Biomarker-Guided Immunotherapy Discontinuation for Melanoma

Recruiting at 456 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: ECOG-ACRIN Cancer Research Group

Must be taking: Anti-PD-1 therapy

Must not be taking: Anticoagulation therapy

Disqualifiers: Brain metastases, Pregnancy, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 52 weeks

150 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial uses drugs that boost the immune system to fight advanced melanoma that can't be surgically removed. It aims to see if doctors can safely shorten the treatment period by using imaging tests to guide decisions. Pembrolizumab and ipilimumab are immunotherapy drugs used to treat advanced melanoma, with pembrolizumab approved for younger patients and ipilimumab showing positive results in previous studies.

Do I have to stop taking my current medications for the trial?

The trial does not specify if you need to stop taking your current medications, but you must not be on other anti-tumor therapies besides the standard anti-PD-1 regimens. If you are on anticoagulation therapy, you may need to pause it for a biopsy procedure.

What safety data exists for pembrolizumab and other similar treatments in humans?

Pembrolizumab (Keytruda) and similar treatments like ipilimumab (Yervoy) and nivolumab (Opdivo) have been generally well-tolerated in clinical trials for melanoma, with common side effects including fatigue, rash, itching, and diarrhea. Some less common but serious immune-related side effects include inflammation of the lungs (pneumonitis), liver (hepatitis), and intestines (colitis), as well as thyroid problems. ^{1 2 3 4 5}

How is the drug Nivolumab or Pembrolizumab unique for treating melanoma?

Nivolumab and Pembrolizumab are unique for treating melanoma because they are immune checkpoint inhibitors that help the immune system recognize and attack cancer cells. Pembrolizumab has shown better outcomes compared to ipilimumab and can lead to durable complete remission even after discontinuation, offering hope for long-term survival. ^{6 7 8 9 10}

What data supports the effectiveness of this drug for melanoma?

Research shows that pembrolizumab works better than ipilimumab for treating advanced melanoma, and nivolumab has shown long-term survival benefits. These drugs, along with others like ipilimumab and nivolumab/ipilimumab combinations, have improved outcomes for melanoma patients, although there are differences in how long patients stay on these treatments. ^{7 8 9 10 11}

Who Is on the Research Team?

Geoffrey T Gibney

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

This trial is for adults with unresectable stage IIIB-IV melanoma. Participants must have had a positive response to initial anti-PD-1 therapy, meet specific health criteria (like normal organ function tests), and not be pregnant or breastfeeding. They should not have brain metastases or other conditions that could affect the study's safety or results.

Inclusion Criteria

Your platelet count is at least 100,000 per microliter, as measured within the last 4 weeks before joining the study.

My heart function is classified as class 2B or better, despite my history of heart issues or treatments.

Your total bilirubin level should be within the normal range, unless you have a history of Gilbert's syndrome, in which case it can be slightly higher.

Exclusion Criteria

I am using or willing to use effective birth control during and after the study as required.

I do not have cancer that has spread to my brain.

Women must not be pregnant or breast-feeding due to potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the anti-PD-1 regimens being used. All females of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy. A female of childbearing potential is defined as any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive standard of care anti-PD-1 therapy, including regimens with nivolumab, pembrolizumab, and ipilimumab, for up to 52 weeks

52 weeks

Evaluation and Decision

Participants are evaluated using FDG-PET/CT scans and biopsies to determine continuation or discontinuation of therapy

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, with follow-up through week 97 and then every 3 months for up to 5 years

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• Nivolumab
• Pembrolizumab

Trial Overview The PET-Stop Trial is testing if biomarkers from PET/CT imaging can guide when to safely stop immunotherapy in patients with advanced melanoma. It involves drugs like Pembrolizumab, Ipilimumab, Nivolumab, and patient observation to determine the effectiveness of early discontinuation.

How Is the Trial Designed?

Group I: Standard of Care (nivolumab, pembrolizumab, ipilimumab) Experimental Treatment 3 Interventions

Patients continue their standard of care anti-PD-1 therapy. Treatment may consist of the following regimens: 1) nivolumab IV over 30 minutes Q2W or Q4W; 2) pembrolizumab IV over 30 minutes Q3W or Q6W; 3) nivolumab IV over 30 minutes and ipilimumab IV Q3W for 4 doses followed by nivolumab IV over 30 minutes Q2W or Q4W; or 4) pembrolizumab IV over 30 minutes and ipilimumab IV Q3W for 4 doses followed by pembrolizumab IV over 30 minutes Q3W or Q6W. Treatment continues until 52 weeks from start of standard of care anti-PD-1 therapy in the absence of disease progression or unacceptable toxicity.

Group II: Arm A (active surveillance) Experimental Treatment 1 Intervention

Patients with a negative FDG-PET/CT scan or a positive FDG-PET/CT scan but with a negative biopsy for viable tumor discontinue the anti-PD-1 therapy and undergo active surveillance.

Group III: Arm B (nivolumab, pembrolizumab, ipilimumab) Active Control 2 Interventions

Patients with a positive FDG-PET/CT scan and positive biopsy for viable tumor or a positive FDG-PET/CT scan and biopsy not performed continue their standard of care anti-PD-1 therapy for 12 months in the absence of disease progression or unacceptable toxicity.

Nivolumab is already approved in United States, European Union, Canada, Switzerland for the following indications:

Approved in United States as Opdivo for:

• Advanced or metastatic gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma
• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Switzerland as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Who Is Running the Clinical Trial?

