ATL001 in Patients With Metastatic or Recurrent Melanoma

Study Overview
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Brief Summary
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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
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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 then be requested to enter a separate long term follow up protocol for a further 5 years (total 84 months)

Official Title
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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

Conditions
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Melanoma

Intervention / Treatment
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* Biological: ATL001
* Drug: Checkpoint Inhibitor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must be at least 18 years old at the screening visit. Patient must have given written informed consent to participate in the study. Patients must have histologically confirmed diagnosis of melanoma. Patients must have received a PD-1/ PD-L1 inhibitor prior to treatment with ATL001 (unless contraindicated). 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. 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. Patient is considered, in the opinion of the Investigator, capable of adhering to the protocol. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1. Adequate organ function per the laboratory parameters defined in the protocol. Female patients who are of childbearing potential must agree to use a highly effective method of contraception during the study 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. Anticipated life expectancy ≥ 6 months at the time of tissue procurement. Patient must have measurable disease according to RECIST v1.1 Additional Inclusion criteria will apply as per the protocol. Exclusion Criteria: Patients with known leptomeningeal or CNS metastases at the time of screening. Patients with ocular, acral or mucosal melanoma. Patients with active infectious disease. Patients with active, known, or suspected, autoimmune disease requiring immunosuppressive treatments. Patients requiring regular treatment with steroids at a dose higher than prednisolone 10mg/day (or equivalent). 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. Patients with a history of immune mediated central nervous system toxicity that was caused by, or suspected to be caused by, immunotherapy. 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) are not excluded. Patients who are pregnant or breastfeeding. Patients who have undergone major surgery in the previous 3 weeks. 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). Patients with a history of organ transplantation. Patients who have previously received any investigational cell or gene therapies. Patients with contraindications for cyclophosphamide, fludarabine and IL-2 at per protocol doses (see Investigator's Brochure for details). Patients with a known history of allergic reactions to amphotericin b, penicillin and/or streptomycin. Additional Exclusion criteria will apply as per the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A<br>Following lymphodepletion, infusion of cell therapy product ATL001, followed by a low dose regimen of IL- 2. | Biological: ATL001<br>* ATL001 infusion<br>|
| Experimental: Cohort B<br>Following lymphodepletion, infusion of cell therapy product ATL001 in combination with a checkpoint inhibitor, followed by a low dose regimen of IL-2. | Biological: ATL001<br>* ATL001 infusion<br>Drug: Checkpoint Inhibitor<br>* Nivolumab<br>|
| Experimental: Cohort C<br>Following lymphodepletion, infusion of cell therapy product ATL001, followed by a higher dose regimen of IL-2. | Biological: ATL001<br>* ATL001 infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of Treatment Emergent Adverse Events to evaluate Safety and Tolerability: CTCAE | Evaluate treatment-emergent adverse events (TEAEs) and serious AEs, per CTCAE, by incidence, severity and relationship to ATL001 | Maximum 84 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Assessment for Change from Baseline in Tumour Size | Evaluate the clinical activity of ATL001 in patients with recurrent or metastatic melanoma using change from baseline in tumour size at week 6, week 12 and best overall change from baseline, as assessed by investigator and independent central review (ICR). | Every 6 weeks for 6 months, then every 3 months for a maximum of 84 months | 
| Disease Assessment for Overall Response Rate | Evaluate the endpoint of overall response rate (ORR), as assessed by investigator and ICR, per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and immune modified RECIST( im-RECIST). | Every 6 weeks for 6 months, then every 3 months for a maximum of 84 months | 
| Disease Assessment for Time to Response and Duration of Response | Evaluate the endpoints of time to response and duration of response (DOR) by the investigator and ICR, per RECIST v1.1 and im-RECIST. | Every 6 weeks for 6 months, then every 3 months for a maximum of 84 months | 
| Disease Assessment for Disease Control Rate | Evaluate the endpoints of disease control rate (DCR) as assessed by the investigator and ICR per RECIST v1.1 and im-RECIST. | Every 6 weeks for 6 months, then every 3 months for a maximum of 84 months | 
| Disease Assessment for Progression-Free Survival | Evaluate the efficacy endpoints of progression-free survival (PFS) as assessed by the investigator and ICR per RECIST v1.1 and im-RECIST. | Every 6 weeks for 6 months, then every 3 months for a maximum of 84 months | 
| Overall survival | Evaluate overall survival (OS) by investigator | Every 6 weeks for 6 months, then every 3 months for a maximum of 84 months |