Multicenter Phase 2 Study to Evaluate the Efficacy and Safety of Autologous Tumor-Infiltrating Lymphocytes (LN-144) for the Treatment of Patients with Metastatic Melanoma

France, Germany, Hungary, Italy, Spain, Switzerland, United Kingdom, United States (ICTRP)

ICTRP Trial ID
EUCTR2017-000760-15 (ICTRP)

Official title (approved by ethics committee)
Étude de phase 2, multicentrique, visant à évaluer l’efficacité et la sécurité d’emploi de lymphocytes autologues infiltrant la tumeur (LN-144) pour le traitement de patients atteints d’un mélanome métastatique (BASEC)

Academic title
A Phase 2, Multicenter Study to Assess the Efficacy and Safety ofAutologous Tumor Infiltrating Lymphocytes (LN 144) for Treatment ofPatients with Metastatic Melanoma - Study of LN-144 in the Treatment of Patients with Metastatic Melanoma (ICTRP)

Public title
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 (ICTRP)

Disease under investigation
Metastatic melanoma
MedDRA version: 21.1Level: PTClassification code 10027480Term: Metastatic malignant melanomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps);Therapeutic area: Diseases [C] - Cancer [C04] (ICTRP)

Intervention under investigation

Product Name: LN-144
Product Code: LN-144
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: LN-144 (lifileucel)
CAS Number: Not avail.
Current Sponsor code: LN-144
Other descriptive name: LN-144
Concentration unit: Other
Concentration type: range
Concentration number: 1000000000-150000000000

Product Name: Fludarabine
Pharmaceutical Form: Concentrate for solution for injection/infusion
INN or Proposed INN: FLUDARABINE PHOSPHATE
CAS Number: 75607-67-9
Current Sponsor code: FLUDARABINE PHOSPHATE
Other descriptive name: FLUDARABINE PHOSPHATE
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 25-

Trade Name: Cyclophosphamide
Product Name: Cyclophosphamide Injection
Pharmaceutical Form: Powder for solution for injection
INN or Proposed INN: Cyclophosphamide
CAS Number: 6055-19-2
Current Sponsor code: Cyclophosphamide
Other descriptive name: CYCLOPHOSPHAMIDE MONOHYDRATE
Concentration unit: g gram(s)
Concentration type: equal
Concentration number: 1-

Trade Name: Proleukin
Product Name: Proleukin
Pharmaceutical Form: Powder for solution for injection/infusion
INN or Proposed INN: Proleukin
CAS Number: 110942-02-4
Other descriptive name: ALDESLEUKIN
Concentration unit: IU international unit(s)
Concentration type: equal
Concentration number: 22000000-

Product Name: Fludarabine
Pharmaceutical Form: Lyophilisate for solution for injection
INN or Proposed INN: FLUDARABINE PHOSPHATE
CAS Number: 75607-67-9
Other descriptive name: FLUDARABINE PHOSPHATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-

Trade Name: Proleukin
Product Name: Aldesleukin
Product Code: L03A C01
Pharmaceutical Form: Powder for solution for injection/infusion
INN or Proposed INN: Proleukin
CAS Number: 110942- (ICTRP)

Type of trial
Interventional clinical trial of medicinal product (ICTRP)

Trial design
Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no (ICTRP)

Inclusion/Exclusion criteria
Gender:
Female: yes
Male: yes

Inclusion criteria:
a. Patients with unresectable metastatic or melanoma (Stage IIIc or
Stage IV)

b. Patients must have progressed following = 1 prior systemic therapy including a PD-1 blocking antibody; and if BRAF V600 mutation-positive, a BRAF inhibitor or BRAF inhibitor in combination with MEK inhibitor

c. Prior to study Enrollment, documentation of radiological disease progression after the most recent therapy

d. 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
If a lesion is partially resected to generate TIL, and remains visible on the Baseline scan after surgery, then the partially resected lesion can be used for RECIST v1.1 response assessment, but only as a non-target lesion

e. 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)

f. 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

g. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix 2) and an estimated life expectancy of = 3 months

h. In the opinion of the Investigator, patients must be able to complete all studyrequired procedures

