Study of Lifileucel (LN-144), Autologous Tumor Infiltrating Lymphocytes, in the Treatment of Patients With Metastatic Melanoma

Sponsor

Iovance Biotherapeutics, Inc. (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT02360579

Collaborator

(none)

178

Enrollment

Locations

Arms

111

Duration (Months)

3.1

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Melanoma	Biological: Lifileucel	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

178 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

Sep 1, 2015

Anticipated Primary Completion Date :

Jul 1, 2021

Anticipated Study Completion Date :

Dec 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1 Lifileucel (LN-144) without cryopreservation (Gen 1 infusion product) (Closed)	Biological: Lifileucel A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. After lymphodepletion, patients are infused with Lifileucel followed by IL-2. Other Names: LN - 144
Experimental: Cohort 2 Cryopreserved lifileucel (LN-144) (Gen 2 infusion product) (Closed)	Biological: Lifileucel A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. After lymphodepletion, patients are infused with Lifileucel followed by IL-2. Other Names: LN - 144
Experimental: Cohort 3 Retreatment cohort: patients from Cohort 1, Cohort 2 or Cohort 4 may rescreen for a second TIL regimen therapy if they meet all Inclusion and Exclusion Criteria (except exclusion criterion b).	Biological: Lifileucel A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. After lymphodepletion, patients are infused with Lifileucel followed by IL-2. Other Names: LN - 144
Experimental: Cohort 4 Cryopreserved lifileucel (LN-144) (Gen 2 infusion product)	Biological: Lifileucel A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. After lymphodepletion, patients are infused with Lifileucel followed by IL-2. Other Names: LN - 144

Outcome Measures

Primary Outcome Measures

Disease Assessment for Objective Response Rate [Every 6 weeks for 6 months, then every 3 months for a maximum of 54 months]
Evaluate the efficacy of LN-144 in patients with unresectable or metastatic melanoma using the objective response rate (ORR), as assessed by the Blinded Independent Review Committee (BIRC) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

Secondary Outcome Measures

Disease Assessment for Duration of Response [Every 6 weeks for 6 months, then every 3 months for a maximum of 54 months]
Evaluate the efficacy endpoints of duration of response (DOR) by the BIRC and by the investigator per RECIST v1.1
Disease Assessment for Disease Control Rate [Every 6 weeks for 6 months, then every 3 months for a maximum of 54 months]
Evaluate the efficacy endpoints of disease control rate (DCR) as assessed by the BIRC and by the investigator per RECIST v1.1
Disease Assessment for Progression-Free Survival [Every 6 weeks for 6 months, then every 3 months for a maximum of 54 months]
Evaluate the efficacy endpoints of progression-free survival (PFS) as assessed by the BIRC and by the investigator per RECIST v1.1
Overall Survival [Until death or up to 60 months]
Evaluate overall survival (OS) and objective response rate (ORR) by the investigator
Adverse Events [Maximum 60 months]
Incidence rate of treatment-emergent adverse events (AEs) and serious AEs by severity and relationship to Lifileucel (LN-144).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Criteria for Inclusion:

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

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)
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
Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and an estimated life expectancy of ≥ 3 months
In the opinion of the Investigator, patients must be able to complete all study-required procedures
Patients must have the following hematologic parameters:

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

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

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

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

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

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
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:

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
Patients who have received an organ allograft or prior cell transfer therapy
Patients with melanoma of uveal/ocular origin
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

