Clinical trial NCT03108495: Study of LN-145, Autologous Tumor Infiltrating Lymphocytes in the Treatment of Patients With Cervical Carcinoma
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Cervical Carcinoma
Keywords: LN-145
Cell Therapy
Autologous Adoptive Cell Transfer
Autologous Adoptive Cell Therapy
Cellular Immuno-therapy
Tumor Infiltrating Lymphocytes
TIL
IL-2
Pembrolizumab
Lead sponsor: Iovance Biotherapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2017-04-11
Enrollment: 189
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

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.

Eligibility criteria: Inclusion Criteria:

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

1. 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.
2. 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.
3. 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)
4. At least one measurable target lesion, as defined by RECIST v1.1.
5. 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
6. 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.
7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
8. Must have adequate organ function.
9. 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
10. 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.
11. 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:

1. 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.
2. Patients who require ongoing systemic steroid therapy (\> 10 mg/day of prednisone or other steroid equivalent dose).
3. 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).
4. . 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)
5. 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.
6. 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
7. Patients who have any form of primary immunodeficiency (such as severe combined immunodeficiency \[SCID\] or acquired immunodeficiency syndrome \[AIDS\])
8. Patients who have a diagnosis of end-stage renal disorder requiring hemodialysis
9. Patients who have a left ventricular ejection fraction (LVEF) \< 45% or who are New York Heart Association (NYHA) Class 2 or higher.
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 (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)
12. 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
13. Patients who have received a live or attenuated vaccine within 28 days prior to beginning the NMA-LD preparative regimen
14. Patients whose cancer requires immediate attention or who would otherwise suffer a disadvantage by participating in this study
15. 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)
16. Patients who have Grade ≥ 2 hemorrhage within 14 days prior to Enrollment (tumor resection)
17. 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 \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.\]).

Primary outcomes:
measure: Cohort 1 and 2: Objective Response Rate
timeFrame: Up to 6 months
measure: Cohort 3: Adverse Events
timeFrame: Up to 60 months
measure: Cohort 4: Efficacy and Adverse Events
timeFrame: Up to 60 months
measure: Cohort 5: Efficacy and Adverse Events
timeFrame: Up to 60 months
Secondary outcomes:
measure: Cohort 1 and 2: Duration of Response
timeFrame: Up to 60 months
measure: Cohort 1 and 2: Disease Control Rate
timeFrame: Up to 60 months
measure: Cohort 1 and 2: Progression-Free Survival
timeFrame: Up to 60 months
measure: Cohort 1 and 2: Objective Response Rate
timeFrame: Up to 60 months
measure: Cohort 1 and 2: Duration of Response
timeFrame: Up to 60 months
measure: Cohort 1 and 2: Disease Control Rate
timeFrame: Up to 60 months
measure: Cohort 1 and 2: Progression-Free Survival
timeFrame: Up to 60 months
measure: Cohort 1 and 2: Overall Survival
timeFrame: Up to 60 months
measure: Cohort 1 and 2: Adverse Events
timeFrame: Up to 60 months
measure: Cohort 3: Objective Response Rate
timeFrame: Up to 60 months
measure: Cohort 3: Duration of Response
timeFrame: Up to 60 months
measure: Cohort 3: Disease Control Rate
timeFrame: Up to 60 months
measure: Cohort 3: Progression-Free Survival
timeFrame: Up to 60 months
measure: Cohort 3: Overall Survival
timeFrame: Up to 60 months
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: St. Joseph's Hospital and Medical Center Center For Women's Health
state: Arizona
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: San Diego
country: United States
facility: University of California San Diego
state: California
city: Miami
country: United States
facility: Sylvester Comprehensive Cancer Center
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: Augusta
country: United States
facility: Augusta University
state: Georgia
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Louisville
country: United States
facility: James Graham Brown Cancer Center
state: Kentucky
city: New Orleans
country: United States
facility: LSU Health Sciences Center
state: Louisiana
city: Baltimore
country: United States
facility: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Newark
country: United States
facility: Rutgers University
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Comprehensive Cancer Center
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Pittsburgh
country: United States
facility: Allegheny Health
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Cancer Center
state: Pennsylvania
city: Sioux Falls
country: United States
facility: Avera Medical Group Oncology
state: South Dakota
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Pierre Bénite
country: France
facility: Centre Hospitalier Lyon Sud
state: Rhone-alpes
city: Lyon
country: France
facility: Centre Léon Bérard
city: Villejuif Cedex
country: France
facility: Gustave Roussy Cancer Campus
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen
state: Bayern
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus
state: Sachsen
city: Miano
country: Italy
facility: Istituto Europeo di Oncologia
state: Milano
city: Amsterdam
country: Netherlands
facility: Academisch Medisch Centrum
state: AZ
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: Institut Català d'Oncologia
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon
city: Madrid
country: Spain
facility: Hospital Universitario Madrid Sanchinarro
city: Bern
country: Switzerland
facility: Inselspital
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois Lausanne - Centre Pluridisciplinaire d'Oncologie
city: Bristol
country: United Kingdom
facility: Bristol Haematology and Oncology Centre
state: England
city: London
country: United Kingdom
facility: Sarah Cannon Research Institute London
state: England
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
state: England
city: Glasgow
country: United Kingdom
facility: NHS Greater Glasgow and Clyde
state: Scotland
city: London
country: United Kingdom
facility: Guy's & St.Thomas NHS Foundation Trust
Study officials:
affiliation: Iovance Biotherapeutics, Inc.
name: Iovance Medical Monitor
role: STUDY_DIRECTOR
References: