Neoadjuvant PD-1 Blockade for Melanoma

Recruiting at 2 trial locations

Overseen By Giorgos Karakousis, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Abramson Cancer Center of the University of Pennsylvania

Must not be taking: Immunosuppressants, Steroids, Live vaccines, others

Disqualifiers: Unresectable disease, Autoimmune disease, 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)

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

Compensation: Varies

Number of Visits: 19

63 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The main purpose of this study is to determine the rate of positive sentinel lymph nodes (i.e. the closest draining lymph node(s) to the primary melanoma site) and to test whether treatment with pembrolizumab before surgery to remove melanoma reduces the rate of positive sentinel lymph nodes in patients with Stage IIB/C melanoma. Subjects with stage II melanoma will receive one dose of pembrolizumab 200 mg, then undergo standard definitive surgery with wide excision and sentinel lymph node (SLN) biopsy approximately 3 weeks after the initial dose of pembrolizumab. Post-operatively, subjects will receive up to 1 year of adjuvant pembrolizumab 200 mg every 3 weeks.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on immunosuppressive therapy or certain other treatments, you may need to stop them before starting the trial. It's best to discuss your specific medications with the trial team.

Is neoadjuvant PD-1 blockade for melanoma safe for humans?

PD-1 blocking drugs like Pembrolizumab (also known as KEYTRUDA or MK-3475) have been used in treating various cancers, including melanoma, and are generally considered safe for outpatient use. However, they can cause immune-related side effects, which occur when the immune system becomes overactive, but these are usually manageable with proper care. ^{1 2 3 4 5}

How is the neoadjuvant PD-1 blockade treatment for melanoma different from other treatments?

Neoadjuvant PD-1 blockade for melanoma is unique because it is given before surgery to help shrink the tumor and improve immune response, potentially leading to better outcomes compared to treatments given after surgery. This approach uses drugs like nivolumab, which have shown to enhance survival and immune responses with lower toxicity compared to some combination therapies. ^{6 7 8 9 10}

What data supports the effectiveness of the treatment Neoadjuvant PD-1 Blockade for Melanoma?

The research highlights the importance of sentinel lymph node biopsy (SLNB) in improving long-term survival for melanoma patients, which is part of the treatment plan. While specific data on Pembrolizumab (a drug that helps the immune system fight cancer) for melanoma isn't provided, SLNB's role in better outcomes suggests the treatment's potential effectiveness. ^{11 12 13 14 15}

Who Is on the Research Team?

Giorgos Karakousis, MD

Principal Investigator

Abramson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults over 18 with Stage IIB/C melanoma that can be surgically removed. They must have good performance status, normal organ function, and agree to contraception rules. Excluded are those with non-resectable melanoma, recent treatments or surgeries, severe allergies to pembrolizumab, active infections including HIV/Hepatitis B/C/TB, certain heart diseases, live vaccines taken recently, immunodeficiencies or suppressive therapies within a week before the trial.

Inclusion Criteria

My melanoma is at stage IIB or IIC and can be surgically removed. I do not have uveal or mucosal melanoma.

I am not pregnant and follow the required birth control guidelines.

I agree to follow the study's rules for using birth control.

Exclusion Criteria

I have not received a live vaccine in the last 30 days.

My liver is not functioning well (Child-Pugh score >6).

Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Treatment

Participants receive one dose of pembrolizumab 200 mg

3 weeks

1 visit (in-person)

Surgery

Participants undergo wide excision and sentinel lymph node biopsy

1 day

1 visit (in-person)

Adjuvant Treatment

Participants receive up to 1 year of adjuvant pembrolizumab 200 mg every 3 weeks

1 year

Approximately 17 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approximately 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• Wide Excision and Sentinel Lymph Node (SLN) Biopsy

Trial Overview The study tests if pembrolizumab given before surgery reduces positive sentinel lymph nodes in patients with Stage IIB/C melanoma. Participants receive one dose of pembrolizumab followed by surgery after about three weeks and then up to one year of adjuvant therapy post-operation.

How Is the Trial Designed?

Group I: Neoadjuvant Pembrolizumab Experimental Treatment 2 Interventions

Subjects will receive one dose of pembrolizumab 200 mg. Approximately 3 weeks after the initial dose of pembrolizumab, subjects will undergo wide excision and sentinel lymph node (SLN) biopsy. Post-operatively, subjects will receive up to 1 year of adjuvant pembrolizumab 200 mg every 3 weeks.

Who Is Running the Clinical Trial?

Abramson Cancer Center of the University of Pennsylvania

Lead Sponsor

Trials

360

Recruited

108,000+

Abramson Cancer Center at Penn Medicine

Lead Sponsor

Trials

425

Recruited

464,000+

Published Research Related to This Trial

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]

Blocking the PD-1 pathway with specific drugs has shown clinical effectiveness in treating advanced cancers like melanoma and lung cancer, by enhancing the body's anti-tumor immune response.

