Summary
EudraCT Number:2018-003446-16
Sponsor's Protocol Code Number:ATX-ME-001
National Competent Authority:UK - MHRA
Clinical Trial Type:EEA CTA
Trial Status:GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:2018-12-19
Trial results
A. Protocol Information
A.1Member State ConcernedUK - MHRA
A.2EudraCT number2018-003446-16
A.3Full title of the trial
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.
A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
A first-in-human clinical trial in adult patients with metastatic or recurrent melanoma of a personalised therapy targeting specific mutations that occur in all cancer cells within a single patient.
A.3.2Name or abbreviated title of the trial where available
ATX-ME-001 - ATL001 for the Treatment of Metastatic or Recurrent Melanoma
A.4.1Sponsor's protocol code numberATX-ME-001
A.7Trial is part of a Paediatric Investigation Plan No
A.8EMA Decision number of Paediatric Investigation Plan
B. Sponsor Information
B.Sponsor: 1
B.1.1Name of SponsorAchilles Therapeutics Limited
B.1.3.4CountryUnited Kingdom
B.3.1 and B.3.2Status of the sponsorCommercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1Name of organisation providing supportAchilles Therapeutics Limited
B.4.2CountryUnited Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1Name of organisationAchilles Therapeutics Limited
B.5.2Functional name of contact pointRegulatory Affairs
B.5.3 Address:
B.5.3.1Street AddressStevenage Bioscience Catalyst
B.5.3.2Town/ cityGunnels Wood Road
B.5.3.3Post codeSG1 2FX
B.5.3.4CountryUnited Kingdom
B.5.4Telephone number+441438906859
B.5.6E-mail[email protected]
D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3IMP RoleTest
D.2 Status of the IMP to be used in the clinical trial
D.2.1IMP to be used in the trial has a marketing authorisation No
D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
D.2.5.1Orphan drug designation number
D.3 Description of the IMP
D.3.1Product nameATL001
D.3.2Product code ATL001
D.3.4Pharmaceutical form Dispersion for infusion
D.3.4.1Specific paediatric formulation No
D.3.7Routes of administration for this IMPIntravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8INN - Proposed INNNot yet available
D.3.9.3Other descriptive nameATL001
D.3.9.4EV Substance CodeSUB193230
D.3.10 Strength
D.3.10.1Concentration unit Other
D.3.10.2Concentration typerange
D.3.10.3Concentration number10000000 to 1000000000
D.3.11 The IMP contains an:
D.3.11.1Active substance of chemical origin No
D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
The IMP is a:
D.3.11.3Advanced Therapy IMP (ATIMP) Yes
D.3.11.3.1Somatic cell therapy medicinal product Yes
D.3.11.3.2Gene therapy medical product No
D.3.11.3.3Tissue Engineered Product No
D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
D.3.11.5Radiopharmaceutical medicinal product No
D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
D.3.11.7Plasma derived medicinal product No
D.3.11.8Extractive medicinal product No
D.3.11.9Recombinant medicinal product No
D.3.11.10Medicinal product containing genetically modified organisms No
D.3.11.11Herbal medicinal product No
D.3.11.12Homeopathic medicinal product No
D.3.11.13Another type of medicinal product No
D.IMP: 2
D.1.2 and D.1.3IMP RoleTest
D.2 Status of the IMP to be used in the clinical trial
D.2.1IMP to be used in the trial has a marketing authorisation Yes
D.2.1.1.1Trade name Opdivo
D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma
D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
D.2.5.1Orphan drug designation number
D.3 Description of the IMP
D.3.4Pharmaceutical form Concentrate for solution for infusion
D.3.4.1Specific paediatric formulation No
D.3.7Routes of administration for this IMPIntravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8INN - Proposed INNNivolumab
D.3.9.3Other descriptive nameNivolumab
D.3.9.4EV Substance CodeSUB122750
D.3.10 Strength
D.3.10.1Concentration unit mg milligram(s)
D.3.10.2Concentration typeup to
D.3.10.3Concentration number480
D.3.11 The IMP contains an:
D.3.11.1Active substance of chemical origin No
D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
The IMP is a:
D.3.11.3Advanced Therapy IMP (ATIMP) No
D.3.11.3.1Somatic cell therapy medicinal product No
D.3.11.3.2Gene therapy medical product No
