Combination Immunotherapy for Stage III Melanoma

Overseen By Michael Egger, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Louisville

Must not be taking: Oncolytic viruses, PD-1 inhibitors

Disqualifiers: Metastatic disease, Mucosal melanoma, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 9

Duration: 6 months

28 Participants Needed

Trial Summary

What is the purpose of this trial?

Determine safety and efficacy of pre-operative combination immunotherapy with Talimogene Laherparepvec (T-VEC)/Pembrolizumab given prior to complete lymph node dissection in resectable stage 3 cutaneous melanoma with clinically apparent lymph node metastases.

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

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you have used certain treatments like T-VEC, pembrolizumab, or other similar drugs before, or if you require ongoing treatment with anti-herpetic drugs.

What data supports the effectiveness of the drug pembrolizumab for stage III melanoma?

Research shows that pembrolizumab helps patients with stage III melanoma live longer without the cancer coming back. In a study, 75.4% of patients who took pembrolizumab were cancer-free after a year, compared to 61% who took a placebo (a harmless pill with no active drug). ^{1 2 3 4 5}

Is the combination immunotherapy for Stage III Melanoma safe for humans?

Pembrolizumab, a part of the combination immunotherapy, has been shown to be generally safe in humans, with common side effects including fatigue, rash, itching, and diarrhea. Less common but more serious side effects can include inflammation of the lungs (pneumonitis), liver (hepatitis), and thyroid issues. ^{6 7 8 9 10}

How is the drug pembrolizumab unique for treating stage III melanoma?

Pembrolizumab is unique because it is a PD-1 inhibitor that helps the immune system attack cancer cells by blocking a pathway that usually keeps immune cells from attacking. It has shown high response rates with low toxicity and is used as an adjuvant therapy to improve recurrence-free survival in stage III melanoma patients. ^{1 4 11 12 13}

Research Team

Michael Egger, MD

Principal Investigator

University of Louisville

Eligibility Criteria

Adults with stage III melanoma that can be surgically removed and have not been treated with T-VEC, pembrolizumab, or similar drugs. Participants must have good performance status, adequate organ function, measurable disease for injection therapy, and no history of certain autoimmune diseases or other cancers within the last three years.

Inclusion Criteria

I have a cancer that can be measured and a lymph node that can be injected for treatment.

My melanoma was diagnosed at stage III or has returned to stage III after initial treatment.

My stage III melanoma is confirmed to be removable by surgery, as determined by a specialist.

Exclusion Criteria

I don't have a history of serious autoimmune diseases or recent treatments for them.

I don't have active herpes skin sores or need regular herpes medication.

I haven't had any cancer except for non-melanoma skin cancer in the last 3 years.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Pre-operative combination immunotherapy with T-VEC and Pembrolizumab administered every 3 weeks for 6 months

6 months

Intra-lesional injection and intravenous administration every 3 weeks

Surgery

Complete lymph node dissection performed after 6 months of treatment

Adjuvant Treatment

Pembrolizumab administered intravenously every 3 weeks for one year following surgery

1 year

Intravenous administration every 3 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Every 3 months

Treatment Details

Interventions

• Pembrolizumab
• Talimogene Laherparepvec

Trial Overview The trial is testing the safety and effectiveness of a combination immunotherapy (Talimogene Laherparepvec plus Pembrolizumab) given before surgery to remove lymph nodes affected by melanoma in patients who are at an advanced stage but not metastatic.

Participant Groups

Group I: Combination T-VEC/Pembrolizumab Experimental Treatment 2 Interventions

Pre-operative talimogene laherparepvec (T-VEC) with Pembrolizumab T-VEC - intra-lesional injection into palpable lymph nodes every 3 weeks for 6 months, or until complete response of target tumors. Pembrolizumab - administered intravenously every 3 weeks for 6 months, then every 3 weeks for one year in the adjuvant setting following complete lymph node dissection.