These PD-1/PD-L1 blocking drugs have a manageable safety profile, making them suitable for outpatient treatment and potential use in combination therapies, with ongoing research focused on identifying biomarkers for better patient selection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antagonists of PD-1 and PD-L1 in Cancer Treatment. Lipson, EJ., Forde, PM., Hammers, HJ., et al.[2022]

Immune checkpoint antibodies targeting the PD-1/PD-L1 pathway have shown significant antitumor activity and have been approved for use as single-agent therapies in metastatic malignant melanoma and nonsmall-cell lung cancer.

Understanding the toxicities associated with PD-1/PD-L1 blockade and having effective management strategies is crucial for maximizing both the safety and efficacy of these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Naidoo, J., Page, DB., Li, BT., et al.[2023]

In a study of 66 patients with advanced melanoma treated with PD-1 antibodies, those with elevated baseline serum lactate dehydrogenase (LDH) had significantly shorter overall survival compared to those with normal LDH levels, indicating that LDH can be a critical prognostic marker.

Changes in LDH levels during treatment were predictive of response; patients with a reduction in LDH were more likely to achieve partial remission, while those with an increase had a shorter overall survival, suggesting LDH could help monitor treatment effectiveness early on.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Serum lactate dehydrogenase as an early marker for outcome in patients treated with anti-PD-1 therapy in metastatic melanoma. Diem, S., Kasenda, B., Spain, L., et al.[2022]

In a study of 37 patients with stage IV metastatic melanoma, high levels of soluble CD73 (sCD73) enzyme activity in the serum were linked to significantly poorer overall survival and progression-free survival when treated with nivolumab.

Patients with high sCD73 activity had a median progression-free survival of only 2.6 months compared to 14.2 months for those with lower activity, suggesting that measuring sCD73 could help predict how well patients will respond to nivolumab therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Soluble CD73 as biomarker in patients with metastatic melanoma patients treated with nivolumab. Morello, S., Capone, M., Sorrentino, C., et al.[2018]

In a phase 2 study of 23 patients with high-risk resectable melanoma, the combination of ipilimumab and nivolumab showed high response rates (73% overall response rate and 45% pathologic complete response) but also resulted in significant toxicity, with 73% of patients experiencing grade 3 treatment-related adverse events.

Nivolumab monotherapy had lower response rates (25% overall response rate and 25% pathologic complete response) but was associated with much lower toxicity (only 8% grade 3 treatment-related adverse events), suggesting that while combination therapy is effective, it comes with higher risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Amaria, RN., Reddy, SM., Tawbi, HA., et al.[2021]

In a study of 655 patients with advanced melanoma, pembrolizumab showed an overall objective response rate of 33%, indicating its efficacy in treating this type of cancer.

The median overall survival for patients receiving pembrolizumab was 23 months, with a 12-month survival rate of 66%, while 14% of patients experienced severe treatment-related adverse events, highlighting its safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma. Ribas, A., Hamid, O., Daud, A., et al.[2022]

Citations

1. India pubmed.ncbi.nlm.nih.gov

Sentinel lymph node status affects long-term survival in patients with intermediate-thickness melanoma. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Long-term follow-up reveals that ulceration and sentinel lymph node status are the strongest predictors for survival in patients with primary cutaneous melanoma. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Primary excision margins, sentinel lymph node biopsy, and completion lymph node dissection in cutaneous melanoma: a clinical practice guideline. [2023]

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

Sentinel-node biopsy or nodal observation in melanoma. [2022]

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

Effect of the time interval between melanoma diagnosis and sentinel node biopsy on the size of metastatic tumour deposits in node-positive patients. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Immune-Related Adverse Events in PD-1 Treated Melanoma and Impact Upon Anti-Tumor Efficacy: A Real World Analysis. [2022]

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

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

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

Antitumor efficacy of combined CTLA4/PD-1 blockade without intestinal inflammation is achieved by elimination of FcγR interactions. [2021]

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

Antagonists of PD-1 and PD-L1 in Cancer Treatment. [2022]

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

Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. [2023]

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

Serum lactate dehydrogenase as an early marker for outcome in patients treated with anti-PD-1 therapy in metastatic melanoma. [2022]

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

Soluble CD73 as biomarker in patients with metastatic melanoma patients treated with nivolumab. [2018]

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

Extended dose ipilimumab with a peptide vaccine: immune correlates associated with clinical benefit in patients with resected high-risk stage IIIc/IV melanoma. [2021]

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

Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. [2021]

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

Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma. [2022]