Study to Investigate Lifileucel Regimen Plus Pembrolizumab Compared With Pembrolizumab Alone in Participants With Untreated Advanced Melanoma.

Study Overview
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Brief Summary
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This is a Phase 3, multicenter, open-label, randomized, parallel group, treatment study to assess the efficacy and safety of lifileucel in combination with pembrolizumab compared with pembrolizumab alone in participants with untreated, unresectable or metastatic melanoma. Participants randomized to the pembrolizumab monotherapy arm who subsequently have a blinded independent central review- verified confirmed progressive disease (PD) will be offered lifileucel monotherapy in an optional crossover period.

Detailed Description
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The study will enroll participants with unresectable or metastatic melanoma (Stage IIIC, IIID, or IV per the American Joint Committee on Cancer [AJCC] staging system) who have had no prior therapy for metastatic disease. Previous adjuvant/neoadjuvant therapy with a single line of protooncogene B-Raf (BRAF) inhibitor with or without a mitogen-activated protein kinase (MEK) inhibitor, PD-1 inhibitor, or cytotoxic T-lymphocyte-associated antigen-4 [CTLA-4] inhibitor is allowed, provided such treatment was completed ≥6 months before progression to metastatic disease.

Official Title
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A Phase 3, Multicenter, Randomized, Open-label, Parallel Group, Treatment Study to Assess the Efficacy and Safety of the Lifileucel (LN-144, Autologous Tumor Infiltrating Lymphocytes [TIL]) Regimen in Combination With Pembrolizumab Compared With Pembrolizumab Monotherapy in Participants With Untreated, Unresectable or Metastatic Melanoma

Conditions
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Metastatic Melanoma, Unresectable Melanoma, Melanoma

Intervention / Treatment
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* Biological: Lifileucel plus Pembrolizumab
* Biological: Pembrolizumab with Optional Crossover Period


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant has a histologically or pathologically confirmed diagnosis of Stage IIIC, IIID, or IV unresectable or metastatic melanoma. In the investigator's assessment, the participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and an estimated life expectancy of > 6 months. Participant is assessed as having at least one resectable lesion (or aggregate lesions) for lifileucel generation. Participant must have at least one measurable disease as defined by RECIST 1.1 following tumor resection. Participants must have adequate organ function. Participants of childbearing potential or those with partners of childbearing potential must be willing to practice an approved method of highly effective birth control. Participants who are > 70 years of age may be allowed to enroll after the investigator discusses with the medical monitor. Exclusion Criteria: Participant has melanoma of uveal/ocular origin. Participant has symptomatic untreated brain metastases. Participant received more than 1 prior line of therapy. Participant received prior therapy for metastatic disease Participants with a BRAF V600 mutation-positive tumor received prior adjuvant/neoadjuvant ICI therapy only Participant has an active medical illness(es) that, in the opinion of the investigator, would pose increased risks for study participation, such as systemic infections; seizure disorders; coagulation disorders; or other active major medical illnesses of the cardiovascular, respiratory, or immune systems. Participant has any form of primary or acquired immunodeficiency (eg, SCID or AIDS). Participant had another primary malignancy within the previous 3 years (except for those that do not require treatment or were curatively treated >1 year ago, and in the judgment of the investigator do not pose a significant risk of recurrence.) Participant has a history of allogeneic cell or organ transplant. Other protocol defined inclusion/exclusion criteria could apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Lifileucel plus Pembrolizumab | Biological: Lifileucel plus Pembrolizumab<br>* A tumor sample is resected from each patient for Lifileucel manufacturing. Patients then receive Pembrolizumab followed by the lifileucel regimen which consists of non-myeloablative lymphodepletion, lifileucel infusion followed by IL-2. Patients will then continue to receive Pembrolizumab every 6 weeks until disease progression.<br>* Other names: Pembrolizumab;|
| Active Comparator: Arm B<br>Pembrolizumab alone with Optional Crossover Period | Biological: Pembrolizumab with Optional Crossover Period<br>* Patient will receive Pembrolizumab monotherapy every 6 weeks until disease progression. Upon verified confirmed disease progression by the blinded independent review central committee, patients may proceed to lifileucel monotherapy during an optional crossover period if they meet eligibility criteria. Optional crossover: A tumor sample is resected from each patient for Lifileucel manufacturing. Patients then receive the lifileucel regimen which consists of non-myeloablative lymphodepletion, lifileucel infusion followed by IL-2.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate and Progression Free Survival | To compare the efficacy of lifileucel plus pembrolizumab with the efficacy of pembrolizumab alone measured by objective response rate (ORR) and progression-free survival (PFS) assessed by the blinded independent review committee (BIRC) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | 5 years total duration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | To compare the efficacy of lifileucel plus pembrolizumab with the efficacy of pembrolizumab alone measured by overall survival (OS) | 7 years total duration | 
| Complete Response Rate, Duration of Response and Event Free Survival | To compare the efficacy of lifileucel plus pembrolizumab with the efficacy of pembrolizumab alone measured by complete response (CR) rate and duration of response (DOR) and event- free survival (EFS) assessed by the BIRC per RECIST v1.1 | 5 years total duration | 
| Objective Response Rate, Progression Free Survival, Complete Response Rate, Duration of Responses, Event Free Survival and PFS2 | To compare the efficacy of lifileucel plus pembrolizumab with the efficacy of pembrolizumab alone measured by ORR, PFS, CR rate, DOR, and EFS assessed by the investigator per RECIST v1.1 and PFS2 assessed by the investigator | 5 years total duration | 
| Adverse Events | To characterize the safety and tolerability profile of lifileucel plus pembrolizumab and pembrolizumab alone in participants with unresectable or metastatic melanoma | 5 years total duration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tumor Infiltrating Lymphocytes, TIL, Metastatic Melanoma, Unresectable Melanoma, Cell Therapy, Cellular Immuno-therapy, IL-2, Non-myeloablative lymphodepletion (NMALD), Check point inhibitor, Melanoma, Lifileucel, Stage III Melanoma, Stage IV Melanoma, Skin cancer, Skin cancer types, Malignant melanoma, Autologous Adoptive Cell Therapy, Autologous Adoptive Cell Transfer, LN-144, Pembrolizumab, Pembro, Adjuvant/Neo-adjuvant, BRAF/MEK, ICI, BRAF v600, Immune checkpoint inhibitor, Tumor infiltrating T-cells