Pembrolizumab is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

University of Louisville

Lead Sponsor

Trials

353

Recruited

76,400+

Findings from Research

In a phase 3 trial involving 1019 patients with resected high-risk stage III melanoma, pembrolizumab significantly improved distant metastasis-free survival at 3.5 years, with 65.3% of patients in the pembrolizumab group remaining free of distant metastasis compared to 49.4% in the placebo group (HR 0.60).

The study also showed that pembrolizumab led to longer recurrence-free survival, with 59.8% of patients in the pembrolizumab group remaining free of recurrence compared to 41.4% in the placebo group, reinforcing its efficacy as an adjuvant therapy for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. Eggermont, AMM., Blank, CU., Mandalà, M., et al.[2021]

In a phase 3 trial involving 1,019 patients with resected high-risk stage III melanoma, pembrolizumab significantly improved recurrence-free survival compared to placebo, with a 1-year rate of 75.4% versus 61.0%.

While pembrolizumab was effective, it was associated with a higher rate of severe adverse events (14.7% vs. 3.4% in the placebo group), including one treatment-related death, indicating the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. Eggermont, AMM., Blank, CU., Mandala, M., et al.[2022]

In a randomized trial comparing FDA-approved immune checkpoint inhibitors for advanced melanoma, pembrolizumab showed significantly better treatment outcomes than ipilimumab.

This study is notable as it is the first to directly compare these two therapies as first-line treatments, highlighting pembrolizumab's potential as a more effective option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab superior to ipilimumab in melanoma. [2017]

In a clinical trial, the PD-1 inhibitor pembrolizumab demonstrated a 12-month recurrence-free survival rate of 75.4% in patients with stage III melanoma, indicating its potential effectiveness as an adjuvant therapy.

In comparison, patients receiving a placebo had a lower recurrence-free survival rate of 61%, highlighting the benefit of pembrolizumab over standard treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant Therapy for Melanoma Prolongs RFS. [2019]

In a phase III trial involving 1,019 patients with resected high-risk stage III melanoma, pembrolizumab significantly prolonged recurrence-free survival (RFS) compared to placebo, with a 3-year RFS rate of 63.7% versus 44.1%.

The benefits of pembrolizumab were consistent across various patient subgroups, including those with different tumor stages and BRAF mutation statuses, indicating its broad efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial. Eggermont, AMM., Blank, CU., Mandala, M., et al.[2023]

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]

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]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating unresectable or metastatic melanoma based on two clinical trials involving 1,374 patients, showing significant improvements in overall survival compared to ipilimumab, with hazard ratios indicating a reduced risk of death.

Patients receiving pembrolizumab also experienced significant improvements in progression-free survival, although some immune-mediated adverse reactions like hypothyroidism and pneumonitis were noted, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. Barone, A., Hazarika, M., Theoret, MR., et al.[2022]

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]

Pembrolizumab is a monoclonal antibody that effectively blocks the PD-1 receptor on T cells, enhancing their ability to attack cancer cells, particularly in melanoma patients.

In a Phase I study involving 411 patients, pembrolizumab demonstrated high durable response rates with minimal toxicity, indicating its potential as a safe and effective treatment option for melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. Hersey, P., Gowrishankar, K.[2017]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

Pembrolizumab (Keytruda) is the first anti-PD-1 therapy approved in the US for treating advanced malignant melanoma, specifically for patients who have progressed after prior treatments.

It is designed to target the PD-1 protein, enhancing the immune system's ability to fight cancer, and is currently under review for approval in the EU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab: first global approval. Poole, RM.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. [2021]

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

Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. [2022]

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

Pembrolizumab superior to ipilimumab in melanoma. [2017]

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

Adjuvant Therapy for Melanoma Prolongs RFS. [2019]

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

Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial. [2023]

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

Pembrolizumab in the management of metastatic melanoma. [2020]

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

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021]

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

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. [2022]

10. England pubmed.ncbi.nlm.nih.gov

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

11. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. [2017]

12. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017]

13. New Zealand pubmed.ncbi.nlm.nih.gov

Pembrolizumab: first global approval. [2021]