LN-144 + Pembrolizumab for Melanoma

Overseen By James Isaacs, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: James Isaacs, MD

Must not be taking: Antibiotics, Steroids

Disqualifiers: Organ allograft, Brain metastases, others

Stay on Your Current Meds You can continue your current medications while participating

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 1 year

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of a new treatment for individuals with high-risk melanoma, a type of skin cancer. The treatment uses the body's immune cells (LN-144, also known as Lifileucel) and the drug Pembrolizumab (KEYTRUDA, an immunotherapy drug). Individuals diagnosed with certain types of Stage III melanoma who have not received prior immunotherapy may qualify. Participants must have a removable tumor for the study and should not have undergone certain recent treatments. As a Phase 1 trial, the research focuses on understanding the treatment's effects in people, offering the opportunity to be among the first to receive this new approach.

Do I need to stop my current medications to join the trial?

The trial requires a washout period of at least 21 days from any prior anti-cancer therapies before starting the new treatment. However, it does not specify if you need to stop other medications, so it's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Previous studies have shown that LN-144, a type of adoptive cell therapy, can cause some side effects. The most common serious ones include low platelet count, low red blood cell count, and fever with low white blood cell count, affecting more than 30% of patients. Despite these side effects, many patients experienced long-lasting positive effects from the treatment.

Pembrolizumab, used in this study alongside LN-144, has been tested for over a decade and maintains a consistent safety record. In some cases, it caused serious side effects in about half of the users, including immune system problems and infusion reactions. Despite these risks, pembrolizumab has demonstrated strong anti-cancer effects and improved survival rates for many patients with advanced melanoma.

Both treatments are currently being tested together in this trial, so their combined safety is still under study. However, each has a track record that provides insights into what participants might expect. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for melanoma, which often include surgery, targeted therapies, and immunotherapies like checkpoint inhibitors, LN-144 offers a unique approach by harnessing the patient’s own immune cells. LN-144 is a type of tumor-infiltrating lymphocyte (TIL) therapy, which involves extracting immune cells directly from the tumor, expanding them in a lab, and then infusing them back into the patient to boost the body's natural ability to fight cancer. This personalized approach may enhance the immune system's precision in targeting melanoma cells. Researchers are excited about LN-144 because it represents a novel way to leverage the body's own defenses, potentially leading to more effective and durable responses in patients with advanced melanoma.

What evidence suggests that LN-144 and Pembrolizumab could be effective for melanoma?

Research has shown that LN-144, also known as lifileucel, may help treat advanced melanoma. Studies have found that about 19.7% of patients remained alive after 5 years, offering hope to those with limited treatment options. In this trial, all participants will receive LN-144 therapy, which includes an infusion of pembrolizumab. Pembrolizumab, a well-known treatment for advanced melanoma, has proven effective, with a 5-year survival rate of 41%, and after 10 years, 34% of patients remained alive. Together, these treatments offer potential for improving survival in melanoma patients. ^{1 3 6 7 8}

Who Is on the Research Team?

James Isaacs, MD

Principal Investigator

Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults over 18 with high-risk Stage III melanoma that can be surgically removed. They should have a life expectancy of at least 3 months, good performance status (able to carry out daily activities), and no prior immunotherapy. Participants need one tumor lesion suitable for TIL harvesting and adequate organ function. Those who've had recent cancer treatments must wait at least 21 days before joining.

Inclusion Criteria

Patients must have adequate organ function: Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times the upper limit of normal (≤ 3 × ULN); patients with liver metastasis ≤ 5 × ULN, Estimated creatinine clearance (eCrCl) ≥ 40 mL/min using the Cockcroft-Gault formula at Screening, Total bilirubin ≤ 2 mg/dL, Patients with Gilbert's syndrome must have a total bilirubin ≤ 3 mg/dL

Patients of childbearing potential (or female partners of male participants) must be willing to take the appropriate precaution to avoid pregnancy or fathering a child for the duration of the study and practice an approved, highly effective method of birth control during treatment and for 12 months after their last dose of IL-2

I understand the study's requirements, have signed the consent form, and agree to follow the study rules and attend all required visits.

Exclusion Criteria

Patients who have a history of hypersensitivity to any component or excipient of LN-144 or other study drugs

I do not have any active illnesses that could increase my risk in the study.

Participated in another clinical study with an investigational product within 21 days of the initiation of treatment

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Harvest and Production

Surgical resection of tumor tissue to provide autologous tissue for LN-144 production at a GMP facility

3-4 weeks

Nonmyeloablative Lymphodepletion

A 5-day nonmyeloablative lymphodepletion (NMA-LD) preparative regimen

1 week

Treatment

Infusion of LN-144 product followed by administration of IV interleukin-2 (IL-2) for ≤ 6 doses and pembrolizumab every 3 weeks for up to 1 year

1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment, including relapse-free survival and overall survival

3 years

What Are the Treatments Tested in This Trial?

