A study to find out if an investigational product, called LN-144 (alsocalled tumour infiltrating lymphocytes) is safe and beneficial in thetreatment of patients with metastatic melanoma

Phase 1

• Conditions: Metastatic melanoma; MedDRA version: 20.0Level: PTClassification code 10027480Term: Metastatic malignant melanomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2017-000760-15-ES
• Lead Sponsor: Iovance Biotherapeutics, Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2017-10-02
• Last Update Posted: 12 March 2018

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

a. Patients with unresectable metastatic melanoma (Stage IIIc or
Stage IV) who progressed following =1 line of prior systemic therapy, including immune checkpoint inhibitor (e.g., anti-PD-1), and if BRAF mutation-positive, after BRAF inhibitor systemic therapy
- At least one measurable target lesion as defined by RECIST version 1.1. Lesions in previously irradiated areas should not be selected as target lesion, unless treatment was >= 3 months prior, and there has been demonstrated progression in the lesion
- At least one resectable lesion to generate TILs of a minimum 1.5 cm in diameter post-resection

b. Patients must be >= 18 years and <= 70 years of age at the time of consent. Enrollment of patients > 70 years of age may be allowed after consultation with the Medical Monitor

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

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

e. Patients of childbearing potential or their partners of childbearing potential must be willing to practice an approved method of birth control during treatment and for 4 months after receiving all protocol related therapy

f. Patients must have the following hematologic parameters:
• absolute neutrophil count (ANC) > 1000/mm3
• hemoglobin > 9.0 g/dL
• platelet count > 100,000/mm3

g. Patients must have adequate organ function:
- serum ALT/SGPT and AST/SGOT < 3 times the upper limit of normal ULN), patients with liver metastasis < 5 times ULN
- an estimated creatinine clearance (eCCr) >= 40 mL/min using the
Cockcroft Gault formula at Screening
- total bilirubin <= 2 mg/dL
o Patients with Gilbert's Syndrome must have a total bilirubin < 3 mg/dL

h. Patients must be seronegative for the HIV antibody, hepatitis B
antigen, and hepatitis C antibody or antigen

i. Patients must have recovered from all prior therapy-related AEs to Grade 1 or less (per CTCAE v4.03), except for alopecia or vitiligo, prior to enrollment (tumor resection)
- A minimal washout period of 4 weeks is required prior to
enrollment (tumor resection)
- Palliative radiation therapy is permitted between biopsy and
nonmyeloablative lymphodepletion if it does not involve lesions being selected as target or non-target lesions
- Patients may undergo pre-planned procedures if within 2-3 weeks prior to the start of nonmyeloablative lymphodepletion

j. Patients with documented Grade 2 or greater 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 start of nonmyeloablative lymphodepletion

k. Patients 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

l. Patients have provided written for use and disclosure of
protected health information
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 55
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 5

Exclusion Criteria

a. Patients with melanoma of uveal/ocular origin

b. Patients who have received prior cell transfer therapy that included a nonmyeloablative or myeloablative chemotherapy regimen (not applicable for patients in the retreatment Cohort 3)

c. Patients with symptomatic and/or untreated brain metastases (of any size and any number)
- Patients with definitively treated brain metastases, will be considered for enrollment after discussion with Medical Monitor, and must be stable for 2-4 weeks prior to the start of treatment nonmyeloablative lymphodepletion)

d. Patients who are pregnant or breastfeeding

e. Patients who are on a systemic steroid therapy at a dose of > 10 mg of prednisone or equivalent per day
- A short course of higher dose steroid therapy is allowed in cases of exacerbation of known disease or for treatments of new acute symptoms

f. Patients who have active medical illness(es) that in the opinion of the Investigator would pose increased risk for study participation, such as systemic infections requiring antibiotics, coagulation disorders or other active major medical illnesses of the cardiovascular, respiratory or immune system

g. Patients who have any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and AIDS)

h. Patients who have a history of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, or IL-2

i. Patients who have a left ventricular ejection fraction (LVEF) < 45% at Screening

j. Patients who have obstructive or restrictive pulmonary disease and have a documented FEV1 (forced expiratory volume in 1 second) of = 60%

k. 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)

l. Patients with known allergic reaction to antibiotics of aminoglycoside group (i.e. streptomycin, gentamicin)

m. Patients who have been shown to be BRAF mutation positive (V600), but have not received prior systemic therapy with a BRAF-directed kinase inhibitor

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To evaluate the efficacy of LN-144 in patients with metastatic<br>melanoma using the objective response rate (ORR);Secondary Objective: To further evaluate efficacy of LN-144 in patients with metastatic<br>melanoma such as complete response (CR) rate, duration of response<br>(DOR), disease control rate (DCR), progression-free survival (PFS), and<br>overall survival (OS)<br>To characterize the safety profile of LN-144 in patients with metastatic<br>melanoma;Primary end point(s): Objective response rate (ORR);Timepoint(s) of evaluation of this end point: After last patient in Cohort 2 reach the 6-month tumor assessment,<br>and final analysis at end of 2-year post-treatment follow up.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): Complete response (CR) rate, duration of response (DOR), disease<br>control rate (DCR), progression free survival (PFS) and overall survival (OS) per RECIST 1.1 criteria by independent and Investigator review<br><br>Incidence, severity, seriousness, relationship to study treatment,<br>and characteristics of treatment-emergent AEs (TEAEs), including AEs leading to early discontinuation from treatment or withdrawal from the study, and AEs resulting in deaths;Timepoint(s) of evaluation of this end point: After last patient in Cohort 2 reach the 6-month tumor assessment,<br>and final analysis at end of 2-year post-treatment follow up.