors  
3  
IV Pethidine 25-50 mg, IV q1h, prn  
No  
Fever  
3  
Paracetamol 500 mg, po, 
q4h; Indomethicin 50-75 mg, po, q8h  
No  
Pruritis  
3  
Chlorpheniramine 10mg IV q6h, prn or 
4mg po q6h, prn; Hydroxyzine HCL 10-
20 mg po q6h, prn; Diphenhydramine 
HCL 25-50 mg, po, q4h, prn  
No  
Nausea/ Vomiting/ 
Anorexia  
3  
Ondansetron 10 mg, IV, q8h, prn; 
Prochlorperazine 25 mg q4h p.r., prn or 
10 mg IV q6h prn; or as per local 
standard  
No  
Diarrhoea  
3  
Loperamide 2 mg, po, q3h, prn; codeine 
sulphate 30-60 mg, po, q4h, prn  
If uncontrolled after 24 
hours despite all 
supportive measures  
Malaise  
3 or 4  
Bedrest  
If other toxicities occur 
simultaneously  
Hyperbilirubinaemia  
3 or 4  
Observation  
If other toxicities occur 
simultaneously  
Anaemia  
3 or 4  
Transfusion with PRBCs  
If uncontrolled despite all 
supportive measures  
Thrombocytopaenia  
3 or 4  
Transfusion with platelets  
If uncontrolled despite all 
supportive measures  
Neutropaenia  
4  
Observation  
No  
Oedema/Weight gain  
3  
Diuretics prn  
No  
Hypotension  
3  
Fluid resuscitation; Vasopressor support  If uncontrolled despite all 
supportive measures  
Dyspnea  
3 or 4  
Oxygen or ventilatory support  
If requires 
ventilatory support  
Oliguria  
3 or 4  
Fluid boluses  
If uncontrolled despite all 
supportive measures  
Increased creatinine  
3 or 4  
Observation  
Yes (grade 4)   
Renal failure  
3 or 4  
Dialysis  
Yes  
Pleural effusion  
3  
Consider thoracentesis  
If uncontrolled despite all 
supportive measures  
Confusion/somnolence  
3  
Observation  
Yes  
Arrhythmia  
3  
Correction of fluid and electrolyte 
imbalances; chemical conversion 
or electrical conversion therapy  
If uncontrolled despite all 
supportive measures  
Elevated Troponin 
levels/myocardial 
infarction  
3 or 4  
Observation/standard supportive care  
Yes  
Elevated transaminases  
3 or 4  
Observation  
For grade 4 without liver 
metastases  
Electrolyte imbalances  
3 or 4  
Electrolyte replacement  
If uncontrolled despite all 
supportive measures  
 
*Unless the toxicity is reversed within 12 hours.  
 
 


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Appendix G: Country Specific Requirements – Germany 
 
The following additional restrictions apply in Germany: 
• 
The administration of any “out of specification” products in Germany is not permitted. 
The following additional requirements apply to sites in Germany participating in the study: 
• 
Patients must undergo pregnancy testing from Day 0 (day of infusion +/– 1 day) and 
then at every 6 week visit for 12 months or until either completion of the study or 
withdrawal of the study, whichever is sooner. Refer to the Schedule of Assessments 
(Section 6.3) for details of pregnancy testing requirements for participating sites in 
Germany. 
• 
Cohort B patients require a higher frequency of pregnancy testing whilst receiving 
nivolumab. Urine or serum pregnancy testing is required prior to each nivolumab 
administration (i.e. every 4 weeks) for female participants of childbearing potential. For 
Cohort B patients being treated at sites in Germany, if nivolumab doses are delayed, 
omitted, or discontinued for any reason then the frequency of pregnancy testing should be 
adjusted accordingly but must satisfy the 6-weekly requirement described above.