Clinical trial NCT02360579: Study of Lifileucel (LN-144), Autologous Tumor Infiltrating Lymphocytes, in the Treatment of Patients With Metastatic Melanoma
Official title: A Phase 2, Multicenter Study to Assess the Efficacy and Safety of Autologous Tumor Infiltrating Lymphocytes (LN-144) for Treatment of Patients With Metastatic Melanoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metastatic Melanoma
Keywords: Autologous Adoptive Cell Transfer
Autologous Adoptive Cell Therapy
Cellular Immuno-therapy
Cell Therapy
Tumor Infiltrating Lymphocytes
TIL
LN-144
IL-2
Melanoma
Lifileucel
Lead sponsor: Iovance Biotherapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2015-02-10
Enrollment: 178
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Disease Assessment for Objective Response Rate
timeFrame: Every 6 weeks for 6 months, then every 3 months for a maximum of 60 months
Secondary outcomes:
measure: Disease Assessment for Duration of Response
timeFrame: Every 6 weeks for 6 months, then every 3 months for a maximum of 60 months
measure: Disease Assessment for Disease Control Rate
timeFrame: Every 6 weeks for 6 months, then every 3 months for a maximum of 60 months
measure: Disease Assessment for Progression-Free Survival
timeFrame: Every 6 weeks for 6 months, then every 3 months for a maximum of 60 months
measure: Overall Survival
timeFrame: Until death or up to 60 months
measure: Adverse Events
timeFrame: Maximum 60 months
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California San Diego Moores Cancer Center
state: California
city: Los Angeles
country: United States
facility: The Angeles Clinic and Research Institute
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles - David Geffen School of Medicine - Westwood Rheumatology
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Miami Beach
country: United States
facility: Mount Sinai Comprehensive Cancer Center
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Orlando
country: United States
facility: University of Florida Health Cancer Center
state: Florida
city: Tampa
country: United States
facility: University of South Florida H. Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Louisville
country: United States
facility: James Graham Brown Cancer Center
state: Kentucky
city: Minneapolis
country: United States
facility: University of Minnesota, Masonic Cancer Center
state: Minnesota
city: Morristown
country: United States
facility: Atlantic Health System
state: New Jersey
city: New Brunswick
country: United States
facility: Rutgers University
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: New York University Langone Medical Center
state: New York
city: Portland
country: United States
facility: Providence Cancer Center Oncology and Hematology Care Clinic
state: Oregon
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center - Hillman Cancer Center
state: Pennsylvania
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Villejuif Cedex
country: France
facility: Gustave Roussy Cancer Campus
state: Ile-de-france
city: Limoges cedex
country: France
facility: Hôpital Dupuytren
state: Limousin
city: Lyon
country: France
facility: Centre Léon Bérard
state: Rhone-alpes
city: Pierre-Bénite
country: France
facility: Centre Hospitalier Lyon Sud
state: Rhone-alpes
city: Heidelberg
country: Germany
facility: Universitaetsklinikum Heidelberg
state: Baden-wuerttemberg
city: Tübingen
country: Germany
facility: Universitaetsklinikum Tuebingen (UKT) - Suedwestdeutschen Tumorzentrum - Zentrum für Neuroonkologie
state: Baden-wuerttemberg
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen
state: Bayern
city: München
country: Germany
facility: Klinikum Rechts der Isar der Technischen Universität München
state: Bayern
city: Halle/Saale
country: Germany
facility: Universitätsklinikum Halle
state: Sachsen-anhalt
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus
state: Sachsen
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
state: Sachsen
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein - Campus Lübeck
state: Schleswig-holstein
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
city: Szeged
country: Hungary
facility: Szegedi Tudomanyegyetem Szent-Györgyi Albert Klinikai Központ
state: Csongrad
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
state: Forli-cesena
city: Aviano
country: Italy
facility: Centro di Riferimento Oncologico di Aviano
state: Pordenone
city: Candiolo
country: Italy
facility: Istituto di Candiolo - Fondazione del Piemonte per l'Oncologia
state: Torino
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori IRCCS Fondazione Pascale
city: Pamplona
country: Spain
facility: Clínica Universidad de Navarra
state: Navarra
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebrón
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Barcelona
country: Spain
facility: Institut Català d'Oncologia
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon
city: Madrid
country: Spain
facility: Hospital 12 de Octubre
city: Madrid
country: Spain
facility: HM Centro Integral Oncológico Clara Campal
city: Madrid
country: Spain
facility: Hospital Universitario Quirónsalud Madrid
city: Valencia
country: Spain
facility: Consorci Hospital General Universitari de València
city: Bern
country: Switzerland
facility: Inselspital
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois Lausanne - Centre Pluridisciplinaire d'Oncologie
city: London
country: United Kingdom
facility: Royal Marsden NHS Trust
state: England
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
state: Scotland
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: London
country: United Kingdom
facility: Sarah Cannon Research Institute London
Study officials:
affiliation: Iovance Biotherapeutics, Inc.
name: Iovance Biotherapeutics Medical Monitor
role: STUDY_CHAIR
References:
citation: Sarnaik AA, Hamid O, Khushalani NI, Lewis KD, Medina T, Kluger HM, Thomas SS, Domingo-Musibay E, Pavlick AC, Whitman ED, Martin-Algarra S, Corrie P, Curti BD, Olah J, Lutzky J, Weber JS, Larkin JMG, Shi W, Takamura T, Jagasia M, Qin H, Wu X, Chartier C, Graf Finckenstein F, Fardis M, Kirkwood JM, Chesney JA. Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma. J Clin Oncol. 2021 Aug 20;39(24):2656-2666. doi: 10.1200/JCO.21.00612. Epub 2021 May 12.