Study of Autologous Tumor Infiltrating Lymphocytes in Patients With Solid Tumors

Study Purpose

A prospective, open-label, multi-cohort, non-randomized, multicenter Phase 2 study evaluating adoptive cell therapy (ACT) with TIL [LN-144/LN-145 (lifileucel)] in combination with immune checkpoint inhibitors or TIL [LN-144/LN-145 (lifileucel) and LN-145-S1] as a single agent therapy.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years and Over
Gender	All

More Inclusion & Exclusion Criteria

Inclusion Criteria.

- Must have a confirmed diagnosis of malignancy of their receptive histologies: unresectable or metastatic melanoma Stage IIIC to IV (Cohorts 1A,1B and 1C), advanced, recurrent or metastatic HNSCC (Cohort 2A), or Stage III or Stage IV non-small cell lung cancer (Cohorts 3A, 3B, and 3C).

Stage IV NSCLC with no actionable mutations (EGFR, ALK, ROS1) with effective targeted therapy (Cohorts 3D and 3E).

- Cohorts 1A, 1D, 2A, 3A, 3D and 3E: If previously treated, patients must have progressed on or after most recent therapy and must not have received ICIs as part of one of the counted lines of prior therapy.

Patients must have radiologically documented disease progression while receiving or after the completion of the most recent prior treatment. Patients may have received up to 3 prior systemic anticancer therapies (except for Cohort 3A, where patients whose tumors harbor actionable mutations may have received up to 4 prior systemic therapies). Patients in Cohort 1D may have had no prior therapy for advanced disease. Patients in Cohorts 3D and 3E may have had no prior systemic therapy for Stage IV disease.

- Cohorts 1B, 1C, 3B, and 3C: Unresectable or metastatic melanoma patients in Cohorts 1B or 1C must have previously received systemic therapy with a PD-1 blocking antibody.

NSCLC patients in Cohort 3B must have previously received systemic therapy with any ICI (except for those patients with known oncogene driver mutations that are sensitive to targeted therapies) as part of 1

- 3 prior lines of therapy.

NSCLC patients in Cohort 3C must have previously received 1 line of ICI monotherapy. No other systemic therapy for metastatic disease is allowed. Prior chemoradiation and/or chemotherapy in the adjuvant and/or neoadjuvant settings are allowed.

- Must have at least 1 resectable lesion.

- Must have remaining measurable disease as defined by RECIST 1.1 following tumor resection.

- Must be ≥ 18 years at the time of consent for Cohorts 1A, 1C, 1D, 2A, 3A, 3B, 3C, 3D and 3E.

Patients must be ≥ 12 years at the time of consent for Cohort 1B. Enrollment of patients > 70 years of age may be allowed after consultation with the Medical Monitor.

- Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and an estimated life expectancy of ≥ 6 months.

- Patients of childbearing potential or those with partners of childbearing potential must be willing to practice an approved method of birth control during treatment and for 12 months after their last dose of aldesleukin, 4 months after their last dose of pembrolizumab, 5 months after their last dose of ipilimumab or nivolumab, or nivolumab-relatlimab; 6 months after the last dose of carboplatin; 14 months after the last dose of cisplatin; and 6 months after the last dose of pemetrexed, paclitaxel, or nab-paclitaxel, whichever occurs later.

Exclusion Criteria.

- Patients with melanoma of uveal/ocular origin.

- Patients who have a history of allogeneic organ transplant or any form of cell therapy involving prior conditioning chemotherapy within the past 20 years.

Patients being retreated with TIL, as part of this study are not excluded.

- Patients who have symptomatic, untreated brain metastases or history of leptomeningeal metastases.

- Patients who are on systemic steroid therapy > 10 mg/day of prednisone or other steroid equivalent.

Patients receiving steroids as replacement therapy for adrenocortical insufficiency at ≤ 10 mg/day of prednisone or other steroid equivalent may be eligible.

- Patients who are pregnant or breastfeeding.

- Patients who have an active medical illness(es), which in the opinion of the Investigator, would pose increased risks for study participation.

