Study of Autologous Tumor Infiltrating Lymphocytes in Patients With Solid Tumors

• ClinicalTrials.gov Identifier: NCT03645928
• Recruitment Status: Recruiting
• First Posted: August 24, 2018
• Last Update Posted: May 9, 2023
• Sponsor: Iovance Biotherapeutics, Inc.
• Information provided by (Responsible Party): Iovance Biotherapeutics, Inc.

Tracking Information

• First Submitted Date: August 22, 2018
• First Posted Date: August 24, 2018
• Last Update Posted Date: May 9, 2023
• Actual Study Start Date: May 7, 2019
• Estimated Primary Completion Date: December 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 26, 2021)

• Objective Response Rate [ Time Frame: Up to 60 months ]
  To evaluate the efficacy of autologous TIL in combination with CPIs in metastatic melanoma, HNSCC, and NSCLC patients and as a single therapy in metastatic melanoma and NSCLC patients as determined by objective response rate (ORR) using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as assessed by Investigator
• Safety Profile Measured by Grade ≥3 TEAEs [ Time Frame: Up to 60 months ]
  To characterize the safety profile of autologous TIL in combination with CPIs in metastatic melanoma, HNSCC, and NSCLC patients and as a single therapy in metastatic melanoma and NSCLC patients as measured by the incidence of Grade ≥ 3 treatment-emergent adverse events (TEAEs)

Original Primary Outcome Measures (submitted: August 22, 2018)

• Objective Response Rate [ Time Frame: Up to 60 months ]
  To evaluate the efficacy of autologous TIL LN-144 (Lifileucel)/LN-145 as a single therapy or in combination with pembrolizumab in patients with metastatic melanoma, HNSCC, or NSCLC by determining the objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
• Safety Profile Measured by Grade ≥3 TEAEs [ Time Frame: Up to 60 months ]
  To characterize the safety profile of TIL LN-144 (Lifileucel)/LN-145 as a single-therapy in NSCLC patients or in combination with pembrolizumab in metastatic melanoma and HNSCC patients as measured by the incidence of Grade ≥3 treatment-emergent adverse events (TEAEs).

Current Secondary Outcome Measures (submitted: August 22, 2018)

• Complete Response Rate [ Time Frame: Up to 60 months ]
  To evaluate efficacy parameters such Complete Response (CR) rate per RECIST 1.1, as assessed by the Investigator
• Duration of Response [ Time Frame: Up to 60 months ]
  To evaluate efficacy parameters such Duration of Response (DOR) per RECIST 1.1, as assessed by the Investigator
• Disease Control Rate [ Time Frame: Up to 60 months ]
  To evaluate efficacy parameters such Disease Control Rate (DCR) per RECIST 1.1, as assessed by the Investigator
• Progression-Free Survival [ Time Frame: Up to 60 months ]
  To evaluate efficacy parameters such Progression-Free Survival (PFS) per RECIST 1.1, as assessed by the Investigator
• Overall Survival [ Time Frame: Up to 60 months ]
  To evaluate efficacy parameters such Overall Survival (OS)

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Autologous Tumor Infiltrating Lymphocytes in Patients With Solid Tumors
• Official Title: A Phase 2, Multicenter Study of Autologous Tumor Infiltrating Lymphocytes (LN 144/LN-145/LN-145-S1) in Patients With Solid Tumors
• Brief Summary: A prospective, open-label, multi-cohort, non-randomized, multicenter Phase 2 study evaluating adoptive cell therapy (ACT) with TIL LN-144 (Lifileucel)/LN-145 in combination with checkpoint inhibitors or TIL LN-144 (Lifileucel)/LN-145/LN-145-S1 as a single agent therapy.
• Detailed Description: LN-144 (Lifileucel)/LN-145/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 a regimen of IL-2. Patients in Cohorts 1A, 2A, 3A and 3C will receive TIL plus checkpoint inhibitors. Patients in Cohorts 1B, 1C, and 3B will receive autologous TIL as a single therapy.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Metastatic Melanoma
• Squamous Cell Carcinoma of the Head and Neck
• Non-small Cell Lung Cancer

Intervention

• 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 IL-2 administration. Lifileucel will be administered to patients once (on Day 0) during the study.
  Other Name: LN-144, TIL, autologous tumor infiltrating lymphocytes, lifileucel
• 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 IL-2 administration. TIL will be administered to patients once (on Day 0) during the study.
  Other Name: TIL, autologous tumor infiltrating lymphocytes
• 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.

  Other Name: Keytruda
• 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 IL-2 administration. TIL will be administered to patients once (on Day 0) during the study.
  Other Name: TIL, autologous tumor infiltrating lymphocytes
• Drug: Ipilimumab

  Monoclonal antibody

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

  Other Name: Yervoy
• 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.

  Other Name: Opdivo

Study 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 checkpoint inhibitors (CPI).
  Interventions:

  • Biological: Lifileucel
  • Drug: Pembrolizumab
• 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.
  Intervention: Biological: LN-145-S1
• 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.
  Intervention: Biological: Lifileucel
• 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 CPIs.
  Interventions:

  • Biological: LN-145
  • Drug: Pembrolizumab
• 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 CPIs, 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).
  Interventions:

  • Biological: LN-145
  • Drug: Pembrolizumab
• 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 CPIs.
  Intervention: Biological: LN-145
• 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 CPI 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.
  Interventions:

  • Biological: LN-145
  • Drug: Ipilimumab
  • Drug: Nivolumab

• Publications *: Hensel J, Metts J, Gupta A, Ladle BH, Pilon-Thomas S, Mullinax J. Adoptive Cellular Therapy for Pediatric Solid Tumors: Beyond Chimeric Antigen Receptor-T Cell Therapy. Cancer J. 2022 Jul-Aug 01;28(4):322-327. doi: 10.1097/PPO.0000000000000603.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 13, 2022): 178
• Original Estimated Enrollment (submitted: August 22, 2018): 36
• Estimated Study Completion Date: December 2024
• Estimated Primary Completion Date: December 2023 (Final data collection date for primary outcome measure)

Eligibility 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).
• Cohorts 1A, 2A, and 3A: If previously treated, patients must have progressed on or after most recent therapy and must not have received CPIs 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)
• 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 CPI (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 CPI 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, 2A, 3A, 3B, and 3C. 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 IL-2, 4 months after their last dose of pembrolizumab, or 5 months after their last dose of ipilimumab or nivolumab, 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
• 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, 2A, 3A, and 3C 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
• Patients who have a left ventricular ejection fraction (LVEF) < 45% or who are New York Heart Association Class II or higher
• 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Iovance Biotherapeutics Study Team; 866-565-4410; Clinical.Inquiries@iovance.com

• Listed Location Countries: Canada, France, Germany, Greece, Spain, Switzerland, United Kingdom, United States

Administrative Information

• NCT Number: NCT03645928
• Other Study ID Numbers: IOV-COM-202; 2018-001608-12 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Iovance Biotherapeutics, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Iovance Biotherapeutics, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Iovance Biotherapeutics Medical Monitor; Iovance Biotherapeutics

• PRS Account: Iovance Biotherapeutics, Inc.
• Verification Date: May 2023