E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated | Metastatic or recurrent melanoma | |
E.1.1.1 | Medical condition in easily understood language | |
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 | E.1.2 | Level | PT | E.1.2 | Classification code | 10025650 | E.1.2 | Term | Malignant melanoma | E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 | E.1.2 | Level | LLT | E.1.2 | Classification code | 10025651 | E.1.2 | Term | Malignant melanoma excision | E.1.2 | System Organ Class | 100000004865 | |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 | E.1.2 | Level | PT | E.1.2 | Classification code | 10025652 | E.1.2 | Term | Malignant melanoma in situ | E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 | E.1.2 | Level | PT | E.1.2 | Classification code | 10025670 | E.1.2 | Term | Malignant melanoma stage III | E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 | E.1.2 | Level | PT | E.1.2 | Classification code | 10025671 | E.1.2 | Term | Malignant melanoma stage IV | E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 | E.1.2 | Level | LLT | E.1.2 | Classification code | 10053571 | E.1.2 | Term | Melanoma | E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 | E.1.2 | Level | LLT | E.1.2 | Classification code | 10027148 | E.1.2 | Term | Melanoma in situ | E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 | E.1.2 | Level | LLT | E.1.2 | Classification code | 10027150 | E.1.2 | Term | Melanoma malignant | E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 | E.1.2 | Level | PT | E.1.2 | Classification code | 10066600 | E.1.2 | Term | Melanoma recurrent | E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 | E.1.2 | Level | PT | E.1.2 | Classification code | 10027480 | E.1.2 | Term | Metastatic malignant melanoma | E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 | E.1.2 | Level | LLT | E.1.2 | Classification code | 10027481 | E.1.2 | Term | Metastatic melanoma | E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 | E.1.2 | Level | PT | E.1.2 | Classification code | 10029488 | E.1.2 | Term | Nodular melanoma | E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial | To assess the safety and tolerability of the investigational product after administration to patients. | |
E.2.2 | Secondary objectives of the trial | To evaluate if patients have a clinically meaningful response to the investigational product. | |
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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.4 | Principal 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.5.1 | Primary 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.5.1.1 | Timepoint(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.5.2 | Secondary 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.5.2.1 | Timepoint(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.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | 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.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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 | |
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 29 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 29 |