Prospective, interventional multicenter study evaluating adoptive cell therapy (ACT) via infusion of LN-144 (autologous TIL) followed by interleukin 2 (IL-2) after a nonmyeloablative lymphodepletion (NMA LD) preconditioning regimen.

Lifileucel is an autologous adoptive cell transfer therapy that utilizes a TIL manufacturing process, as originally developed by the NCI, for the treatment of patients with metastatic melanoma. The adoptive cell transfer therapy used in this study involves patients receiving a lymphocyte depleting preconditioning regimen, prior to infusion of autologous TIL, followed by the administration of a regimen of IL-2.

Patients must meet all of the following inclusion criteria to be eligible for participation in the study:

Criteria for Inclusion:

1. Patients with unresectable or metastatic melanoma (Stage IIIc or Stage IV)

2. Patients must have progressed following ≥ one 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 with mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor

3. At least one measurable target lesion, as defined by RECIST v1.1

   • 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 particular lesion

4. 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)

5. Patients must be ≥ 18 years of age at the time of consent. Enrollment of patients > 70 years of age may be allowed after consultation with the Medical Monitor

6. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and an estimated life expectancy of ≥ 3 months

7. In the opinion of the Investigator, patients must be able to complete all study-required procedures

8. Patients must have the following hematologic parameters:

   • Absolute neutrophil count (ANC) ≥ 1000/mm3
   • Hemoglobin (Hb) ≥ 9.0 g/dL
   • Platelet ≥ 100,000/mm3

9. Patients must have adequate organ function:

   • 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

10. Patients must have recovered from all prior therapy-related adverse events (AEs) to ≤ Grade 1 (per Common Terminology Criteria for Adverse Events [CTCAE] v4.03), except for alopecia or vitiligo, prior to Enrollment (tumor resection)

    • 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

11. Patients must have a washout period ≥ 28 days from prior anticancer therapy(ies) to the start of the planned NMA-LD preconditioning regimen:

    • Targeted therapy: MEK/BRAF or other targeted agent
    • Chemotherapy
    • Immunotherapy: anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)/anti-PD-1, other monoclonal antibody (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 v4.03

12. Patients of childbearing potential or their partners of childbearing potential 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 receiving the last protocol-related therapy

    • 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 (eg, calendar ovulation, symptothermal, post-ovulation methods) is not acceptable

13. 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 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

14. Patients have provided written authorization for use and disclosure of protected health information

Criteria for Exclusion:

Patients who meet any of the following criteria are not eligible for participation in this study:

1. 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

2. Patients who have received an organ allograft or prior cell transfer therapy

3. Patients with melanoma of uveal/ocular origin

4. 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)
   • Antibiotics (ABX) of the aminoglycoside group (ie, 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

5. 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 NMA LD preconditioning regimen

6. Patients who are on chronic systemic steroid therapy for any reason

7. Patients who have active medical illness(es) that would pose increased risk for study participation, including: active systemic infections requiring systemic ABX, coagulation disorders, or other active major medical illnesses of the cardiovascular, respiratory, or immune system

8. Patients who have any form of primary immunodeficiency (such as severe combined immunodeficiency disease [SCID] and acquired immunodeficiency syndrome [AIDS])

9. 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

10. Patients who have a documented forced expiratory volume in 1 second (FEV1) of ≤ 60%

11. Patients who have had another primary malignancy within the previous 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)

12. Patients who have received a live or attenuated vaccine within 28 days of beginning the NMA-LD preconditioning regimen

13. Patients who are pregnant or breastfeeding

14. Patients whose cancer requires immediate attention or who would otherwise suffer a disadvantage by participating in this trial

15. Patients protected by the following constraints:

    • Hospitalized persons without consent or persons deprived of liberty because of a judiciary or administrative decision
    • Adult persons with a legal protection measure or persons who cannot express their consent
    • Patients in emergency situations who cannot consent to participate in the trial