Biomarker-Guided Immunotherapy Discontinuation for Melanoma

Recruiting at 472 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 tests whether doctors can safely shorten the duration of a standard treatment for advanced melanoma, a type of skin cancer that cannot be surgically removed. Biomarkers from PET/CT scans determine if patients can stop their anti-PD-1 therapy (such as Nivolumab or Pembrolizumab) earlier than usual. Depending on scan and biopsy results, participants may either stop therapy and be monitored or continue the standard treatment. Individuals who have been on anti-PD-1 therapy for about a year, with melanoma that cannot be surgically removed, may be suitable candidates. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research shows that the treatments nivolumab, pembrolizumab, and ipilimumab are generally well-tolerated for melanoma. Studies indicate that nivolumab, often used with ipilimumab, has a reliable safety record, with no new safety issues over long-term use. Pembrolizumab also maintains a strong long-term safety record, with evidence supporting its consistent safety in treating advanced melanoma. When combined with nivolumab, ipilimumab demonstrates a good safety profile and helps improve survival rates. The FDA has approved all three treatments for melanoma, confirming their safety for this condition. However, like any medication, some patients may experience side effects, so discussing these options with healthcare professionals is important. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it explores a new way to manage melanoma treatment by using biomarker-guided decisions. Unlike the traditional approach where patients remain on anti-PD-1 therapies like nivolumab and pembrolizumab for extended periods, this trial investigates the possibility of safely discontinuing these treatments based on the results of FDG-PET/CT scans and biopsies. The goal is to minimize unnecessary exposure to these drugs, which could reduce side effects and improve quality of life without compromising effectiveness. This innovative approach could pave the way for more personalized and efficient cancer care.

What evidence suggests that this trial's treatments could be effective for melanoma?

Research has shown that both nivolumab and pembrolizumab, included in this trial's treatment options, effectively treat melanoma, a type of skin cancer. In studies, patients using nivolumab alone had a five-year survival rate of 44%, which increased to 52% when combined with ipilimumab. Pembrolizumab resulted in a 34% survival rate over ten years for those with advanced melanoma. Ipilimumab, often used with these drugs, improved survival by reducing the risk of death by 28% compared to a placebo. These findings suggest that these treatments effectively control and slow the progression of melanoma. Participants in this trial may receive these treatments as part of the standard of care arm or may undergo active surveillance based on biomarker guidance. ^{1 2 6 7 8}

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 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]

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 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]

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 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 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]

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]

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 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 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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12080919/

Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in ... In patients who were progression-free at 3-years, 10-year melanoma-specific survival rates were 96% with nivolumab-plus-ipilimumab, 97% with ...

2. curemelanoma.org curemelanoma.org/patient-eng/melanoma-treatment/options/yervoy-ipilimumab

Ipilimumab, Yervoy - MRA The results showed that ipilimumab extended the amount of time before cancer returned by an average of 9 months.

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa2210233

Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in ... The estimates of 6-month progression-free survival were 34% (90% CI, 25 to 44) in the combination-treatment group and 13% (90% CI, 4 to 27) in ...

4. annalsofoncology.org annalsofoncology.org/article/S0923-7534(19)37101-7/fulltext

Efficacy and safety of ipilimumab in metastatic melanoma ... Survival rates at 2 and 3 years were 25% (24 of 95) and 25% (13 of 53) with ipilimumab alone and 19% (54 of 284) and 15% (24 of 156) with ipilimumab plus gp100.

5. news.bms.com news.bms.com/news/details/2016/Yervoy-ipilimumab-Improves-Overall-Survival-in-Fully-Resected-Stage-III-Melanoma-Patients-From-Phase-3-Study/default.aspx

Yervoy (ipilimumab) Improves Overall Survival in Fully ... Yervoy demonstrated a 28% reduction in the risk of death versus placebo in first disclosure of overall survival data from pivotal study ...

6. nejm.org nejm.org/doi/full/10.1056/NEJMoa1611299

Prolonged Survival in Stage III Melanoma with Ipilimumab ... At a median follow-up of 2.7 years, adjuvant ipilimumab was associated with significantly prolonged recurrence-free survival, the primary end ...

7. news.bms.com news.bms.com/news/details/2024/Bristol-Myers-Squibb-Presents-Landmark-10-Year-Follow-Up-Data-from-CheckMate--067-Which-Showed-Continued-Durable-Long-Term-Survival-Benefit-with-Opdivo-plus-Yervoy-in-Advanced-Melanoma/default.aspx

067 Which Showed Continued Durable Long-Term ... With a minimum follow up of 10 years, median overall survival (OS) was 71.9 months with Opdivo plus Yervoy (95% CI: 38.2-114.4) - the longest ...

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.21.02229

Long-Term Outcomes With Nivolumab Plus Ipilimumab or ... Durable, improved clinical outcomes with nivolumab plus ipilimumab or nivolumab versus ipilimumab in patients with advanced melanoma.