PD-1 Inhibitor Therapy Duration for Melanoma

(STOP-GAP Trial)

Recruiting at 38 trial locations

Overseen By Janet Dancey

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Canadian Cancer Trials Group

Must be taking: PD-1 inhibitors

Disqualifiers: Contraindications to PD-1, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 104 weeks

614 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to compare the effects on patients with metastatic melanoma of taking a government approved and paid-for PD-1 inhibitor intermittently, with taking the same type of agent continuously. Researchers want to see if the two ways of giving this type of treatment work equally well in extending the life of patients with melanoma, or not.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are on anti-PD-1 therapy, you may need to stop it if you are randomized to the intermittent treatment group.

What data supports the effectiveness of the PD-1 inhibitor drug for melanoma?

Research shows that PD-1 inhibitors can lead to long-lasting benefits for melanoma patients, with some achieving complete or partial responses even after stopping the drug. Studies indicate that these drugs have improved survival rates, with some patients experiencing durable remissions. ^{1 2 3 4 5}

Is PD-1 inhibitor therapy generally safe for humans?

PD-1 inhibitors, like nivolumab and pembrolizumab, are generally safer than older treatments, but they can still cause side effects, mostly related to the immune system. Most side effects are mild and manageable, but some can be serious, affecting the skin, lungs, and nerves. ^{6 7 8 9 10}

How is PD-1 inhibitor therapy different from other treatments for melanoma?

PD-1 inhibitors are unique because they help the immune system recognize and attack melanoma cells by blocking a protein that prevents immune cells from attacking cancer. Unlike traditional chemotherapy, which directly kills cancer cells, PD-1 inhibitors work by enhancing the body's natural immune response to fight the cancer. ^{1 4 11 12 13}

Research Team

Xinni Song

Principal Investigator

Ottawa Hospital Research Institute

Tara Baetz

Principal Investigator

Cancer Centre of Southeastern Ontario at Kingston

Eligibility Criteria

Adults with metastatic melanoma who are eligible for government-funded PD-1 inhibitor therapy can join. They must have stable disease, including brain metastases if present, and be willing to complete questionnaires in English or French. Those not willing to potentially pause treatment or with contraindications to PD-1 inhibitors cannot participate.

Inclusion Criteria

Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements

My cancer cannot be removed by surgery and can be monitored but doesn't need to be measurable.

My cancer has not worsened and I have no new or growing brain tumors for at least 4 weeks.

Exclusion Criteria

I am not willing to stop my anti-PD-1 therapy if required.

I cannot take PD-1 inhibitors due to health risks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive PD-1 inhibitor therapy either continuously or intermittently for up to 2 years

Up to 104 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Treatment Details

Interventions

• PD-1 inhibitor

Trial Overview The trial is testing two methods of administering a PD-1 inhibitor: intermittently stopping and restarting treatment versus continuous use without breaks. The goal is to see which method better extends the lives of patients with metastatic melanoma.

Participant Groups

Group I: Arm 1: Intermittent PD-1 Inhibitor therapy Active Control 1 Intervention

Any PD-1 inhibitor that is commercially available, government approved and publicly funded. Dose as recommended by the manufacturer.

Group II: Arm 2: Continuous PD-1 Inhibitor therapy Active Control 1 Intervention

Any PD-1 inhibitor that is commercially available, government approved and publicly funded. Dose as recommended by the manufacturer.

PD-1 inhibitor is already approved in United States, European Union, China for the following indications:

Approved in United States as Nivolumab (Opdivo) for:

• Melanoma
• Non-small cell lung cancer
• Kidney cancer
• Head and neck cancers
• Hodgkin lymphoma
• Colorectal cancer
• Hepatocellular carcinoma
• Urothelial carcinoma

Approved in United States as Pembrolizumab (Keytruda) for:

• Melanoma
• Non-small cell lung cancer
• Head and neck cancers
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Endometrial carcinoma
• Cervical cancer
• Esophageal cancer
• Cutaneous squamous cell carcinoma

Approved in United States as Cemiplimab (Libtayo) for:

• Cutaneous squamous cell carcinoma
• Non-small cell lung cancer

Approved in European Union as Nivolumab (Opdivo) for:

• Melanoma
• Non-small cell lung cancer
• Kidney cancer
• Head and neck cancers
• Hodgkin lymphoma
• Colorectal cancer
• Urothelial carcinoma

Approved in European Union as Pembrolizumab (Keytruda) for:

• Melanoma
• Non-small cell lung cancer
• Head and neck cancers
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma

Approved in European Union as Cemiplimab (Libtayo) for:

• Cutaneous squamous cell carcinoma

Approved in China as Toripalimab (Loqtorzi) for:

• Melanoma
• Non-small cell lung cancer
• Urothelial carcinoma

Approved in United States as Toripalimab (Loqtorzi) for:

• Nasopharyngeal carcinoma

Who Is Running the Clinical Trial?

