Dapansutrile + Pembrolizumab for Melanoma

Overseen By Emily Bolch

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: April Salama, M.D.

Must not be taking: Cytotoxic chemotherapy

Disqualifiers: Ocular melanoma, Active CNS metastases, Autoimmune disease, others

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

Compensation: Varies

Number of Visits: Unknown

26 Participants Needed

Trial Summary

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

The trial information does not specify if you need to stop taking your current medications. However, if you are on chronic systemic steroid therapy or any form of immunosuppressive therapy, you may need to stop or adjust it, as the trial excludes participants on these treatments.

What data supports the effectiveness of the drug Dapansutrile + Pembrolizumab for melanoma?

Pembrolizumab, one of the drugs in the treatment, has been shown to be effective in treating advanced melanoma, with studies indicating high response rates and better outcomes compared to other treatments. It has been approved for use in patients with advanced melanoma, demonstrating its effectiveness in this condition. ^{1 2 3 4 5}

Is the combination of Dapansutrile and Pembrolizumab safe for humans?

Pembrolizumab, also known as Keytruda, has been shown to be generally safe in humans, with common side effects including fatigue, rash, itching, and diarrhea. Less common side effects can include inflammation of the thyroid, colon, liver, and lungs. There is no specific safety data available for Dapansutrile in combination with Pembrolizumab, but Pembrolizumab alone has a favorable safety profile. ^{2 6 7 8 9}

What makes the drug combination of Dapansutrile and Pembrolizumab unique for treating melanoma?

This treatment combines Dapansutrile, which is being explored for its anti-inflammatory properties, with Pembrolizumab, a PD-1 inhibitor that helps the immune system attack cancer cells. The combination aims to enhance the immune response against melanoma, potentially offering a novel approach compared to using Pembrolizumab alone. ^{1 2 6 10 11}

What is the purpose of this trial?

This phase 1/2 trial will be conducted in two parts. Part 1 (Dose Selection) is designed to find the dose of dapansutrile with acceptable tolerability in combination with pembrolizumab. Part 1 will consist of up to 2 dose selection cohorts to evaluate the safety and tolerability of dapansutrile + pembrolizumab in patients with PD-1 resistant melanoma to find the recommended part 2 dose (RP2D). Part 1 will include a lead-in phase of dapansutrile monotherapy at 500 mg PO BID. At day 15, combination therapy with pembrolizumab will be initiated. Dose escalation is planned to a maximum of 1000 mg BID of dapansutrile + pembrolizumab. Part 2 (Dose Expansion) is designed to assess preliminary efficacy of dapansutrile + pembrolizumab in PD-1 resistant melanoma. Once all patients in Part 1 have completed 4 weeks of dapansutrile therapy, the expansion phase will start enrolling. Part 2 will also include a 14-day lead-in period of dapansutrile monotherapy at the RP2D.

Research Team

April Salama

Principal Investigator

Duke University

Eligibility Criteria

This trial is for adults with advanced melanoma that didn't respond to previous anti-PD-1/PD-L1 therapy. They must have measurable disease, adequate organ function, and no other recent cancer treatments or active infections. Participants need a performance status of 0-2 and can't be pregnant or breastfeeding. Those with certain health conditions like immunodeficiency, pneumonitis, or CNS metastases are excluded.

Inclusion Criteria

My melanoma diagnosis was confirmed through lab tests.

My cancer got worse within 6 months after my last anti-PD-1/L1 treatment.

My side effects from cancer treatment are mild, except for hair loss or hormone issues.

Exclusion Criteria

I had another cancer but was treated successfully and have been cancer-free for 2 years.

I have had chemotherapy for melanoma before joining this study.

I have a history of Hepatitis B or an active Hepatitis C infection.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Selection

Part 1 involves dose selection to evaluate safety and tolerability of dapansutrile + pembrolizumab, starting with dapansutrile monotherapy followed by combination therapy.

4 weeks

Multiple visits for dose escalation and monitoring

Dose Expansion

Part 2 assesses preliminary efficacy of dapansutrile + pembrolizumab with a 14-day lead-in period of dapansutrile monotherapy at the RP2D.