Interventions

• LN-144
• Pembrolizumab

Trial Overview The study tests the effectiveness of LN-144 (a type of adoptive cell therapy using patient's own immune cells) combined with IL-2 after chemotherapy preparation, followed by Pembrolizumab treatment in patients with resectable melanoma.

How Is the Trial Designed?

Group I: LN-144 Therapy Experimental Treatment 6 Interventions

All patients will receive LN-144 therapy, consisting of these steps: 1. Harvest (surgical resection of tumor tissue) to provide the autologous tissue that serves as the source of LN-144. 2. Production of LN-144 investigational product (IP) at a central Good Manufacturing Practice (GMP) facility 3. A 5-day nonmyeloablative lymphodepletion (NMA-LD) preparative regimen 4. Infusion of the LN-144 product (Day 0) 5. Administration of IV interleukin-2 (IL-2) for ≤ 6 doses. 6. Infusion of pembrolizumab 200 mg (Week 12) every 3 weeks for up to 1 year (17 cycles)

LN-144 is already approved in United States for the following indications:

Approved in United States as Lifileucel for:

• Advanced unresectable or metastatic melanoma who progressed on or after prior anti–PD-1/L1 therapy and targeted therapy

Who Is Running the Clinical Trial?

James Isaacs, MD

Lead Sponsor

Trials

1

Recruited

10+

Iovance Biotherapeutics, Inc.

Industry Sponsor

Trials

26

Recruited

1,800+

Published Research Related to This Trial

Pembrolizumab (PEM) significantly improved short-term treatment effectiveness and long-term survival rates in patients with advanced cutaneous malignant melanoma compared to chemotherapy with Temozolomide, with a notable increase in one-year survival rates (53.85% vs. 40.00%).

The use of PEM did not lead to a higher incidence of adverse reactions compared to the control group, indicating that it is a relatively safe treatment option for patients with this type of melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical application effect of Pembrolizumab in the treatment of advanced cutaneous malignant melanoma. Fu, L., Zhang, H., Jiang, J., et al.[2021]

In a study of 88 advanced melanoma patients treated with pembrolizumab, 81.8% experienced any-grade toxicities, with skin and gastrointestinal issues being the most common side effects.

Despite the high incidence of side effects, pembrolizumab was found to be well tolerated in real-world settings, and severe toxicities were manageable with systemic steroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world experience with pembrolizumab toxicities in advanced melanoma patients: a single-center experience in the UK. So, AC., Board, RE.[2022]

In a post hoc analysis of the KEYNOTE-006 study involving 555 patients with advanced melanoma, both ipilimumab and BRAF ± MEK inhibitors showed antitumor activity as subsequent therapies after pembrolizumab, with overall response rates (ORR) of 17.5% for ipilimumab and 30.5% for BRAF ± MEK inhibitors.

Patients who had not previously received BRAF ± MEK inhibitors showed a significantly higher ORR of 43.2% when treated with these agents after pembrolizumab, indicating that prior treatment status may influence the effectiveness of subsequent therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of ipilimumab or BRAF ± MEK inhibition after pembrolizumab treatment in patients with advanced melanoma: analysis from KEYNOTE-006. Long, GV., Arance, A., Mortier, L., et al.[2022]

In a study of 103 Chinese patients with advanced melanoma, pembrolizumab demonstrated a 16.7% objective response rate, indicating its effectiveness as a second-line treatment, particularly in aggressive melanoma subtypes.

The treatment was well tolerated, with 84.5% of patients experiencing treatment-related adverse events, but only a small percentage (8.7%) had severe side effects, and no treatment-related deaths occurred.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase Ib Study of Pembrolizumab as Second-Line Therapy for Chinese Patients With Advanced or Metastatic Melanoma (KEYNOTE-151). Si, L., Zhang, X., Shu, Y., et al.[2020]

Pembrolizumab, an anti-PD-1 antibody, has shown significant efficacy in treating advanced melanoma, demonstrating superior progression-free survival compared to chemotherapy in Phase II trials and improved overall survival in Phase III trials.

The treatment is generally well tolerated with a favorable safety profile, though common side effects include fatigue and rash, while less frequent but serious immune-related adverse events can occur.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in the management of metastatic melanoma. Spain, L., Younger, E., Hatipoglu, E., et al.[2020]

In the phase III trial, pembrolizumab significantly improved recurrence-free survival in patients with stage III cutaneous melanoma, with a 3-year progression-free survival (PFS) rate of 32% for those who crossed over from placebo to treatment after recurrence.