D.3.11.3.3Tissue Engineered Product No
D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
D.3.11.5Radiopharmaceutical medicinal product No
D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
D.3.11.7Plasma derived medicinal product No
D.3.11.8Extractive medicinal product No
D.3.11.9Recombinant medicinal product Yes
D.3.11.10Medicinal product containing genetically modified organisms No
D.3.11.11Herbal medicinal product No
D.3.11.12Homeopathic medicinal product No
D.3.11.13Another type of medicinal product No
D.8 Information on Placebo
E. General Information on the Trial
E.1 Medical condition or disease under investigation
E.1.1Medical condition(s) being investigated
Metastatic or recurrent melanoma
E.1.1.1Medical condition in easily understood language
Melanoma
E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
MedDRA Classification
E.1.2 Medical condition or disease under investigation
E.1.2Version 21.1
E.1.2Level PT
E.1.2Classification code 10025650
E.1.2Term Malignant melanoma
E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
E.1.2 Medical condition or disease under investigation
E.1.2Version 21.1
E.1.2Level LLT
E.1.2Classification code 10025651
E.1.2Term Malignant melanoma excision
E.1.2System Organ Class 100000004865
E.1.2 Medical condition or disease under investigation
E.1.2Version 21.1
E.1.2Level PT
E.1.2Classification code 10025652
E.1.2Term Malignant melanoma in situ
E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
E.1.2 Medical condition or disease under investigation
E.1.2Version 21.1
E.1.2Level PT
E.1.2Classification code 10025670
E.1.2Term Malignant melanoma stage III
E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
E.1.2 Medical condition or disease under investigation
E.1.2Version 21.1
E.1.2Level PT
E.1.2Classification code 10025671
E.1.2Term Malignant melanoma stage IV
E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
E.1.2 Medical condition or disease under investigation
E.1.2Version 21.1
E.1.2Level LLT
E.1.2Classification code 10053571
E.1.2Term Melanoma
E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
E.1.2 Medical condition or disease under investigation
E.1.2Version 20.0
E.1.2Level LLT
E.1.2Classification code 10027148
E.1.2Term Melanoma in situ
E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
E.1.2 Medical condition or disease under investigation
E.1.2Version 20.0
E.1.2Level LLT
E.1.2Classification code 10027150
E.1.2Term Melanoma malignant
E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
E.1.2 Medical condition or disease under investigation
E.1.2Version 20.0
E.1.2Level PT
E.1.2Classification code 10066600
E.1.2Term Melanoma recurrent
E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
E.1.2 Medical condition or disease under investigation
E.1.2Version 21.1
E.1.2Level PT
E.1.2Classification code 10027480
E.1.2Term Metastatic malignant melanoma
E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
E.1.2 Medical condition or disease under investigation
E.1.2Version 20.0
E.1.2Level LLT
E.1.2Classification code 10027481
E.1.2Term Metastatic melanoma
E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
E.1.2 Medical condition or disease under investigation
E.1.2Version 21.1
E.1.2Level PT
E.1.2Classification code 10029488
E.1.2Term Nodular melanoma
E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
E.1.3Condition being studied is a rare disease No
E.2 Objective of the trial
E.2.1Main objective of the trial
To assess the safety and tolerability of the investigational product after administration to patients.
E.2.2Secondary objectives of the trial
To evaluate if patients have a clinically meaningful response to the investigational product.
E.2.3Trial contains a sub-study No
E.3Principal inclusion criteria
Inclusion criteria will apply at multiple timepoints.

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 inhibitor prior to treatment with ATL001.
5. Patients whose tumour is known to have a BRAF V600 mutation must have received BRAF targeted therapy (as well as a PD-1 inhibitor) 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 x10^9/L.
c. Absolute Neutrophil Count (ANC) ≥ 1.5 x10^9/L.
d. Platelets ≥ 100 x10^9/L.
e. PT and APTT < 1.5x ULN (unless receiving therapeutic anticoagulation).
f. AST or ALT ≤ 2.5x ULN.