Canadian Cancer Trials Group

Lead Sponsor

Trials

135

Recruited

70,300+

Melanoma and Skin Cancer Trials Limited

Collaborator

Trials

18

Recruited

6,500+

Findings from Research

In a study of 52 patients with metastatic melanoma who discontinued PD-1 therapy after 1 year, 75% remained without disease progression after a median follow-up of 20.5 months, suggesting that shorter treatment durations may be effective.

The findings indicate that elective discontinuation of PD-1 inhibitors at 1 year could potentially reduce treatment costs and side effects without compromising patient outcomes, as most patients maintained stable disease or responded positively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world experience with elective discontinuation of PD-1 inhibitors at 1 year in patients with metastatic melanoma. Pokorny, R., McPherson, JP., Haaland, B., et al.[2023]

Recent advancements in melanoma treatment have improved the 5-year survival rate from approximately 10% to around 20%, particularly for patients receiving immunotherapy like high-dose interleukin-2 and ipilimumab, which can lead to long-term survival of at least 5 years.

The review emphasizes the need for combination strategies in immunotherapy and targeted agents to enhance durable benefits and survival rates, while also addressing the limitations of traditional evaluation metrics and emerging clinical decision-making challenges.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durable benefit and the potential for long-term survival with immunotherapy in advanced melanoma. McDermott, D., Lebbé, C., Hodi, FS., et al.[2022]

Immune checkpoint inhibitors significantly improve overall survival and progression-free survival in patients with advanced melanoma, offering hope where traditional treatments have limited effectiveness.

While these treatments can cause immune-related adverse events, most are manageable, and their benefits can persist even after treatment is stopped, highlighting their potential as a long-term therapy option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melanoma and Immune Checkpoint Inhibitors. Furue, M., Ito, T., Wada, N., et al.[2019]

In a study of 237 patients with metastatic melanoma, 85.7% maintained progression-free survival (PFS) after discontinuing anti-PD-1 therapy, indicating that long-lasting responses can occur even after treatment stops.

Recurrences were more common in patients who did not achieve a complete response (CR) before stopping treatment, with only 7.8% of those who discontinued in CR experiencing disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discontinuation of anti-PD1 in advanced melanoma: an observational retrospective study from the Italian Melanoma Intergroup. Rubatto, M., Fava, P., Stanganelli, I., et al.[2023]

In a study of 324 advanced melanoma patients who discontinued anti-PD-1 treatment without disease progression, those with a complete response had a median treatment duration of 11.2 months and showed a 64% progression-free survival rate at 24 months.

Patients who were re-treated with anti-PD-1 after initial discontinuation had a 63% response rate, indicating that durable remissions can occur even after stopping treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discontinuation of anti-PD-1 monotherapy in advanced melanoma-Outcomes of daily clinical practice. van Zeijl, MCT., van den Eertwegh, AJM., Wouters, MWJM., et al.[2022]

Immunotherapies, particularly anti-PD-1 checkpoint inhibitors like nivolumab and pembrolizumab, have significantly improved survival rates for metastatic melanoma patients while being less toxic than traditional treatments.

Despite their better tolerability, anti-PD-1 therapies can still cause a range of immune-related adverse events, most of which are mild, but there is a pressing need to understand and manage severe side effects due to the increased life expectancy of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety of anti PD-1 therapeutics for the treatment of melanoma. Ramelyte, E., Schindler, SA., Dummer, R.[2018]

In a meta-analysis of 11,465 patients from 18 clinical trials, PD-1/PD-L1 inhibitors were found to significantly increase the risk of developing dermatologic adverse effects like rash and pruritus compared to chemotherapy, with relative risks of 1.84 and 3.74, respectively.

PD-1/PD-L1 inhibitors showed a lower risk of mucosal inflammation and alopecia compared to chemotherapy, indicating a distinct safety profile that differs from traditional cancer treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of dermatologic and mucosal adverse events associated with PD-1/PD-L1 inhibitors in cancer patients: A meta-analysis of randomized controlled trials. Yang, W., Li, S., Yang, Q.[2021]

A patient with primary central nervous system diffuse large B-cell lymphoma developed an atypical skin reaction resembling erythema multiforme after treatment with the PD-1 inhibitor nivolumab, highlighting a potential adverse effect of this immunotherapy.

