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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Achilles Therapeutics UK Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

22 Dec 2022 → 18 Sep 2024

Decision date (initial)

2024-05-06

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Achilles Therapeutics UK Limited

External identifiers

EU CT number

2024-513062-19-00

EudraCT number

2018-003446-16

ClinicalTrials.gov

NCT03997474

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy, Dose response

To assess the safety and tolerability of ATL001 as a monotherapy and in combination with nivolumab

Secondary objectives 1

1. To evaluate the clinical activity of ATL001 treatment as a monotherapy and in combination with nivolumab

Conditions and MedDRA coding

Metastatic or recurrent melanoma

Regulatory references

Scientific advice from competent authorities

Medicines And Healthcare Products Regulatory Agency, Paul-Ehrlich-Institut

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

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. 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
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
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)
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 25

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
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
15. Patients with a confirmed history of allergic reactions to amphotericin b, penicillin and/or streptomycin
16. Patients who have received any cytotoxic chemotherapy within the 3 weeks prior to tissue and blood procurement
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
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
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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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 7

1. Percentage change from baseline in tumour size at 6 weeks, 12 weeks and best change from baseline
2. Overall Response Rate (ORR) (based on RECIST v1.1 and imRECIST)
3. Time to response (based on RECIST v1.1 and imRECIST)
4. Duration of response (based on RECIST v1.1 and imRECIST)
5. Disease Control Rate (CR + PR + durable SD) (based on RECIST v1.1)
6. Progression free survival (PFS) (based on RECIST v1.1 and imRECIST)
7. Overall survival (OS)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Achilles Therapeutics UK Limited

Sponsor organisation

Achilles Therapeutics UK Limited

Address

245 Hammersmith Road

City

London

Postcode

W6 8PW

Country

United Kingdom

Scientific contact point

Organisation

Achilles Therapeutics UK Limited

Contact name

Achilles Therapeutics UK Limited

Public contact point

Organisation

Achilles Therapeutics UK Limited

Contact name

Achilles Therapeutics UK Limited

Third parties 3

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 3 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications