Study of LN-145, Autologous Tumor Infiltrating Lymphocytes in the Treatment of Patients With Cervical Carcinoma

Sponsor

Iovance Biotherapeutics, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03108495

Collaborator

(none)

189

Enrollment

Locations

Arms

161.3

Anticipated Duration (Months)

4.7

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Prospective, multicenter, single-arm, open label, interventional study evaluating adoptive cell therapy (ACT) with autologous tumor infiltrating lymphocytes (TIL) infusion (LN-145) followed by IL-2 after a non-myeloablative (NMA) lymphodepletion preparative regimen for the treatment of patients with recurrent, metastatic, or persistent cervical carcinoma

Condition or Disease	Intervention/Treatment	Phase
Cervical Carcinoma	Biological: LN-145 Biological: LN-145 + pembrolizumab	Phase 2

Detailed Description

LN-145 is an adoptive cell transfer therapy that utilizes an autologous TIL manufacturing process, as originally developed by the NCI, for the treatment of patients with recurrent, metastatic, or persistent cervical carcinoma. The cell transfer therapy used in this study involves patients receiving a NMA lymphocyte depleting preparative regimen, followed by infusion of autologous TIL followed by the administration of a regimen of IL-2.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

189 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 2, Multicenter Study to Evaluate the Efficacy and Safety Using Autologous Tumor Infiltrating Lymphocytes (LN-145) in Patients With Recurrent, Metastatic or Persistent Cervical Carcinoma

Actual Study Start Date :

Jun 22, 2017

Anticipated Primary Completion Date :

Dec 1, 2025

Anticipated Study Completion Date :

Dec 1, 2030

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1 LN-145 monotherapy Post-NMA lymphodepletion, patients are infused with their autologous TIL (LN-145) followed by IL-2 administration.	Biological: LN-145 A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. Other Names: TIL, autologous tumor infiltrating lymphocytes
Experimental: Cohort 2 LN-145 monotherapy Patients previously treated with an antiprogrammed cell death protein-1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) checkpoint inhibitor: Post-NMA lymphodepletion, patients are infused with their autologous TIL (LN-145) followed by IL-2 administration.	Biological: LN-145 A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. Other Names: TIL, autologous tumor infiltrating lymphocytes
Experimental: Cohort 3 - Combination Arm (TIL + Pembrolizumab) - US Only Patients will be administered with pembrolizumab, followed by NMA lymphodepletion, then infused with their autologous TIL (LN-145) followed by pembrolizumab every 3 or 6 weeks post IL-2 administration up to 24 months.	Biological: LN-145 + pembrolizumab A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. The first dose of anti-PD-1 immunotherapy will be administered following tumor resection. Other Names: TIL, autologous tumor infiltrating lymphocytes; pembrolizumab (anti-PD-1 immunotherapy)
Experimental: Cohort 4 - Non-enrolling Cohort Cohort includes patient population not meeting inclusion criteria in cohort 1 and 2. Post-NMA lymphodepletion, patients are infused with their autologous TIL (LN-145) followed by IL-2 administration.	Biological: LN-145 A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. Other Names: TIL, autologous tumor infiltrating lymphocytes
Experimental: Cohort 5 Retreatment Cohort Patients who have been previously treated with LN-145 may be given a second treatment with TIL.	Biological: LN-145 A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. Other Names: TIL, autologous tumor infiltrating lymphocytes

Outcome Measures

Primary Outcome Measures

Cohort 1 and 2: Objective Response Rate [Up to 6 months]
To evaluate the efficacy of LN-145 in patients with recurrent, metastatic, or persistent cervical carcinoma based on the objective response rate (ORR) as assessed by the Independent Review Committee (IRC) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
Cohort 3: Adverse Events [Up to 60 months]
To characterize the safety profile of LN-145 in combination with pembrolizumab in patients with recurrent, metastatic, or persistent cervical carcinoma as assessed by incidence of adverse events.
Cohort 4: Efficacy and Adverse Events [Up to 60 months]
To explore the efficacy and safety profile of LN-145 in previously enrolled patients with recurrent, metastatic, or persistent cervical carcinoma
Cohort 5: Efficacy and Adverse Events [Up to 60 months]
To explore the efficacy and safety profile of LN-145 in re-treated patients with recurrent, metastatic, or persistent cervical carcinoma

Secondary Outcome Measures

Cohort 1 and 2: Duration of Response [Up to 60 months]
To evaluate the efficacy parameters of LN-145 in patients with recurrent, metastatic, or persistent cervical carcinoma by assessing duration of response (DOR) as assessed by the IRC per RECIST v1.1
Cohort 1 and 2: Disease Control Rate [Up to 60 months]
To evaluate the efficacy parameters of LN-145 in patients with recurrent, metastatic, or persistent cervical carcinoma by assessing disease control rate (DCR) as assessed by the IRC per RECIST v1.1
Cohort 1 and 2: Progression-Free Survival [Up to 60 months]
To evaluate the efficacy parameters of LN-145 in patients with recurrent, metastatic, or persistent cervical carcinoma by assessing progression-free survival (PFS) as assessed by the IRC per RECIST v1.1
Cohort 1 and 2: Objective Response Rate [Up to 60 months]
To evaluate the efficacy of LN-145 in patients with recurrent, metastatic, or persistent cervical carcinoma based on the objective response rate (ORR) as assessed by the Investigator per RECIST v1.1
Cohort 1 and 2: Duration of Response [Up to 60 months]
To evaluate the efficacy of LN-145 in patients with recurrent, metastatic, or persistent cervical carcinoma by assessing duration of response (DOR) as assessed by the Investigator per RECIST v1.1
Cohort 1 and 2: Disease Control Rate [Up to 60 months]
To evaluate the efficacy of LN-145 in patients with recurrent, metastatic, or persistent cervical carcinoma by assessing disease control rate (DCR) as assessed by the Investigator per RECIST v1.1
Cohort 1 and 2: Progression-Free Survival [Up to 60 months]
To evaluate the efficacy of LN-145 in patients with recurrent, metastatic, or persistent cervical carcinoma by assessing progression-free survival (PFS) as assessed by the Investigator per RECIST v1.1
Cohort 1 and 2: Overall Survival [Up to 60 months]
To evaluate overall survival (OS) in patients with recurrent, metastatic, or persistent cervical carcinoma
Cohort 1 and 2: Adverse Events [Up to 60 months]
To characterize the safety profile of LN-145 in patients with recurrent, metastatic, or persistent cervical carcinoma as assessed by incidence of adverse events
Cohort 3: Objective Response Rate [Up to 60 months]
To evaluate the efficacy of LN-145 in combination with pembrolizumab in patients with recurrent, metastatic, or persistent cervical carcinoma based on the objective response rate (ORR) as assessed by the Investigator per RECIST v1.1
Cohort 3: Duration of Response [Up to 60 months]
To evaluate the efficacy of LN-145 in combination with pembrolizumab in patients with recurrent, metastatic, or persistent cervical carcinoma by assessing duration of response (DOR) as assessed by the Investigator per RECIST v1.1.
Cohort 3: Disease Control Rate [Up to 60 months]
To evaluate the efficacy of LN-145 in combination with pembrolizumab in patients with recurrent, metastatic, or persistent cervical carcinoma by assessing disease control rate (DCR) as assessed by the Investigator per RECIST v1.1.
Cohort 3: Progression-Free Survival [Up to 60 months]
To evaluate the efficacy of LN-145 in combination with pembrolizumab in patients with recurrent, metastatic, or persistent cervical carcinoma by assessing progression-free survival (PFS) as assessed by the Investigator per RECIST v1.1.
Cohort 3: Overall Survival [Up to 60 months]
To evaluate overall survival (OS) in patients with recurrent, metastatic, or persistent cervical carcinoma

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

To be eligible for the study, patients must meet ALL of the following criteria prior to participation:

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.
Must have recurrent, metastatic, or persistent squamous cell carcinoma (SCC), adenosquamous carcinoma (ASC), or adenocarcinoma (AC) of the cervix that is not amenable to curative treatment with surgery and/or radiation therapy.
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)
At least one measurable target lesion, as defined by RECIST v1.1.
Cohort 1 and Cohort 2: Progression during or following at least one, but no more than three, prior systemic chemotherapeutic treatments for recurrent, metastatic, or persistent cervical carcinoma

A line of systemic therapy is defined as any chemotherapy or multiple-agent chemotherapy regimen that was administered for recurrent, metastatic, or persistent SCC, ASC, or AC of the cervix.
A bevacizumab and chemotherapy combination is encouraged as a prior line of treatment.
Neither chemoradiation, nor chemotherapy in the neoadjuvant or adjuvant settings are considered as a prior line of systemic therapy.

Cohort 2: Must also have previously received treatment with a checkpoint inhibitor (ie, PD-1, PD-L1]) in the setting of recurrent, metastatic, or persistent disease either as monotherapy or in combination (eg, in combination with chemotherapy or another immune agent)

Cohort 3 (United States only): Must have not received any therapies other than prior chemoradiation or surgery for loco-regional disease

Any prior therapy directed at the malignant tumor, including chemotherapy, biologic/targeted agents, and immunologic agents must be discontinued at least 28 days prior to tumor resection.
Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Must have adequate organ function.
Patient has no evidence of any active viral, bacterial, or fungal infection requiring ongoing systemic treatment. Patients must be seronegative for the human immunodeficiency virus (HIV). Patients with acute or chronic hepatitis infections may be enrolled if the viral load by nucleic acid amplification test (NAAT) is undetectable with/without active treatment
Patients of childbearing potential must be willing to take the appropriate precaution to avoid pregnancy 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.
Prior to study Enrollment (tumor resection), patient must have documentation of radiological disease progression after the most recent therapy

Exclusion Criteria:

Patients who meet any of the following criteria are not eligible for participation in this study:

Patients who have received an organ allograft or prior cell transfer therapy except for prior LN-145 therapy in the setting of re-treatment only.
Patients who require ongoing systemic steroid therapy (> 10 mg/day of prednisone or other steroid equivalent dose).
Patients who currently have prior therapy-related toxicities Grade > 1 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0; except for peripheral neuropathy, alopecia, or vitiligo prior to Enrollment (tumor resection).
. Patients who have a history of hypersensitivity to any component or excipient of

