Pilot Trial of Autologous Tumor Infiltrating Lymphocytes (LN-144) for Patients With Metastatic Uveal Melanoma

Inclusion Criteria:

Must have a confirmed diagnosis of metastatic Uveal Melanoma.
One (1) lesion at least 1.5cm in size (solitary or aggregate) available for TIL harvesting that has not undergone prior embolization or 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
Patients must have an estimated life expectancy of ≥ 6 months in the opinion of the Investigator.

Patients must have the following hematologic parameters:

Absolute neutrophil count (ANC) ≥ 1000/mm3
Hemoglobin (Hb) ≥ 9.0 g/dL
Platelet ≥ 100,000/mm^3 Note: Transfusions or growth factors are not allowed 28 days prior to signing the ICF and continuing through the Screening Period

Patients must have adequate organ function:

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 (Rapid Plasma Reagin [RPR] test or venereal disease research laboratory [VDRL] test)
Cytomegalovirus (CMV) IgM antibody titer or PCR assay; and Epstein-Barr virus (EBV) IgM or PCR assay indicating active infection
Herpes simplex virus (HSV)-1 and HSV-2 IgM serology or PCR assay
Patients who are HSV immunoglobulin M (IgM) or PCR assay positive will need to receive appropriate treatment and become IgM or 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 NMA-LD.
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, 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.

Patients must have recovered from all prior anti-cancer therapy-related adverse events (AEs) to ≤ Grade 1 (per Common Terminology Criteria for Adverse Events [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 inhibitortreatment, by visual assessment, prior to tumor resection.
Patients with immunotherapy-related endocrinopathies (e.g. hypothyroidism) stable for at least 6 weeks and controlled with hormonal replacement 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 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 (eg, 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 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 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®, aldesleukin, IL-2
Antibiotics (ABX) 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).

o Patients with definitively treated brain metastases may be considered for enrollment, if, prior to tumor resection for TIL, the patient is clinically stable for ≥ 14 days, there are no symptomatic brain lesions, and that the patient does not require ongoing corticosteroid treatment.

Patients who are on chronic systemic immunosuppressive 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. Transient use of steroids, e.g. in the perioperative period, is not an exclusion.
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 requiring systemic ABX, 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 a smoking history or signs or symptoms of 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 of surgery or NMA-LD. An uncomplicated bacterial UTI treated successfully with symptom resolution is not an exclusion.
Participation in another clinical study with an investigational product within 21 days of the initiation of NMA-LD.

Eligibility Designation for Lymphodepletion

Patients meeting eligibility criteria above between Day -21 and Day -8 prior to the planned initiation of lifileucel will be enrolled to the therapeutic portion of the protocol.

All patients' eligibility criteria, including repeating cardiopulmonary function tests as necessary, will be reassessed within several days prior to the scheduled lymphodepletion in all cases.

Prior to beginning the NMA-LD preparative regimen the following requirements must be met:

Patients must meet all eligibility criteria at the time of NMA-LD.
Full resolution of any active infection should be documented
Critical evaluation of changes in cardiovascular, respiratory, renal, coagulopathy, or immune problems and other major illnesses that may have developed or worsened must be documented
Patients with symptomatic, recurrent, pleural effusions that require drainage should not proceed to lymphodepletion without prior placement of a temporary in-dwelling pleural drain
All active medical issues must be addressed by Investigator or designee. Re-evaluation with additional imaging or testing may be required

Subsequent delays of lymphodepletion up to 14 days due to logistical issues such as production of lifileucel and/or major weather events will not constitute protocol violations and out of window assessments will not need to be repeated unless there is a change in clinical status.