Phase 3 Study of Lifileucel and Pembrolizumab Versus Pembrolizumab Monotherapy in Untreated Unresectable or Metastatic Melanoma
- Trial ID
- 2022-503140-41-00
- Protocol
- IOV-MEL-301
- Sponsor
- Iovance Biotherapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **efficacy** of the combination of lifileucel and pembrolizumab with pembrolizumab monotherapy in participants with untreated, unresectable, or metastatic **melanoma**. This comparison is measured using assessments by the blinded independent review committee (BIRC) according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The clinical relevance of this objective lies in determining whether the addition of lifileucel, an autologous tumor-infiltrating lymphocyte therapy, enhances the therapeutic effect of pembrolizumab, a PD-1 inhibitor, in this patient population.
Secondary objectives include: - Comparing the efficacy of lifileucel plus pembrolizumab with pembrolizumab alone, measured by survival rates. - Comparing the efficacy using assessments by the BIRC per RECIST v1.1. - Comparing the efficacy using assessments by the investigator per RECIST v1.1. - Characterizing the safety and tolerability profile of lifileucel plus pembrolizumab versus pembrolizumab alone in participants with unresectable or metastatic melanoma.
Participants
The clinical trial involves a total of **520 participants** diagnosed with **melanoma**, specifically Stage IIIC, IIID, or IV unresectable or metastatic forms. The study population includes both male and female subjects, aged between **18 to 70 years**. Participants were selected based on their ability to provide informed consent and meet specific health criteria, including adequate hematologic and organ function, as well as a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale. The trial does not exclude vulnerable populations. Participants are required to have at least one measurable lesion and must have recovered from any prior anticancer treatment-related adverse events to a Grade 1 level. Lifestyle considerations such as smoking history and reproductive health are also taken into account, with specific requirements for contraception and smoking cessation. The trial aims to compare the efficacy of lifileucel plus pembrolizumab against pembrolizumab alone, with assessments conducted by a blinded independent review committee.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, parallel group study to evaluate the efficacy and safety of a combination therapy involving **lifileucel** and **pembrolizumab** compared to pembrolizumab monotherapy in participants with untreated, unresectable, or metastatic **melanoma**. The trial aims to assess the primary endpoint of progression-free survival (PFS) and the secondary endpoint of overall survival (OS), with evaluations conducted by a blinded independent review committee using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The trial is expected to commence recruitment on February 16, 2024, and is estimated to conclude by March 1, 2030.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, including age, hematologic parameters, organ function, and performance status. Following randomization, participants will receive the assigned treatment regimen. The study includes regular follow-up visits to monitor treatment response and safety, with assessments conducted at predefined intervals. The end-of-study visit will occur after the final treatment cycle or upon early termination, which may result from disease progression, unacceptable toxicity, or withdrawal of consent.
The expected duration of participant involvement varies depending on the treatment arm and individual response, with the maximum treatment period for pembrolizumab being 60 weeks. Conditions that may lead to early termination include adverse events, non-compliance with study procedures, or investigator discretion based on clinical judgment. Participants are required to adhere to study protocols, including the use of contraception and abstaining from certain activities, to ensure the integrity of the trial data and participant safety.
Treatment
The clinical trial involves the administration of several experimental and non-experimental treatments. **Lifileucel** is a dispersion for infusion, containing the active substance lifileucel, a structurally diverse substance used in cell therapy. It is administered via infusion with a maximum daily dose of 100 billion cells and a total dose of 100 billion cells over a single treatment period. The treatment is provided by Iovance Biotherapeutics, Inc. and is not a pediatric formulation.
**Pembrolizumab**, marketed as KEYTRUDA, is a concentrate for solution for infusion. It is a protein-based therapeutic agent, specifically a monoclonal antibody, administered via infusion. The maximum daily and total dose is 400 mg, with a treatment period extending up to 60 cycles. This product is provided by Merck Sharp & Dohme B.V. and is designated as an orphan drug.
**Fludarabine phosphate** is used in various formulations, including Fludarabine - PCH, Fludarabina Teva, Fludarabine Accord, and Fludarabin Actavis, all as concentrates for solution for injection or infusion. The active substance is a chemical compound administered via infusion, with a maximum daily dose of 25 mg/m² and a total dose of 125 mg/m² over a 5-day treatment period. These products are provided by different manufacturers, including Pharmachemie BV, Teva Pharma S.L.U., and Accord Healthcare B.V.
