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

Trial Summary

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.

What data supports the effectiveness of the drug LN-144 + Pembrolizumab for treating melanoma?

Research shows that pembrolizumab, a part of this treatment, has strong antitumor effects and is safe for patients with advanced melanoma, including those with aggressive forms. It has been effective in patients who did not respond to other treatments, providing long-term disease control for some. ^{1 2 3 4 5}

Is the combination of LN-144 and Pembrolizumab safe for treating melanoma?

Pembrolizumab, also known as KEYTRUDA, has been shown to be generally safe in treating advanced melanoma, with common side effects including tiredness, rash, itching, and diarrhea. Less common side effects can include thyroid issues, inflammation of the colon, liver, or lungs. ^{2 6 7 8 9}

What makes the treatment LN-144 + Pembrolizumab unique for melanoma?

LN-144 (Lifileucel) is a type of cell therapy that uses a patient's own immune cells to fight cancer, which is different from traditional drugs like pembrolizumab that block proteins to boost the immune response. This combination aims to enhance the body's ability to attack melanoma by using both personalized cell therapy and immune checkpoint inhibition. ^{1 3 4 8 10}

What is the purpose of this trial?

The purpose of this study is to evaluate the efficacy of adjuvant adoptive cell therapy (ACT) via infusion of LN-144 (autologous TIL) followed by interleukin-2 (IL-2) after a nonmyeloablative lymphodepletion (NMA-LD) preparative regimen, followed by Pembrolizumab.

Research Team

James Isaacs, MD

Principal Investigator

Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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 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 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]

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 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 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]

References

1. England 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. [2022]

2. United States 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). [2020]

3. England 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. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Clinical application effect of Pembrolizumab in the treatment of advanced cutaneous malignant melanoma. [2021]

5. England 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. [2021]

6. England pubmed.ncbi.nlm.nih.gov

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

7. England pubmed.ncbi.nlm.nih.gov

Long-term safety of pembrolizumab monotherapy and relationship with clinical outcome: A landmark analysis in patients with advanced melanoma. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab in the management of metastatic melanoma. [2020]

9. England pubmed.ncbi.nlm.nih.gov

Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. [2023]

10. England 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. [2021]