A first-in-human clinical trial in adult patients with advanced non-small cell lung cancer of a personalised therapy targeting specific mutations that occur in all cancer cells within a single patient

Prior treatment

• Patients with known 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
• 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
• Patients who have undergone major surgery in the previous 3 weeks
• Patients who have previously received any investigational cell or gene therapies
• Patients who have received any cytotoxic chemotherapy or anti-angiogenesis agent within the 3 weeks prior to tissue and blood procurement
• Patients who have received a live vaccination within the 28 days prior to lymphodepletion
• Patients who have received any cytotoxic chemotherapy within the 3 weeks prior to lymphodepletion
• Patients requiring regular treatment with steroids at a dose higher than prednisolone 10 mg/day (or equivalent)

Other illness

• 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 with evidence of disease progression at the first scan after commencing standard first line therapy (i.e. primary refractory disease), unless responsive to subsequent lines of therapy. Patients who are refractory to pembrolizumab monotherapy are not excluded
• Patients with a confirmed history of allergic reactions to amphotericin b, penicillin and/or streptomycin
• Patients with hepatitis B or C, human immunodeficiency virus infection (HIV1/2), syphilis or HTLVI/II infection
• Patients with an active infection requiring antibiotics
• Patients with active, known, or suspected autoimmune disease requiring immunosuppressive treatments
• Patients with superior vena cava syndrome
• Patients with a history of immune mediated central nervous system toxicity that was caused by, or suspected to be caused by, immunotherapy

Lab values

• Patients for whom there is documented evidence of an actionable tumour driver oncogene mutation (EGFR, ALK or ROS-1) at the time of initial screening. Patients who have progressed on standard targeted therapies, or for whom no approved targeted treatments are available, are not excluded
• 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. Additionally, the following criteria apply: a. Patients with a Left Ventricular Ejection Fraction (LVEF) < 45%. b. Patients with a history of coronary revascularization. c. Patients with clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, 2° or 3° heart block. d. Patients with a forced expiratory volume in one second (FEV1) of less than or equal to 60% of their predicted normal

Other

• Patients who are pregnant or breastfeeding
• Patients with contraindications for cyclophosphamide, fludarabine and IL-2 at per protocol doses
• Patients with any contraindications for pembrolizumab
• Patients who have never smoked (defined as having smoked < 100 cigarettes in their lifetime, per WHO criteria)

• Patient must be between 18 and 75 years old at the screening visit
• Anticipated life expectancy ≥ 6 months at the time of tissue procurement
• Patients must have locally advanced unresectable or metastatic NSCLC 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
• Patients must have measurable disease according to RECIST v1.1 criteria prior to lymphodepletion
• 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)
• 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
• In addition to the need for highly effective contraception as outlined in Inclusion Criterion 8 above, female patients in Cohort B of childbearing potential must agree to use effective contraception during treatment with pembrolizumab and for at least 4 months after the last dose of pembrolizumab. Patients must also agree to provide a serum or urine pregnancy test before each pembrolizumab administration during the treatment period in Cohort B
• Patient must have given written informed consent to participate in the study
• Patients must have histologically confirmed diagnosis of non-small cell lung cancer that is considered to be smoking-related
• 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 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 (without support of filgrastim (G-CSF)). 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 (< 3x ULN in Gilbert’s Syndrome). h. Creatinine clearance/estimated glomerular filtration rate (GFR) ≥ 50 mL/min
• 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
• To be eligible to enter this study for procurement, the patient must fall into one of the following groups: a. Patients with advanced stage (III-IV) NSCLC who have accessible sites of disease suitable for collection of adequate tissue for ATL001 manufacture prior to starting standard treatment. b. Patients with advanced stage (III-IV) NSCLC who have received or are receiving standard treatments and have accessible sites of residual 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