The skin condition improved significantly after stopping nivolumab and administering glucocorticoids, emphasizing the importance of recognizing and managing rare dermatologic toxicities associated with PD-1 inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A 65-Year-Old Male with Primary Central Nervous System Diffuse Large B-Cell Lymphoma on Nivolumab with Oral Mucositis and Targetoid Plaques. Cao, S., Rohani, P., Nazarian, RM., et al.[2022]

PD-1 inhibitor therapies are effective standard treatments for advanced melanoma, but they can cause unique immune-related adverse events (irAEs) that differ from traditional chemotherapy side effects.

Nurses play a crucial role in recognizing and managing these irAEs, and the article provides consensus statements and care pathways to help them support patients effectively during PD-1 inhibitor therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-1 Inhibitor Therapy: Consensus Statement From the Faculty of the Melanoma Nursing Initiative on Managing Adverse Events . McGettigan, S., Rubin, KM.[2018]

In a study of 5 patients undergoing anti-PD1/PDL1 therapy for various cancers, psoriasis exacerbation was observed, particularly severe in those treated with durvalumab, highlighting a potential side effect of these immunotherapies.

Patients with a personal or family history of psoriasis are at increased risk for exacerbations during treatment, emphasizing the need for careful skin monitoring to manage potential adverse effects and maintain treatment continuity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-PD1/PDL1 induced psoriasis. Voudouri, D., Nikolaou, V., Laschos, K., et al.[2022]

In a study of 38 patients with metastatic melanoma treated with a limited six-month PD-1 blockade program, the overall response rate was 39%, but only 33% of these responses were ongoing, indicating a shorter duration of response compared to other studies.

The median progression-free survival for patients who completed the six-month treatment was 12 months, suggesting that while the treatment is effective, limiting the duration may risk reducing the length of time patients benefit from the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Limited-duration anti-PD-1 therapy for patients with metastatic melanoma. Mäkelä, S., Kohtamäki, L., Laukka, M., et al.[2020]

In a study of 41 metastatic melanoma patients with preexisting autoimmune disorders or previous immune-related adverse events (irAE), 42% experienced a flare of their autoimmune conditions during PD-1 inhibitor therapy, but these were manageable and did not require stopping treatment.

Despite the flares, the response rates to PD-1 inhibitors were promising, with 32% in patients with preexisting autoimmunity and 45% in those with previous irAE, indicating that PD-1 therapy can be safely considered for these patients based on the severity of their conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed cell death protein-1 (PD-1) inhibitor therapy in patients with advanced melanoma and preexisting autoimmunity or ipilimumab-triggered autoimmunity. Gutzmer, R., Koop, A., Meier, F., et al.[2018]

In a study of 139 patients with advanced melanoma treated with anti-PD-1 therapy, those who survived at least 5 years showed a remarkable overall survival rate of 90.1% at 7 years, indicating strong long-term efficacy of the treatment.

Patients who completed their anti-PD-1 therapy without needing further treatment by the 5-year mark had a 95.7% chance of remaining treatment-free for an additional 2 years, suggesting a favorable long-term prognosis for these individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beyond the 5-year milestone: Long-term survivorship of melanoma patients treated off-trial with anti-PD-1. Loo, K., Kalvin, HL., Panageas, KS., et al.[2023]

References

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

Real-world experience with elective discontinuation of PD-1 inhibitors at 1 year in patients with metastatic melanoma. [2023]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Durable benefit and the potential for long-term survival with immunotherapy in advanced melanoma. [2022]

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

Melanoma and Immune Checkpoint Inhibitors. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Discontinuation of anti-PD1 in advanced melanoma: an observational retrospective study from the Italian Melanoma Intergroup. [2023]

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

Discontinuation of anti-PD-1 monotherapy in advanced melanoma-Outcomes of daily clinical practice. [2022]

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

The safety of anti PD-1 therapeutics for the treatment of melanoma. [2018]

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

Risk of dermatologic and mucosal adverse events associated with PD-1/PD-L1 inhibitors in cancer patients: A meta-analysis of randomized controlled trials. [2021]

8. Switzerland pubmed.ncbi.nlm.nih.gov

A 65-Year-Old Male with Primary Central Nervous System Diffuse Large B-Cell Lymphoma on Nivolumab with Oral Mucositis and Targetoid Plaques. [2022]

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

PD-1 Inhibitor Therapy: Consensus Statement From the Faculty of the Melanoma Nursing Initiative on Managing Adverse Events . [2018]

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

Anti-PD1/PDL1 induced psoriasis. [2022]

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

Limited-duration anti-PD-1 therapy for patients with metastatic melanoma. [2020]

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

Programmed cell death protein-1 (PD-1) inhibitor therapy in patients with advanced melanoma and preexisting autoimmunity or ipilimumab-triggered autoimmunity. [2018]

13. England pubmed.ncbi.nlm.nih.gov

Beyond the 5-year milestone: Long-term survivorship of melanoma patients treated off-trial with anti-PD-1. [2023]