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. Patients with female partners of childbearing potential must agree to use adequate contraception for at least 6 months after the ATL001 infusion. See Section 4.3 for details of acceptable methods of contraception.
In addition to 1-10, the following inclusion criteria must 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 advance 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 1-10, the following inclusion criteria must be met prior to lymphodepletion for treatment with ATL001:
13. Patients must have metastatic melanoma whose disease has progressed or recurred following standard of care or who are ineligible for, or who cannot tolerate, standard of care therapies, e.g. immune checkpoint inhibitors.
14. Patients must have measurable disease according to RECIST v1.1 criteria prior to lymphodepletion. (If patients have no measurable disease following standard therapy, lymphodepletion and ATL001 treatment may be delayed until there is evidence of measurable disease).
15. Patient is considered well enough to receive ATL001 treatment (this will be checked prior to lymphodepletion and again prior to receiving ATL001).
In addition to 1-15, the following inclusion criteria must be met for patients to be eligible for treatment in Cohort B:
16. Prior to treatment with ATL001, the most recent treatment regimen must have included a PD-1 inhibitor and patients should have experienced radiological disease progression on this treatment regimen.
E.4Principal exclusion criteria
Exclusion criteria will apply at multiple timepoints.

Exclusion Criteria:
1. Patients with known leptomeningeal disease or CNS metastases at the time of screening.
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).
4. Patients with active 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 who are pregnant or breastfeeding.
9. Patients who have undergone major surgery in the previous 3 weeks.
10. 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).
11. Patients with a history of organ transplantation.
12. Patients who have previously received any investigational cell or gene therapies.
13. Patients with contraindications for cyclophosphamide, fludarabine and IL-2 at per protocol doses (see Investigator’s Brochure for details).
14. Patients with a known history of allergic reactions to amphotericin b, penicillin and/or streptomycin.
In addition to 1-14, the following exclusion criteria apply to patients who have received anti-cancer therapy prior to study entry:
15. Patients who have received any cytotoxic chemotherapy within the 3 weeks prior to blood and tumour tissue procurement.
In addition, the following exclusion criteria will apply for eligibility for Cohort B:
16. Patients with any contraindications for nivolumab (Refer to the latest available prescribing information (e.g. SmPC) or the Investigator's Brochure for safety information for nivolumab).
In addition to 1-14, the following exclusion criteria apply to all patients prior to lymphodepletion for treatment with ATL001:
17. Patients who have received a live vaccination within the 28 days prior to lymphodepletion.
18. Patients with an active infection requiring antibiotics.
19. Patients who have received any cytotoxic chemotherapy within the 3 weeks prior to lymphodepletion.
E.5 End points
E.5.1Primary end point(s)
The primary outcome measure is the frequency and severity of adverse events and serious adverse events following tissue procurement and administration of lymphodepletion agents, ATL001 and IL-2.
E.5.1.1Timepoint(s) of evaluation of this end point
The following interim analyses of efficacy will be conducted:

1. When approximately 10 evaluable patients have been followed up for 6 and 12 weeks.
2. When all patients in a treatment cohort separately 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 reviews of data may be undertaken as it arises and as deemed necessary by the Sponsor.
E.5.2Secondary end point(s)
To evaluate the clinical efficacy of ATL001 treatment.

• Percentage change from baseline in tumour size at 6 weeks, 12 weeks and best change from baseline
• Best percentage change from baseline in tumour size
• 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)
E.5.2.1Timepoint(s) of evaluation of this end point
The following interim analyses of efficacy may be performed:

1. When approximately 10 evaluable patients have been followed up for 6 and 12 weeks.
2. When all patients in a treatment cohort separately 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 reviews of data may be undertaken as it arises and as deemed necessary by the Sponsor.