- Cohort 1A, 1D, 2A, 3A, 3C, 3D and 3E patients may not have a medical history of autoimmune disorders (including pneumonitis) requiring treatment or active management.

- Patients who have received a live or attenuated vaccination within 28 days prior to the start of treatment.

- Patients who have any form of primary immunodeficiency.

- Patients with a history of hypersensitivity to any component of the study drugs to be administered in the pertinent cohort(s).

- Patients who have a left ventricular ejection fraction (LVEF) < 45% or who are New York Heart Association Class II or higher.

A cardiac stress test demonstrating any irreversible wall movement abnormality in any patients ≥60 years of age or in patients who have a history of ischemic heart disease, cardiac chest pain, or clinically significant atrial and/or ventricular arrhythmias.

- Patients with respiratory dysfunction or history of smoking are excluded if not meeting either of forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) > 0.7 or FEV1 > 50%.

- Patients who have had another primary malignancy within the previous 3 years.

- Participation in another interventional clinical study within 21 days prior to the initiation of treatment.

- Patients in Cohorts 1D, 3D, or 3E who previously received adjuvant or neoadjuvant ICI(s) for non-metastatic disease and had an immune-related AE(s) requiring systemic steroid treatment or discontinuation of immune checkpoint inhibitor therapy.

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT03645928
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 2
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	Iovance Biotherapeutics, Inc.
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Iovance Biotherapeutics Medical Monitor
Principal Investigator Affiliation	Iovance Biotherapeutics
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Industry
Overall Status	Recruiting
Countries	Canada, France, Germany, Greece, Spain, Switzerland, United Kingdom, United States
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Metastatic Melanoma, Squamous Cell Carcinoma of the Head and Neck, Non-small Cell Lung Cancer

Additional Details

TIL [LN-144/LN-145 (lifileucel) and LN-145-S1] is an adoptive cell transfer therapy that utilizes an autologous TIL for the treatment of patients with unresectable or metastatic melanoma, advanced, recurrent, or metastatic squamous cell carcinoma of the head and neck, and locally advanced or metastatic non-small cell lung cancer. The adoptive cell transfer therapy used in this study involves patients receiving a nonmyeloablative (NMA) lymphodepletion regimen, followed by infusion of autologous TIL followed by the administration of aldesleukin. Patients in Cohorts 1A, 1D, 2A, 3A, 3C, 3D, and 3E will receive TIL plus immune checkpoint inhibitors. Patients in Cohorts 1B, 1C, and 3B will receive autologous TIL as a single therapy.

Arms & Interventions

Arms

Experimental: Cohort 1A

LN-144 therapy in combination with pembrolizumab in patients with Stage IIIC to IV unresectable or metastatic melanoma with ≤ 3 prior lines of systemic therapy, excluding immune checkpoint inhibitors (ICI).

Experimental: Cohort 1B

LN-145-S1 therapy as a single agent in patients with Stage IIIC or Stage IV unresectable or metastatic melanoma, who have previously received systemic therapy with a PD-1 blocking antibody. If the tumor is proto-oncogene B-Raf (BRAF) V600 mutation positive, patients must have received a BRAF inhibitor with or without a mitogen-activated extracellular signal-related kinase (MEK) inhibitor.

Experimental: Cohort 1C

LN-144 Generation 3 (Gen 3) therapy as a single agent in patients with Stage IIIC or Stage IV unresectable or metastatic melanoma, who have previously received systemic therapy with a PD-1 blocking antibody. If the tumor is BRAF V600 mutation positive, patients must have received BRAF inhibitor with or without a MEK inhibitor.

Experimental: Cohort 2A

LN-145 therapy in combination with pembrolizumab in patients with advanced, recurrent, or metastatic HNSCC, with ≤ 3 prior lines of systemic therapy, excluding ICIs.