ECOG-ACRIN Cancer Research Group

Lead Sponsor

Trials

122

Recruited

160,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 2322 metastatic melanoma patients treated with immune checkpoint inhibitors (CPIs) in England, overall survival rates for ipilimumab, ipinivo, and nivolumab were consistent with randomized controlled trial outcomes, while pembrolizumab showed lower than expected survival rates.

Patients treated with ipinivo experienced higher emergency hospital admission rates and a higher incidence of colitis compared to those on pembrolizumab, but had lower 30-day mortality rates, suggesting that while ipinivo may be effective, it carries a higher risk of treatment-related complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metastatic melanoma patient outcomes since introduction of immune checkpoint inhibitors in England between 2014 and 2018. Board, R., Smittenaar, R., Lawton, S., et al.[2021]

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]

Nivolumab is shown to be the most cost-effective treatment option for advanced melanoma patients in England, with incremental cost-effectiveness ratios of £24,483 for BRAF mutation-negative and £17,362 for mutation-positive patients.

The analysis utilized a Markov state-transition model based on patient-level data from clinical trials, indicating that nivolumab provides long-term survival benefits while being economically favorable compared to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England. Meng, Y., Hertel, N., Ellis, J., et al.[2020]

In a study of 833 patients with advanced melanoma, pembrolizumab showed significantly better progression-free survival (PFS) and overall survival (OS) rates compared to ipilimumab, regardless of whether patients were treatment-naive or had previously received treatment.

The efficacy of pembrolizumab was particularly notable in patients with PD-L1-positive tumors, where it resulted in higher survival rates than ipilimumab, supporting its use as a standard treatment for advanced melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes by line of therapy and programmed death ligand 1 expression in patients with advanced melanoma treated with pembrolizumab or ipilimumab in KEYNOTE-006: A randomised clinical trial. Carlino, MS., Long, GV., Schadendorf, D., et al.[2022]

In a study of 876 metastatic melanoma patients treated with checkpoint inhibitors, nearly half discontinued therapy within 12 months, with discontinuation rates of 49.9% for pembrolizumab, 58.8% for nivolumab, and 59.2% for nivolumab/ipilimumab.

Patients starting nivolumab or nivolumab/ipilimumab were more likely to discontinue therapy compared to those starting pembrolizumab, suggesting that pembrolizumab may have a more favorable continuation rate that warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world analyses of therapy discontinuation of checkpoint inhibitors in metastatic melanoma patients. Machado, MAÁ., de Moura, CS., Chan, K., 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]

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 274 elderly patients with advanced melanoma, the risk of developing colitis was similar for those treated with anti-CTLA4 (ipilimumab) and anti-PD1 (nivolumab or pembrolizumab) therapies.

However, when considering patients across all stages of melanoma, anti-PD1 treatment was associated with a significantly lower risk of colitis compared to anti-CTLA4, suggesting a safer profile for anti-PD1 in this broader patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of immune-checkpoint inhibitors and the risk of immune-related colitis among elderly patients with advanced melanoma: real-world evidence from the SEER-Medicare database. Almutairi, AR., Slack, M., Erstad, BL., et al.[2022]

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]

In a meta-analysis of 15 studies involving cancer patients treated with either nivolumab or pembrolizumab, nivolumab was associated with a higher overall incidence of cardiotoxicity (55.7%) compared to pembrolizumab (27.31%), although this difference was not statistically significant.

However, when looking specifically at myocarditis, pembrolizumab showed a significant increase in cardiotoxicity risk, suggesting that while nivolumab may be more commonly reported for general cardiotoxicity, pembrolizumab poses a greater risk for this specific heart condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative cardiotoxicity risk of pembrolizumab versus nivolumab in cancer patients undergoing immune checkpoint inhibitor therapy: A meta-analysis. Ndjana Lessomo, FY., Wang, Z., Mukuka, C.[2023]

In the KEYNOTE-001 study, 16% of patients with metastatic melanoma achieved a complete response (CR) after treatment with pembrolizumab, with a median follow-up of 43 months showing a high disease-free survival rate of 90.9% at 24 months post-CR.

Most patients (86.7%) who achieved CR were able to discontinue pembrolizumab and enter observation without additional therapy, indicating that some patients may experience durable remission after stopping treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durable Complete Response After Discontinuation of Pembrolizumab in Patients With Metastatic Melanoma. Robert, C., Ribas, A., Hamid, O., et al.[2022]

Citations

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

Metastatic melanoma patient outcomes since introduction of immune checkpoint inhibitors in England between 2014 and 2018. [2021]

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

Pembrolizumab superior to ipilimumab in melanoma. [2017]

3. Germany pubmed.ncbi.nlm.nih.gov

The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England. [2020]

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

Outcomes by line of therapy and programmed death ligand 1 expression in patients with advanced melanoma treated with pembrolizumab or ipilimumab in KEYNOTE-006: A randomised clinical trial. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Real-world analyses of therapy discontinuation of checkpoint inhibitors in metastatic melanoma patients. [2021]

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

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

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

Pembrolizumab in the management of metastatic melanoma. [2020]

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

Association of immune-checkpoint inhibitors and the risk of immune-related colitis among elderly patients with advanced melanoma: real-world evidence from the SEER-Medicare database. [2022]

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

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

10. Switzerland pubmed.ncbi.nlm.nih.gov

Comparative cardiotoxicity risk of pembrolizumab versus nivolumab in cancer patients undergoing immune checkpoint inhibitor therapy: A meta-analysis. [2023]

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

Durable Complete Response After Discontinuation of Pembrolizumab in Patients With Metastatic Melanoma. [2022]