Lifileucel (LN-144) for the Treatment of Patients with Non-uveal Melanoma that has Spread to the Brain

Inclusion Criteria

• Must have a confirmed diagnosis of metastatic non-uveal melanoma
• At least one (1) intracranial lesion measuring 5-30mm visible on gadolinium-enhanced MRI to be used as target lesion defined in mRECIST. Multiple intracranial lesions are allowed as long as all lesions are 30mm in size or less
• Subjects must be free of neurologic signs and symptoms related to metastatic brain lesions and must not have required or received systemic corticosteroid therapy > 10mg prednisone equivalent in the 10 days prior to beginning protocol therapy
• Must have received prior anti-PD-1 (with or without anti-CTLA-4) for metastatic melanoma with radiographic and/or pathologic progression of disease. If there is a BRAF V600E/K mutation, the patient must have received prior BRAF+MEK targeted therapy with demonstrated progression of disease
• One (1) lesion at least 1.5cm in size (solitary or aggregate) available for TIL harvesting that has not undergone prior embolization or radiation therapy (RT) in prior 3 months unless subsequent growth is demonstrated (at least 0.5cm)
• Patients must be >= 18 years of age at the time of consent
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and an estimated life expectancy of >= 6 months in the opinion of the Investigator
• Absolute neutrophil count (ANC) >= 1000/mm^3 (independent of transfusion and/or blood product support for at least 3 days prior to laboratory testing)
• Hemoglobin (Hb) >= 8.0 g/dL (independent of transfusion and/or blood product support for at least 3 days prior to laboratory testing)
• Platelet >= 100,000/mm^3 (independent of transfusion and/or blood product support for at least 3 days prior to laboratory testing)
• Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 times the upper limit of normal (=< 3 × ULN); patients with liver metastasis =< 5 × ULN
• Estimated creatinine clearance (eCrCl) >= 40 mL/min using the Cockcroft-Gault formula at Screening
• Total bilirubin =< 2 mg/dL
• Patients with Gilbert’s syndrome must have a total bilirubin =< 3 mg/dL
• Patients must be seronegative for the following: * Human immunodeficiency virus (HIV)-1 or HIV-2 antibodies * Hepatitis B antigen (HBsAg), hepatitis B core antibody (anti- HBc), or hepatitis C antibody (HCV Ab). Patients with acute or chronic hepatitis infections may be enrolled if the viral load by polymerase chain reaction (PCR) is undetectable with/without active treatment * Syphilis (enzyme immunoassay [EIA] immunoglobulin [Ig] screen followed by Rapid Plasma Reagin [RPR] test or venereal disease research laboratory [VDRL] test if screen is positive) * Cytomegalovirus (CMV) PCR assay (IgM antibody titer if indicated); and Epstein-Barr virus (EBV) IgM or PCR assay indicating active infection * Herpes simplex virus (HSV)-1 and HSV-2 PCR assay
• Patients who are HSV PCR assay positive will need to receive appropriate treatment and become PCR assay negative prior to starting the NMA-LD pre-conditioning regimen
• Anyone with prior COVID-19 infection must be asymptomatic for >30 days prior to lymphodepletion
• Patients must have a washout period >= 28 days (or 5 half-lives for oral medications) from prior anti-cancer therapy(ies) to the start of the planned NMA-LD pre-conditioning regimen
• Palliative radiation therapy is permitted so long as it does not involve lesions being selected for TIL harvest or the lesion is the single site of intracranial metastasis such that response to LN-144 could not be assessed. Washout is not required if all related toxicities have resolved to =< Grade 1 as per Common Terminology Criteria for Adverse Events (CTCAE) v 5.0
• Patients must have recovered from all prior anti-cancer therapy-related adverse events (AEs) to =< Grade 1 (per CTCAE v 5.0), except for alopecia or vitiligo, prior to enrollment * Patients with documented >= Grade 2 diarrhea or colitis as a result 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 (e.g., hypothyroidism, hypopituitarism) stable for at least 6 weeks and controlled with hormonal replacement (including prednisone < 10 mg/day or equivalent) are allowed
• Previous surgical procedure(s) is/are permitted provided that wound healing has occurred, all complications have resolved, and at least 14 days have elapsed (for major operative procedures) prior to the tumor resection
• Patients of childbearing potential (or female partners of male participants) must be willing to take the appropriate precaution to avoid pregnancy or fathering a child for the duration of the study and practice an approved, highly effective method of birth control during treatment and for 12 months after their last dose of interleukin-2 (IL-2). Approved methods of birth control are as follows: * Combined (estrogen and progesterone containing) hormonal birth control associated with inhibition of ovulation: oral, intravaginal, transdermal * Progesterone-only hormonal birth control associated with inhibition of ovulation: oral, injectable, implantable * Intrauterine device (IUD) * Intrauterine hormone-releasing system (IUS) * Bilateral tubal occlusion * Vasectomized partner * True sexual abstinence when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar ovulation, symptothermal, post-ovulation methods) is not acceptable
• Patients (or legally authorized representative) must have the ability to understand the requirements of the study, have provided written informed consent as evidenced by signature on an informed consent form (ICF) approved by an Institutional Review Board/Independent Ethics Committee (IRB/IEC), and agree to abide by the study restrictions and return to the site for the required assessments, including the OS Follow-up Period

Exclusion Criteria

• Patients who have received an organ allograft or prior cell transfer therapy within the past 20 years that included a non-myeloablative or myeloablative chemotherapy regimen
• Patients who have a history of hypersensitivity to any component or excipient of LN-144 or other study drugs: * NMA-LD preconditioning regimen (cyclophosphamide, mesna, and fludarabine) * Proleukin (copyright), aldesleukin, IL-2 * Antibiotics of the aminoglycoside group (i.e., streptomycin, gentamicin); except those who are skin-test negative for gentamicin hypersensitivity * Any component of the LN-144 infusion product formulation including dimethyl sulfoxide (DMSO), human serum albumin (HSA), IL-2, and dextran-40
• Patients with symptomatic brain metastases (of any size and any number) that require corticosteroids of >=10 mg/day of prednisone or equivalent
• Patients who are on chronic systemic steroid therapy except for those requiring steroid therapy for management of adrenal insufficiency; these patients may receive no more than 10 mg of prednisone or its equivalent daily
• Patients who cannot receive gadolinium-enhanced MRI
• Patients who are pregnant or breastfeeding
• Patients who have active medical illness(es) that would pose increased risk for study participation, including: active systemic infections, coagulation disorders, or other active major medical illnesses of the cardiovascular, respiratory, or immune systems
• Patients who have received a live or attenuated vaccination within 28 days prior to the start of NMA-LD pre-conditioning regimen
• 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 obstructive or restrictive pulmonary disease and have a documented forced expiratory volume in 1 second (FEV1) of =< 60% of predicted normal: * If a patient is not able to perform reliable spirometry due to abnormal upper airway anatomy (i.e., tracheostomy), a 6-minute walk test may be used to assess pulmonary function * Patients who are unable to walk a distance of at least 80% predicted for age and sex or demonstrates evidence of hypoxia at any point during the test (SpO2 < 90%) are excluded
• Patients who have had another primary malignancy within the previous three (3) years (with the exception of carcinoma in situ of the breast, cervix, or bladder; localized prostate cancer; and non-melanoma skin cancer that has been adequately treated)
• Active, uncontrolled systemic infections, including COVID-19, within 30 days
• Participation in another clinical study with an investigational product within 21 days of the initiation of NMA-LD