Lifileucel with Reduced Dose Fludarabine/Cyclophosphamide Lymphodepletion and Interleukin-2 for the Treatment of Patients with Unresectable or Metastatic Melanoma

Inclusion Criteria

• Ability of participant OR Legally Authorized Representative (LAR) to understand this study, and participant or LAR willingness to sign a written informed consent
• Patients must agree to abide by the study restrictions and return to the site for the required assessments, including the OS follow-up period
• In the opinion of the investigator, patients must be able to complete all study- required procedures
• Males and females age ≥ 18 years Enrollment of patients ≥ 70 years of age may be allowed at principal investigator discretion
• Life expectancy of ≥ 3 months
• Eastern Cooperative Oncology Group (ECOG) performance status 0 - 1
• At least one measurable target lesion, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 * Lesions in previously irradiated areas (or other local therapy) should not be selected as target lesions, unless treatment was ≥ 3 months prior to Screening, and there has been demonstrated disease progression in that lesion
• Women of childbearing potential must have a negative serum pregnancy test 48 hours prior to initiating treatment
• Patients with unresectable or metastatic melanoma (stage IIIc or stage IV)
• Patients must have progressed following 1-3 prior systemic therapy including a programmed cell death protein-1 (PD-1) blocking antibody; and if proto-oncogene B-Raf (BRAF) V600 mutation positive, a BRAF inhibitor or BRAF inhibitor in combination mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor
• Prior to study enrollment, documentation of radiological disease progression after the most recent therapy
• At least one resectable lesion (or aggregate of lesions resected) of a minimum 1.5 cm in diameter post-resection to generate TIL; surgical removal with minimal morbidity (defined as any procedure for which expected hospitalization is ≤ 3 days)
• Absolute neutrophil count ≥ 0.5 K/UL
• Platelets ≥ 30 K/UL
• Hemoglobin ≥ 8 g/dL
• Serum alanine transaminase (ALT)/serum glutamic-pyruvic transaminase (SGPT) and aspartate transaminase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) ≤ 3 times the upper limit of normal (ULN); patients with liver metastasis ≤ 5 times ULN
• Estimated creatinine clearance (eCrCl) ≥ 40 mL/min using the Cockcroft- Gault formula
• Total bilirubin ≤ 2 mg/dL. Patients with Gilbert’s syndrome must have a total bilirubin ≤ 3 mg/dL
• Patients must have recovered from all prior therapy-related adverse events (AEs) to ≤ grade 1 (per Common Terminology Criteria for Adverse Events [CTCAE] version [v] 5.0), except for alopecia or vitiligo, prior to enrollment (tumor resection) * Patients with documented ≥ grade 2 diarrhea or colitis because of previous treatment with immune checkpoint inhibitor(s) must have been asymptomatic for at least 6 months and/or had a normal colonoscopy post-immune checkpoint inhibitor treatment, by visual assessment, prior to tumor resection
• Patients with immunotherapy-related endocrinopathies stable for at least 6 weeks (eg, hypothyroidism), and controlled with hormonal replacement (non-corticosteroids), are allowed
• Patients must have a washout period of ≥ 28 days from prior anticancer therapy(ies) to the start of the planned reduced dose lymphodepletion (RDL) preconditioning regimen: * Targeted therapy: MEK/BRAF or other targeted agents * Chemotherapy * Immunotherapy: anti-CTLA-4/anti-PD-1, other monoclonal antibodies (mAb), or vaccine * Palliative radiation therapy is permitted so long as it does not involve lesions being selected for TIL, or as target or non-target lesions. Washout is not required if all related toxicities have resolved to ≤ grade 1 as per CTCAE v 5.0
• Women of child-bearing potential and men with partners of child-bearing potential must agree to practice sexual abstinence or to use the forms of contraception listed in Child-Bearing Potential/Pregnancy section for the duration of study participation and for 12 months following the last dose of IL-2 or until the first dose of the next anti-cancer therapy, whichever occurs first

Exclusion Criteria

• Simultaneously enrolled in any therapeutic clinical trial
• Current or anticipating use of other anti-neoplastic or investigational agents while participating in this study
• Diagnosed with a psychiatric illness or is in a social situation that would limit compliance with study requirements
• Is pregnant or breastfeeding
• Active grade 3 (per the National Cancer Institute [NCI] CTCAE, version 5.0 ) or higher viral, bacterial, or fungal infection within 2 weeks prior to the first dose of study treatment
• Patients who have active medical illness(es) that would pose increased risk for study participation, including active systemic infections requiring systemic antibiotics, coagulation disorders, or other active major medical illnesses of the cardiovascular, respiratory, or immune system
• Patients who have been shown to be BRAF mutation positive (V600), but have not received prior systemic therapy with a BRAF inhibitor alone or a BRAF inhibitor in combination with a MEK inhibitor
• Patients who have received an organ allograft or prior cell transfer therapy
• Patients with melanoma of uveal/ocular origin
• Patients who have a history of hypersensitivity to any component or excipient of Lifileucel or other study drugs
• Patients who have any form of primary immunodeficiency (such as severe combined immunodeficiency disease [SCID] and acquired immunodeficiency syndrome [AIDS])
• Patients who have a left ventricular ejection fraction (LVEF) < 45% or New York Heart Association (NYHA) functional classification class > 1 Patients ≥ 60 years of age and who have a history of ischemic heart disease, chest pain, or clinically significant atrial and/or ventricular arrhythmias must have a cardiac stress test. Patients with any irreversible wall movement abnormalities are excluded
• Patients who have a documented forced expiratory volume in 1 second (FEV1) of ≤ 60%
• Patients who have had another primary malignancy within the previous 3 years (except for carcinoma in situ of the breast, cervix, or bladder; localized prostate cancer; and non-melanoma skin cancer that has been adequately treated)
• Patients who have received a live or attenuated vaccine within 28 days of beginning the RDL preconditioning regimen
• Patients whose cancer requires immediate attention or who would otherwise suffer a disadvantage by participating in this trial
• Patients with symptomatic and/or untreated brain metastases (of any size and any number) * Patients with definitively treated brain metastases may be considered for Enrollment, and must be stable for ≥ 14 days prior to beginning the RD-LD preconditioning regimen