i. Patients must have the following hematologic parameters:
? Absolute neutrophil count (ANC) = 1000/mm3
? Hemoglobin (Hb) = 9.0 g/dL
? Platelet = 100,000/mm3
Note: Transfusions or growth factors are not allowed 28 days prior to signing the informed consent form (ICF) and continuing through the Screening Period

j. 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

k.Patients must have recovered from all prior therapy-related 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
? Patients with immunotherapy-related endocrinopathies stable for at least 6 weeks (eg, hypothyroidism), and controlled with hormonal replacement (non-corticosteroids), are allowed

l. Patients must have a washout period of = 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-CTLA-4/anti-PD-1, other mAb, or vaccine
? Palliative radiation therapy is permitted so long as it does not involve lesions being selected for TIL, or as target or n (ICTRP)

Exclusion criteria:
a. 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
b. Patients who have received an organ allograft or prior cell transfer therapy
c. Patients with melanoma of uveal/ocular origin
d. 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 DMSO, HSA, IL-2, and dextran-40
e. 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
f. Patients who are on chronic systemic steroid therapy for any reason
g. 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
h. Patients who have = Grade 2 hemorrhage within 14 days prior to
Enrollment (tumor resection)
i. Patients who are seropositive for any of the following:
? Human immunodeficiency virus (HIV)-1 or HIV-2 antibodies
? Hepatitis B antigen (HBsAg), hepatitis B core antibody (anti-HBc antibody),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
? Positive herpes simplex virus (HSV)-1 and HSV-2 IgM serologyor 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 preconditioning regimen
j. Patients who have any form of primary immunodeficiency (such as severe combined immunodeficiency disease [SCID] and acquired immunodeficiency syndrome [AIDS])
k. 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
l. Patients who have a documented forced expiratory volume in 1 second (FEV1) of = 60%
m. 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)
n. Patients who have received a live or attenuated vaccine within 28 days of beginning the NMA-LD preconditioning regimen
o. Patients who are pregnant or breastfeeding
p. Patients whose cancer requires immediate

Primary and secondary end points
Main Objective: Evaluate the efficacy of LN-144 in patients with unresectable or metastatic melanoma using the ORR, as assessed by the IRC per RECIST v1.1;Secondary Objective: ? Evaluate the efficacy endpoints of duration of response (DOR), disease control rate (DCR), and PFS, as assessed by the IRC per RECIST v1.1
? Further evaluate efficacy of LN-144 in patients with metastatic unresectable or melanoma by assessing ORR, DOR, DCR, and PFS, as assessed by the Investigator per RECIST v1.1
? Evaluate OS
? Characterize the safety profile of LN-144 in patients with unresectable or metastatic melanoma;Primary end point(s): ORR, as assessed by the IRC per RECIST v1.1;Timepoint(s) of evaluation of this end point: Every 6 weeks for 6 months, then every 3 months for a maximum of 54 months (ICTRP)

Secondary end point(s): ?The DOR, DCR, and PFS per RECIST v1.1 as assessed by IRC
?The ORR, DOR, DCR, and PFS, per RECIST v1.1 as assessed by the Investigator
?OS
?Incidence, severity, seriousness, relationship to study treatment, and characteristics of treatment-emergent adverse events (TEAEs), including AEs leading to early discontinuation from treatment or withdrawal from the Response Assessment Period study follow-up, and AEs resulting in deaths;Timepoint(s) of evaluation of this end point: Every 6 weeks for 6 months, then every 3 months for a maximum of 54 months;
OS: Time Frame: Until death or up to 60 months;
adverse events: Time Frame: Maximum 60 months (ICTRP)

Registration date
14.09.2017 (ICTRP)

Incorporation of the first participant
06.12.2018 (ICTRP)

Secondary sponsors
not available

Additional contacts
Tina Niazi, c14401.melanoma@iovance.com, +14156406956, Iovance Biotherapeutics, Inc. (ICTRP)

Secondary trial IDs
C-144-01, NCT02360579, 2017-000760-15-GB (ICTRP)

Results-Individual Participant Data (IPD)
not available

Further information on the trial
https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-000760-15 (ICTRP)