**Cyclophosphamide** is provided as a solution for injection, with the active substance being a chemical compound. It is administered via infusion, with a maximum daily dose of 60 mg/kg and a total dose of 120 mg/kg over a 2-day treatment period. This product is supplied by Baxter Healthcare Ltd.
**Mesna** is available in two forms: a film-coated tablet and a solution for infusion. It is a chemical compound used to mitigate the side effects of cyclophosphamide. The maximum daily dose is 240 mg/m², with a total dose of 480 mg/m² over a 2-day treatment period. Mesna is administered orally or via infusion.
**Aldesleukin**, marketed as PROLEUKIN, is a powder for solution for injection or infusion. It is a protein-based therapeutic agent administered via infusion, with a maximum daily dose of 60,000 IU/kg and a total dose of 3,600,000 IU/kg over a 4-day treatment period. This product is provided by Clinigen Healthcare Ltd.
Efficacy
The efficacy of the clinical trial will be assessed by comparing the combination of **lifileucel** and pembrolizumab with pembrolizumab monotherapy in participants with untreated, unresectable, or metastatic melanoma. The primary endpoint for evaluating efficacy is Progression-Free Survival (PFS), defined as the time from the date of randomization until disease progression as assessed by the Blinded Independent Review Committee (BIRC) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or death due to any cause. The secondary endpoint is Overall Survival (OS), which is defined as the time from the date of randomization to death due to any cause.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant is 18 to 70 years of age at the time of signing the informed consent form
- 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) with an estimated minimum diameter of 1.5 cm for lifileucel generation.
- Participant will have at least one measurable lesion, as defined by RECIST v1.1, at Baseline/cBaseline.
- If the participant has pre-planned surgical procedure(s), the procedure will take place at least 14 days (for major operative procedures) prior to the tumor resection. Wound healing will have occurred, and all complications will have resolved at the time of tumor resection.
- Participant has recovered from all prior anticancer treatment-related AEs to Grade ≤1
- The participant agrees to abide by the following: a. Male Participants: Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 12 months after the last dose of study intervention: • Refrain from donating sperm PLUS, either: − Be abstinent from heterosexual intercourse as their preferred and usual lifestyle and agree to remain abstinent OR − Must agree to use contraception as detailed below: Agree to use a male condom with female partner use of an additional highly effective contraceptive method with a failure rate of <1% per year as described in Appendix 4. These participants should also be advised of the importance for a female partner of childbearing potential who is not currently pregnant to use a highly effective method of contraception as a condom may break or leak when having sexual intercourse b. Female Participants: A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies: Is a woman of nonchildbearing potential (WONCBP) as defined in Appendix 4 OR • Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% Per year) preferably with low user dependency, as described in Appendix 4 during the study intervention period and for at least 12 months after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of study intervention. • A WOCBP must have a negative serum or urine pregnancy test within 24 hours before the tumor resection. • Additional requirements for pregnancy testing during and after study intervention are located in Section 8.3.8 • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
- Participant is capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the ICF and in this protocol and the understanding that there are other FDA approved therapies for advanced melanoma and, if randomized to the lifileucel regimen, there may be a need for intensive supportive care measures.
- Participant provided written authorization for use and disclosure of protected health information.
- Participant has the following hematologic parameters: • ANC ≥1000/mm3 or ≥1 × 109/L • Hemoglobin ≥8.0 g/dL or ≥4.96 mmol/L • Platelet count ≥100,000/mm3 or ≥100 × 109/L
- Participant has adequate organ function with the following laboratory values: • Serum ALT and AST ≤3 × ULN; participants with liver metastasis may have ALT and AST ≤5 × ULN • Total bilirubin ≤2 mg/dL; participants with Gilbert’s Syndrome may have total bilirubin ≤3 mg/dL • Estimated CrCl ≥40 mL/min using the Cockcroft-Gault formula
- Participant has an LVEF >45% and is NYHA Class 1. For participants ≥60 years of age
- A participant who meets any of the following criteria must achieve either a FEV1/FVC >70% or FEV1 >50% with or without a bronchodilator:: • Has a history of cigarette smoking of ≥20 pack-years • Ceased smoking within the past 2 years or continues to smoke • Has a history of COPD • Has any signs or symptoms of respiratory dysfunction • Has a history of pleural drainage within the past 3 months
- Participant is willing to receive optimal supportive care, including intensive care, from enrollment until the first post treatment tumor assessment.