The safety profile showed that 37% of patients experienced immune-related adverse events (irAEs), with 7% having severe (grade III-V) events, indicating that while pembrolizumab is effective, it does carry a risk of significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Crossover and rechallenge with pembrolizumab in recurrent patients from the EORTC 1325-MG/Keynote-054 phase III trial, pembrolizumab versus placebo after complete resection of high-risk stage III melanoma. Eggermont, AM., Meshcheryakov, A., Atkinson, V., et al.[2021]

In a study of 655 patients with advanced melanoma, pembrolizumab showed a 5-year overall survival rate of 34%, with even better outcomes (41%) for treatment-naive patients, indicating its long-term efficacy.

The treatment was generally well-tolerated, with 86% of patients experiencing treatment-related adverse events, but only 7.8% discontinued due to these effects, suggesting a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Hamid, O., Robert, C., Daud, A., et al.[2023]

In a study of 355 patients with metastatic melanoma resistant to anti-PD-(L)1 therapy, combining ipilimumab with anti-PD-1 (either pembrolizumab or nivolumab) resulted in a significantly higher objective response rate (31%) compared to ipilimumab alone (13%).

Patients receiving the combination therapy also experienced longer overall survival (20.4 months vs. 8.8 months) and longer progression-free survival (3.0 months vs. 2.6 months), while the rates of severe adverse events were similar between the two treatment groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study. Pires da Silva, I., Ahmed, T., Reijers, ILM., et al.[2021]

In a study involving 173 patients with advanced melanoma who had not responded to previous treatments, pembrolizumab showed an overall response rate of 26% at both 2 mg/kg and 10 mg/kg doses, indicating its potential effectiveness in this challenging patient population.

The treatment was well tolerated with no drug-related deaths, and the safety profiles were similar across both doses, with fatigue, pruritus, and rash being the most common side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Robert, C., Ribas, A., Wolchok, JD., et al.[2022]

In a long-term safety analysis of pembrolizumab involving 1567 melanoma patients over a median follow-up of 42.4 months, most adverse events were mild to moderate, with serious treatment-related adverse events occurring in 17.7% of patients, and only two deaths attributed to the drug.

The efficacy of pembrolizumab remained consistent regardless of the occurrence of immune-mediated adverse events or the use of systemic corticosteroids, indicating that these factors did not significantly impact treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety of pembrolizumab monotherapy and relationship with clinical outcome: A landmark analysis in patients with advanced melanoma. Robert, C., Hwu, WJ., Hamid, O., et al.[2021]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.9515

Lifileucel in patients with advanced melanoma: 5-year ... Median time to best response was 1.5 mo (range, 1.3–30.4). Median OS was 13.9 mo (95% CI: 10.6–17.8); the 5-year OS rate was 19.7% (95% CI: 13.3 ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40454684/

Long-term Efficacy and Safety of Lifileucel Tumor ... Median overall survival (OS) was 13.9 months, with 5-year OS of 19.7%. Adverse events were consistent with nonmyeloablative lymphodepletion and ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT02360579

NCT02360579 | Study of Lifileucel (LN-144), Autologous ... Evaluate the efficacy of LN-144 in patients with unresectable or metastatic melanoma using the objective response rate (ORR), as assessed by the Blinded ...

4. onclive.com onclive.com/view/lifileucel-shows-durable-5-year-benefit-in-advanced-melanoma-resistant-to-immune-checkpoint-inhibitors

Lifileucel Shows Durable 5-Year Benefit in Advanced ... The data showed that one-time lifileucel therapy produced durable responses, with a 5-year overall survival rate of 19.7%. 1 Notably, after the ...

5. jitc.bmj.com jitc.bmj.com/content/11/Suppl_1/A873

776 Long-term efficacy and safety of lifileucel tumor ... In heavily pretreated patients with advanced melanoma, one-time lifileucel TIL cell therapy demonstrated a 4-year OS rate of 22.2%, and 20.8% of ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO-25-00765

Long-Term Efficacy and Safety of Lifileucel Tumor ... One-time lifileucel therapy resulted in durable responses and a 5-year OS rate of 19.7%; 31.3% of responders completed the 5-year assessment ...

7. jitc.bmj.com jitc.bmj.com/content/10/12/e005755

Efficacy and safety of lifileucel, a one-time autologous ... Lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, demonstrated an investigator-assessed objective response rate (ORR) of 36% ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36600653/

Efficacy and safety of lifileucel, a one-time autologous tumor ... The most common grade 3/4 treatment-emergent adverse events (≥30%) were thrombocytopenia (76.9%), anemia (50.0%), and febrile neutropenia (41.7%). Conclusions: ...