Experimental: Cohort 3A

LN-145 therapy in combination with pembrolizumab in patients with locally advanced or metastatic (Stage III or Stage IV) non-small-cell lung cancer (NSCLC) with ≤ 3 prior lines of systemic therapy, excluding ICIs, or ≤ 4 lines if 2 or more of the lines are TKI therapy for those with tumors that harbored actionable mutations (eg, EGFR, ALK, ROS).

Experimental: Cohort 3B

LN-145 therapy as a single agent in patients with Stage III or Stage IV NSCLC, who have previously received 1-3 lines of prior systemic therapy. Patients with known oncogene drivers (eg, EGFR, ALK, ROS) who have mutations that are sensitive to targeted therapies are not required to have received prior systemic therapy with ICIs.

Experimental: Cohort 3C

LN-145 therapy in combination with ipilimumab and nivolumab in patients with Stage III or Stage IV NSCLC who have previously received 1 line of ICI monotherapy. No other systemic therapy for metastatic disease is allowed. Prior chemoradiation and/or chemotherapy in the adjuvant and/or neo-adjuvant settings are allowed.

Experimental: Cohort 1D

The lifileucel regimen in combination with nivolumab-relatlimab in patients with Stage IIIC to IV unresectable or metastatic (advanced) melanoma who have had no prior therapy for advanced disease.

Experimental: Cohort 3D

The lifileucel regimen in combination with pembrolizumab with or without pemetrexed, after tumor resection before 4 cycles of frontline platinum doublet chemotherapy plus pembrolizumab, in patients with Stage IV NSCLC without EGFR, ALK, or ROS1 driver mutations, who have had no prior therapy for advanced disease.

Experimental: Cohort 3E

The lifileucel regimen in combination with pembrolizumab with or without pemetrexed, after tumor resection during 4 cycles of frontline platinum doublet chemotherapy plus pembrolizumab, in patients with Stage IV NSCLC without EGFR, ALK, or ROS1 driver mutations.

Interventions

Biological: - Lifileucel

A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. After NMA lymphodepletion, patients are infused with Lifileucel followed by aldesleukin administration. Lifileucel will be administered to patients once (on Day 0) during the study.

Biological: - LN-145

A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. After NMA lymphodepletion, patients are infused with their autologous TIL (LN-145) followed by aldesleukin administration. TIL will be administered to patients once (on Day 0) during the study.

Drug: - Pembrolizumab

Humanized antibody. Pembrolizumab will be administered following tumor resection and will continue every 3 weeks or every 6 weeks thereafter for up to 2 years.

Biological: - LN-145-S1

A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. After NMA lymphodepletion, patients are infused with their autologous TIL (LN-145-S1) followed by aldesleukin administration. TIL will be administered to patients once (on Day 0) during the study.

Drug: - Ipilimumab

Monoclonal antibody Ipilimumab will be administered as a single dose prior to tumor resection.

Drug: - Nivolumab

Monoclonal antibody Nivolumab will be administered once prior to tumor resection. The second dose will be administered prior to TIL administration and dosing will continue every 4 weeks for up to 2 years.

Drug: - Nivolumab-relatlimab

Nivolumab-relatlimab will be administered following tumor resection and will continue every 4 weeks thereafter for up to 2 years.

Drug: - Cisplatin

Cisplatin administered intravenously at the protocol-defined dose every 3 weeks for up to 4 cycles.

Drug: - Carboplatin

Carboplatin administered intravenously at the protocol-defined dose every 3 weeks for up to 4 cycles.

Drug: - Paclitaxel

Paclitaxel administered intravenously at the protocol-defined dose every 3 weeks for up to 4 cycles.

Drug: - Nab-Paclitaxel

Nab-Paclitaxel administered intravenously at the protocol-defined dose every 3 weeks for up to 4 cycles.

Drug: - Pemetrexed

Pemetrexed administered intravenously at the protocol-defined dose every 3 weeks for up to 4 cycles. Optional continuation maintenance every 3 weeks, if applicable.

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

University of California, San Diego, La Jolla, California

Status

Terminated

Address

University of California, San Diego

La Jolla, California, 92093

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