Exclusion Criteria
- Participant has melanoma of uveal/ocular origin.
- Participant has symptomatic untreated brain metastases. Participants with brain metastases may be evaluated for study participation with the following considerations and only after dicussion with the medical monitor : • Participants with asymptomatic brain metastases not newly diagnosed at Screening and who do not clinically require treatment may be considered for study participation. • A participant with historically treated brain metastases (ie, treatment was completed >28 days prior to consenting for study participation) may be considered for study participation if the participant is clinically stable for ≥2 weeks, there are no new or worsening brain lesions via screening MRI, and the participant does not require ongoing corticosteroid treatment (>10 mg/day prednisone or equivalent). • If there are progressive or new brain metastases on the screening MRI, the participant should first receive treatment for them prior to restarting or continuing screening. A participant with recently treated brain metastases (ie, treatment of brain metastases was completed ≤28 days prior to consenting for study participation) may be considered for study participation if the participant is asymptomatic, clinically stable for ≥2 weeks, and does not require corticosteroids (>10 mg/day prednisone or equivalent). Repeat brain imaging is not required after treatment; however, brain imaging is required at Baseline.
- Participant received any of the following previous therapies: • 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 active uveitis that requires active treatment. Participants with a history of uveitis must have an eye examination performed by a trained eye specialist at Screening to rule out active uveitis that requires treatment.
- Participant has any form of primary or acquired immunodeficiency (eg, SCID or AIDS).
- Participant has a history of hypersensitivity to any component of the study intervention, including, but not limited to, any of the following: • NMA-LD (cyclophosphamide, mesna, and fludarabine) • Proleukin®, aldesleukin, IL-2 • Antibiotics of the aminoglycoside group (ie, streptomycin, gentamicin). These participants may be eligible if current hypersensitivity has been excluded. • Any component of the lifileucel product formulation, including DMSO, HSA, IL-2, or dextran 40 • Pembrolizumab
- 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 including, but not limited to, non-melanoma skin cancer, DCIS, LCIS, prostate cancer Gleason score ≤6, or superficial bladder cancer)
- Participant has a history of allogeneic cell or organ transplant.
- Participant requires systemic steroid therapy >10 mg/day of prednisone or another steroid equivalent dose.
- Participant received or will receive a live or attenuated vaccination within 28 days prior to the start of study medication.
- Participant has evidence of any active viral, bacterial, or fungal infection requiring ongoing systemic treatment or that is identified during screening
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Recruiting | 16 Feb 2024 | 25 |
 Czechia | Not Recruiting | 16 Feb 2024 | 5 |
 Finland | Recruiting | 16 Feb 2024 | 5 |
 France | Recruiting | 16 Feb 2024 | 45 |
 Germany | Recruiting | 16 Feb 2024 | 35 |
 Greece | Not Recruiting | 16 Feb 2024 | 10 |
 Italy | Recruiting | 16 Feb 2024 | 70 |
 The Netherlands | Recruiting | 16 Feb 2024 | — |
 Poland | Not Recruiting | 16 Feb 2024 | 10 |
 Slovenia | Not Recruiting | 16 Feb 2024 | 5 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 400 | 60 | PRD12081134 |
MESNA | Other | — | INFUSION | 240 | 2 | SUB08784MIG |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 400 | 60 | PRD12081132 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 400 | 60 | PRD4323105 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 400 | 60 | PRD12081135 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 400 | 60 | PRD12081133 |
Proleukin 18 x 106 IE Poeder voor oplossing voor injectie of infusie | Other | POEDER VOOR OPLOSSING VOOR INJECTIE OF INFUSIE | INFUSION | 60000 | 4 | PRD11294442 |
Endoxan | Other | SOLUTION FOR INJECTION | INFUSION | 60 | 2 | PRD11980406 |
Флударабин Актавис 25 mg/ml концентрат за инжекционен или инфузионен разтвор | Other | КОНЦЕНТРАТ ЗА ИНЖЕКЦИОНЕН ИЛИ ИНФУЗИОНЕН РАЗТВОР | INFUSION | 25 | 5 | PRD930525 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 400 | 60 | PRD4323784 |