E.6 and E.7 Scope of the trial
E.6Scope of the trial
E.6.1Diagnosis No
E.6.2Prophylaxis No
E.6.3Therapy Yes
E.6.4Safety Yes
E.6.5Efficacy Yes
E.6.6Pharmacokinetic No
E.6.7Pharmacodynamic No
E.6.8Bioequivalence No
E.6.9Dose response Yes
E.6.10Pharmacogenetic No
E.6.11Pharmacogenomic No
E.6.12Pharmacoeconomic No
E.6.13Others No
E.7Trial type and phase
E.7.1Human pharmacology (Phase I) Yes
E.7.1.1First administration to humans Yes
E.7.1.2Bioequivalence study No
E.7.1.3Other No
E.7.1.3.1Other trial type description
E.7.2Therapeutic exploratory (Phase II) Yes
E.7.3Therapeutic confirmatory (Phase III) No
E.7.4Therapeutic use (Phase IV) No
E.8 Design of the trial
E.8.1Controlled No
E.8.1.1Randomised No
E.8.1.2Open Yes
E.8.1.3Single blind No
E.8.1.4Double blind No
E.8.1.5Parallel group No
E.8.1.6Cross over No
E.8.1.7Other No
E.8.2 Comparator of controlled trial
E.8.2.1Other medicinal product(s) No
E.8.2.2Placebo No
E.8.2.3Other No
E.8.3 The trial involves single site in the Member State concerned No
E.8.4 The trial involves multiple sites in the Member State concerned Yes
E.8.4.1Number of sites anticipated in Member State concerned7
E.8.5The trial involves multiple Member States No
E.8.6 Trial involving sites outside the EEA
E.8.6.1Trial being conducted both within and outside the EEA No
E.8.6.2Trial being conducted completely outside of the EEA No
E.8.7Trial has a data monitoring committee Yes
E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
LVLS
E.8.9 Initial estimate of the duration of the trial
E.8.9.1In the Member State concerned years4
E.8.9.1In the Member State concerned months10
E.8.9.1In the Member State concerned days29
E.8.9.2In all countries concerned by the trial years4
E.8.9.2In all countries concerned by the trial months10
E.8.9.2In all countries concerned by the trial days29
F. Population of Trial Subjects
F.1 Age Range
F.1.1Trial has subjects under 18 No
F.1.1Number of subjects for this age range: 0
F.1.1.1In Utero No
F.1.1.1.1Number of subjects for this age range: 0
F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
F.1.1.2.1Number of subjects for this age range: 0
F.1.1.3Newborns (0-27 days) No
F.1.1.3.1Number of subjects for this age range: 0
F.1.1.4Infants and toddlers (28 days-23 months) No
F.1.1.4.1Number of subjects for this age range: 0
F.1.1.5Children (2-11years) No
F.1.1.5.1Number of subjects for this age range: 0
F.1.1.6Adolescents (12-17 years) No
F.1.1.6.1Number of subjects for this age range: 0
F.1.2Adults (18-64 years) Yes
F.1.2.1Number of subjects for this age range: 30
F.1.3Elderly (>=65 years) Yes
F.1.3.1Number of subjects for this age range: 10
F.2 Gender
F.2.1Female Yes
F.2.2Male Yes
F.3 Group of trial subjects
F.3.1Healthy volunteers No
F.3.2Patients Yes
F.3.3Specific vulnerable populations Yes
F.3.3.1Women of childbearing potential not using contraception No
F.3.3.2Women of child-bearing potential using contraception Yes
F.3.3.3Pregnant women No
F.3.3.4Nursing women No
F.3.3.5Emergency situation No
F.3.3.6Subjects incapable of giving consent personally No
F.3.3.7Others No
F.4 Planned number of subjects to be included
F.4.1In the member state40
F.4.2 For a multinational trial
F.4.2.1In the EEA 40
F.4.2.2In the whole clinical trial 40
F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
The investigational medicinal product is administered as a single infusion of autologous cells. It is anticipated that most patients will receive a single administration of cells. Re-administration may be possible if the patient is fit enough to undergo a second tumour biopsy for the manufacture of a second dose or re-conditioning with fludarabine and cyclophosphamide if needed in the case a second dose was able to be manufactured from the initial tumour biopsy upon initial entry to the study.
G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
N. Review by the Competent Authority or Ethics Committee in the country concerned
N.Competent Authority Decision Authorised
N.Date of Competent Authority Decision2019-01-25
N.Ethics Committee Opinion of the trial applicationFavourable
N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
N.Date of Ethics Committee Opinion2019-05-10
P. End of Trial
P.End of Trial StatusGB - no longer in EU/EEA