Olaparib + Pembrolizumab for Eye Melanoma

Overseen By Malik Hall

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: Anti-PD-1, PARP inhibitors

Disqualifiers: Pregnancy, Active infection, CNS metastases, 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

Compensation: Varies

Number of Visits: Unknown

Duration: up to 24 months

37 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a prospective phase II multi-center trial of the combination of the PARP inhibitor olaparib with the immune checkpoint inhibitor pembrolizumab in advanced uveal melanoma.

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

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have received certain cancer therapies or live vaccines recently, and you should not be on high-dose steroids or immunosuppressive therapy.

What data supports the effectiveness of the drug pembrolizumab for treating eye melanoma?

Research shows that pembrolizumab, a drug that helps the immune system fight cancer, has been effective in treating advanced melanoma, a type of skin cancer, by improving survival rates and reducing the chance of cancer returning. This suggests it might also be helpful for eye melanoma. ^{1 2 3 4 5}

Is the combination of Olaparib and Pembrolizumab generally safe for humans?

Pembrolizumab, also known as KEYTRUDA, has been studied in patients with melanoma and shown to have a safety profile that includes some common side effects like fatigue, cough, and nausea. More serious immune-related side effects can occur, such as inflammation of the lungs (pneumonitis) and thyroid issues, but these are less common. ^{1 2 6 7 8}

How is the drug combination of Olaparib and Pembrolizumab unique for treating eye melanoma?

This treatment combines Olaparib, which targets cancer cell DNA repair, with Pembrolizumab, an immune system booster that helps T cells attack cancer cells. This combination is novel for eye melanoma, as there are no standard treatments specifically for this condition. ^{1 2 9 10 11}

Research Team

Nikhil Khushalani, MD

Principal Investigator

Moffitt Cancer Center

Eligibility Criteria

Adults with confirmed metastatic uveal melanoma can join this trial if they're not pregnant, breastfeeding, or planning to conceive. They must be able to take oral meds and have good organ function. Prior treatments for eye melanoma are okay, but no recent cancer therapies or live vaccines, and no history of certain diseases like active hepatitis or tuberculosis.

Inclusion Criteria

I can take pills by mouth.

My organs are functioning well.

You have a specific amount of disease that can be measured using a standard guideline.

Exclusion Criteria

Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study

I have had pneumonitis treated with steroids or currently have it.

I have received a transplant from another person.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 200 mg Pembrolizumab IV every 21 days and 300 mg Olaparib by mouth twice daily for each 21-day cycle, continuing until progression, unacceptable toxicity, or for a maximum of 35 cycles

up to 24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

Treatment Details

Interventions

• Olaparib
• Pembrolizumab

Trial Overview The study is testing a combination of two drugs: Olaparib (a PARP inhibitor) and Pembrolizumab (an immune checkpoint inhibitor), in patients with advanced eye melanoma. It's a phase II trial to see how well these drugs work together against this type of cancer.

Participant Groups

Group I: Pembrolizumab and Olaparib Experimental Treatment 2 Interventions

Participants will be given 200 mg Pembrolizumab IV every 21 days + will take 300 mg Olaparib by mouth twice daily days 1-21 of each 21 day cycle. Treatment will continue until progression, unacceptable toxicity, or for a maximum of 35 treatment cycles

Olaparib is already approved in European Union, United States for the following indications:

Approved in European Union as Lynparza for:

• Breast cancer
• Ovarian cancer
• Fallopian tube cancer
• Peritoneal cancer
• Pancreatic cancer
• Prostate cancer
• Endometrial cancer

Approved in United States as Lynparza for:

• Ovarian, fallopian tube, and primary peritoneal cancer
• Breast cancer
• Prostate cancer
• Pancreatic cancer

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

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

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]

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]

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]

A systematic review of four trials involving 3425 patients found that lower doses of pembrolizumab (2 mg/kg every 3 weeks) are equally effective as higher doses (10 mg/kg) in treating advanced melanoma and non-small-cell lung cancer (NSCLC).

The safety profile of pembrolizumab was similar across different doses, suggesting that the lower dose may be sufficient for routine treatment without compromising efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of efficacy and safety of different pembrolizumab dose/schedules in treatment of non-small-cell lung cancer and melanoma: a systematic review. Abdel-Rahman, O.[2018]

In a randomized phase III trial involving 1301 patients with high-risk resected melanoma, adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) compared to standard treatments like high-dose IFNα-2b and ipilimumab, with a hazard ratio of 0.77.

Pembrolizumab had a much lower rate of severe treatment-related adverse events (19.5%) compared to IFNα-2b (71.2%) and ipilimumab (49.2%), indicating a better safety profile while improving RFS but not overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant Pembrolizumab versus IFNα2b or Ipilimumab in Resected High-Risk Melanoma. Grossmann, KF., Othus, M., Patel, SP., et al.[2023]

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]

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 (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, 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]

In a study involving 173 patients with advanced melanoma who had not responded to previous treatments, pembrolizumab showed an overall response rate of 26% at both 2 mg/kg and 10 mg/kg doses, indicating its potential effectiveness in this challenging patient population.

The treatment was well tolerated with no drug-related deaths, and the safety profiles were similar across both doses, with fatigue, pruritus, and rash being the most common side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Robert, C., Ribas, A., Wolchok, JD., et al.[2022]

Pembrolizumab treatment for metastatic uveal melanoma can lead to the development of uveitis and retinal vasculitis, as demonstrated in a case report of a 54-year-old woman who experienced significant eye symptoms after four infusions.

The uveitis was effectively managed with a dexamethasone implant, indicating that while pembrolizumab can induce eye inflammation, it can be treated successfully, highlighting the importance of monitoring patients for ocular side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PEMBROLIZUMAB ADMINISTRATION ASSOCIATED WITH POSTERIOR UVEITIS. Aaberg, MT., Aaberg, TM.[2018]

References

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

Pembrolizumab superior to ipilimumab in melanoma. [2017]

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

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

3. 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]

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

Evaluation of efficacy and safety of different pembrolizumab dose/schedules in treatment of non-small-cell lung cancer and melanoma: a systematic review. [2018]

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

Adjuvant Pembrolizumab versus IFNα2b or Ipilimumab in Resected High-Risk Melanoma. [2023]

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

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

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

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

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

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

9. England pubmed.ncbi.nlm.nih.gov

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

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

Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. [2022]

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

PEMBROLIZUMAB ADMINISTRATION ASSOCIATED WITH POSTERIOR UVEITIS. [2018]