6 weeks

Regular visits every three weeks for pembrolizumab administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Dapansutrile
• Pembrolizumab

Trial Overview The study tests Dapansutrile in combination with Pembrolizumab on patients whose melanoma resisted PD-1 inhibitors. It has two parts: finding the best dose (with up to 1000 mg BID of Dapansutrile) and then expanding the trial at this dose to assess effectiveness against advanced melanoma.

Participant Groups

Group I: Dose Selection Experimental Treatment 2 Interventions

Dapansutrile starting at 500 mg PO BID plus Pembrolizumab 200 mg IV every three weeks. Dose escalation is planned to a maximum of 1000 mg BID of dapansutrile + pembrolizumab.

Group II: Dose Expansion Experimental Treatment 2 Interventions

Dapansutrile at the RP2D plus Pembrolizumab 200 mg IV every three weeks

Who Is Running the Clinical Trial?

April Salama, M.D.

Lead Sponsor

Trials

1

Recruited

30+

Olatec Therapeutics LLC

Industry Sponsor

Trials

10

Recruited

1,100+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

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 (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]

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 post hoc analysis of the KEYNOTE-006 study involving 555 patients with advanced melanoma, both ipilimumab and BRAF ± MEK inhibitors showed antitumor activity as subsequent therapies after pembrolizumab, with overall response rates (ORR) of 17.5% for ipilimumab and 30.5% for BRAF ± MEK inhibitors.

Patients who had not previously received BRAF ± MEK inhibitors showed a significantly higher ORR of 43.2% when treated with these agents after pembrolizumab, indicating that prior treatment status may influence the effectiveness of subsequent therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of ipilimumab or BRAF ± MEK inhibition after pembrolizumab treatment in patients with advanced melanoma: analysis from KEYNOTE-006. Long, GV., Arance, A., Mortier, L., et al.[2022]

In a real-life study of 125 patients with advanced melanoma treated with pembrolizumab, the median overall survival was 16.9 months, which indicates a significant benefit, but lower than the efficacy seen in clinical trials.

While 82% of patients experienced adverse events, the safety profile was comparable to that observed in the KEYNOTE-006 clinical trial, suggesting that pembrolizumab is generally safe for use in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monitoring real-life utilization of pembrolizumab in advanced melanoma using the Portuguese National Cancer Registry. Borges, FC., Ramos, C., Ramos, A., 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]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

Pembrolizumab (KEYTRUDA) received accelerated FDA approval for treating recurrent locally advanced or metastatic Merkel cell carcinoma (MCC) based on a study of 50 patients, showing an overall response rate of 56% and a complete response rate of 24%.

The treatment demonstrated promising durability, with 96% of responding patients maintaining their response for over 6 months, and 54% for over 12 months, although common side effects included fatigue, pain, and gastrointestinal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Accelerated Approval of Pembrolizumab for Recurrent Locally Advanced or Metastatic Merkel Cell Carcinoma. Bradford, D., Demko, S., Jin, S., et al.[2021]

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, an anti-PD-1 antibody used for treating malignant pleural mesothelioma, can cause serious side effects such as minimal change disease (MCD), which was identified in a 62-year-old patient who developed nephrotic syndrome and acute renal failure after treatment.

The patient's symptoms improved significantly after discontinuing pembrolizumab and starting steroid treatment, highlighting the importance of monitoring renal function and recognizing potential autoimmune reactions in patients receiving this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab-associated minimal change disease in a patient with malignant pleural mesothelioma. Bickel, A., Koneth, I., Enzler-Tschudy, A., et al.[2022]

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]

References

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

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

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

Pembrolizumab: first global approval. [2021]

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

Pembrolizumab superior to ipilimumab in melanoma. [2017]

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

Antitumor activity of ipilimumab or BRAF ± MEK inhibition after pembrolizumab treatment in patients with advanced melanoma: analysis from KEYNOTE-006. [2022]

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

Monitoring real-life utilization of pembrolizumab in advanced melanoma using the Portuguese National Cancer Registry. [2021]

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

Pembrolizumab in the management of metastatic melanoma. [2020]

7. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]

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

FDA Accelerated Approval of Pembrolizumab for Recurrent Locally Advanced or Metastatic Merkel Cell Carcinoma. [2021]

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

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

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

Pembrolizumab-associated minimal change disease in a patient with malignant pleural mesothelioma. [2022]

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

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