LN-145 or other study drugs:

• NMA-LD preparative regimen (cyclophosphamide, mesna, and fludarabine)

Patients who have active systemic infections, coagulation disorders, or other active major medical illness(es) of the cardiovascular, respiratory, or immune system, including evidence in the medical history of urinary tract obstruction, a positive cardiac stress test, myocardial infarction, cardiac arrhythmia, obstructive or restrictive pulmonary disease, or other conditions that in the opinion of the Investigator would increase the risk of participation.
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 preparative regimen

Patients who have any form of primary immunodeficiency (such as severe combined immunodeficiency [SCID] or acquired immunodeficiency syndrome [AIDS])
Patients who have a diagnosis of end-stage renal disorder requiring hemodialysis
Patients who have a left ventricular ejection fraction (LVEF) < 45% or who are New York Heart Association (NYHA) Class 2 or higher.
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 (except for curatively treated localized malignancy that has not required treatment for > 1 year, and in the judgement of the Investigator, does not pose a significant risk of recurrence including, but not limited to, non-melanoma skin cancer or bladder cancer)
Patients who are of the following protected classes will be excluded, including:

Pregnant, parturient, or breastfeeding women
Persons who are hospitalized without consent or those deprived of liberty because of a judiciary or administrative decision
Patients with a legal protection measure or a person who cannot express his/her consent
Patients in emergency situations who cannot consent to the study

Patients who have received a live or attenuated vaccine within 28 days prior to beginning the NMA-LD preparative regimen
Patients whose cancer requires immediate attention or who would otherwise suffer a disadvantage by participating in this study
Cohort 1 and Cohort 3: Patients who have received prior treatment with immunotherapy (eg, PD-1, PD-L1, or anti-cytotoxic T lymphocyte-associated antigen-4 [CTLA-4] antibodies)
Patients who have Grade ≥ 2 hemorrhage within 14 days prior to Enrollment (tumor resection)
Cohort 3: Patients may not have active or prior documented autoimmune or inflammatory disorders (including pneumonitis, inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St. Joseph's Hospital and Medical Center Center For Women's Health	Phoenix	Arizona	United States	85013
2	University of Southern California	Los Angeles	California	United States	90033
3	University of California San Diego	San Diego	California	United States	92093
4	Sylvester Comprehensive Cancer Center	Miami	Florida	United States	33136
5	University of Florida Health Cancer Center	Orlando	Florida	United States	32806
6	University of South Florida H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612
7	Augusta University	Augusta	Georgia	United States	30912-0003
8	University of Chicago	Chicago	Illinois	United States	60637
9	James Graham Brown Cancer Center	Louisville	Kentucky	United States	40202
10	LSU Health Sciences Center	New Orleans	Louisiana	United States	70112
11	The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21287-0013
12	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
13	Karmanos Cancer Institute	Detroit	Michigan	United States	48201
14	Rutgers University	Newark	New Jersey	United States	07103
15	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
16	Cleveland Clinic	Cleveland	Ohio	United States	44195
17	The Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
18	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
19	UPMC Cancer Center	Pittsburgh	Pennsylvania	United States	15232
20	MD Anderson Cancer Center	Houston	Texas	United States	77030
21	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53225
22	Centre Hospitalier Lyon Sud	Pierre Bénite	Rhone-alpes	France	69495
23	Centre Léon Bérard	Lyon		France	69008
24	Gustave Roussy Cancer Campus	Villejuif Cedex		France	94805
25	Universitätsklinikum Erlangen	Erlangen	Bayern	Germany	91054
26	Universitätsklinikum Carl Gustav Carus	Dresden	Sachsen	Germany	01307
27	Istituto Europeo di Oncologia	Miano	Milano	Italy	20141
28	Academisch Medisch Centrum	Amsterdam	AZ	Netherlands	1105
29	Clínica Universidad de Navarra	Pamplona	Navarra	Spain	31008
30	Hospital Universitari Vall d'Hebrón	Barcelona		Spain	08035
31	Institut Català d'Oncologia	Barcelona		Spain	08908
32	Hospital General Universitario Gregorio Marañon	Madrid		Spain	28007
33	Hospital Universitario Madrid Sanchinarro	Madrid		Spain	28050
34	Inselspital	Bern		Switzerland	CH-3010
35	Centre Hospitalier Universitaire Vaudois Lausanne - Centre Pluridisciplinaire d'Oncologie	Lausanne		Switzerland
36	Bristol Haematology and Oncology Centre	Bristol	England	United Kingdom	BS2 8ED
37	Sarah Cannon Research Institute London	London	England	United Kingdom	W1G 6AD
38	University College London Hospitals NHS Foundation Trust	London	England	United Kingdom	W1G 6BW
39	NHS Greater Glasgow and Clyde	Glasgow	Scotland	United Kingdom	G12 0YN
40	Guy's & St.Thomas NHS Foundation Trust	London		United Kingdom	SE1 9RT