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

Patients who are on chronic systemic steroid therapy for any reason
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
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 documented forced expiratory volume in 1 second (FEV1) of ≤ 60%
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)
Patients who have received a live or attenuated vaccine within 28 days of beginning the NMA-LD preconditioning regimen
Patients who are pregnant or breastfeeding
Patients whose cancer requires immediate attention or who would otherwise suffer a disadvantage by participating in this trial
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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California San Diego Moores Cancer Center	La Jolla	California	United States	92093
2	The Angeles Clinic and Research Institute	Los Angeles	California	United States	90048
3	University of California Los Angeles - David Geffen School of Medicine - Westwood Rheumatology	Los Angeles	California	United States	90095
4	California Pacific Medical Center	San Francisco	California	United States	94115
5	University of Colorado Cancer Center	Aurora	Colorado	United States	80049
6	Yale Cancer Center	New Haven	Connecticut	United States	06510
7	Mount Sinai Comprehensive Cancer Center	Miami Beach	Florida	United States	33140
8	University of Miami	Miami	Florida	United States	33136
9	University of Florida Health Cancer Center	Orlando	Florida	United States	32806
10	University of South Florida H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612
11	Indiana University	Indianapolis	Indiana	United States	46202-5116
12	James Graham Brown Cancer Center	Louisville	Kentucky	United States	40202
13	University of Minnesota, Masonic Cancer Center	Minneapolis	Minnesota	United States	55455
14	Atlantic Health System	Morristown	New Jersey	United States	07960
15	Rutgers University	New Brunswick	New Jersey	United States
16	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
17	New York University Langone Medical Center	New York	New York	United States	10016
18	Providence Cancer Center Oncology and Hematology Care Clinic	Portland	Oregon	United States	97213
19	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19701
20	University of Pittsburgh Medical Center - Hillman Cancer Center	Pittsburgh	Pennsylvania	United States	15232
21	Virginia Commonwealth University	Richmond	Virginia	United States	23298
22	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
23	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
24	Gustave Roussy Cancer Campus	Villejuif Cedex	Ile-de-france	France	94805
25	Hôpital Dupuytren	Limoges cedex	Limousin	France	87042
26	Centre Léon Bérard	Lyon	Rhone-alpes	France	69008
27	Centre Hospitalier Lyon Sud	Pierre-Bénite	Rhone-alpes	France	69495
28	Universitaetsklinikum Heidelberg	Heidelberg	Baden-wuerttemberg	Germany	69120
29	Universitaetsklinikum Tuebingen (UKT) - Suedwestdeutschen Tumorzentrum - Zentrum für Neuroonkologie	Tübingen	Baden-wuerttemberg	Germany	72076
30	Universitätsklinikum Erlangen	Erlangen	Bayern	Germany	91052
31	Klinikum Rechts der Isar der Technischen Universität München	München	Bayern	Germany	81675
32	Universitätsklinikum Halle	Halle/Saale	Sachsen-anhalt	Germany	06120
33	Universitätsklinikum Carl Gustav Carus	Dresden	Sachsen	Germany
34	Universitätsklinikum Leipzig	Leipzig	Sachsen	Germany	4103
35	Universitätsklinikum Schleswig-Holstein - Campus Lübeck	Lübeck	Schleswig-holstein	Germany	23538
36	Universitätsklinikum Würzburg	Würzburg		Germany	97080
37	Szegedi Tudomanyegyetem Szent-Györgyi Albert Klinikai Központ	Szeged	Csongrad	Hungary	6720
38	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori	Meldola	Forli-cesena	Italy	47014
39	Centro di Riferimento Oncologico di Aviano	Aviano	Pordenone	Italy	33081
40	Istituto di Candiolo - Fondazione del Piemonte per l'Oncologia	Candiolo	Torino	Italy	10060
41	Istituto Europeo di Oncologia	Milano		Italy	20141
42	Istituto Nazionale Tumori IRCCS Fondazione Pascale	Napoli		Italy	80131
43	Clínica Universidad de Navarra	Pamplona	Navarra	Spain	31008
44	Hospital Universitari Vall d'Hebrón	Barcelona		Spain	08035
45	Hospital Clinic de Barcelona	Barcelona		Spain	08036
46	Institut Català d'Oncologia	Barcelona		Spain	08907
47	Hospital General Universitario Gregorio Marañon	Madrid		Spain	28007
48	Hospital 12 de Octubre	Madrid		Spain	28041
49	HM Centro Integral Oncológico Clara Campal	Madrid		Spain	28050
50	Hospital Universitario Quirónsalud Madrid	Madrid		Spain	28233
51	Consorci Hospital General Universitari de València	Valencia		Spain
52	Inselspital	Bern		Switzerland	3010
53	Centre Hospitalier Universitaire Vaudois Lausanne - Centre Pluridisciplinaire d'Oncologie	Lausanne		Switzerland
54	Royal Marsden NHS Trust	London	England	United Kingdom	SW3 6JJ
55	Beatson West of Scotland Cancer Centre	Glasgow	Scotland	United Kingdom	G12 0YN
56	Addenbrooke's Hospital	Cambridge		United Kingdom	CB2 0QQ
57	Sarah Cannon Research Institute London	London		United Kingdom	W1G 6AD