Olaparib + Pembrolizumab for Eye Melanoma

Overseen By Inaya Lemus

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination of olaparib (a PARP inhibitor) and pembrolizumab (an immunotherapy drug) for individuals with advanced uveal melanoma, a rare eye cancer that has metastasized. The goal is to determine how effectively these two drugs work together to slow or halt cancer growth. Researchers seek participants diagnosed with metastatic uveal melanoma who have measurable cancer growth that can be tracked. As a Phase 2 trial, this research focuses on assessing 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 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.

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

Research has shown that using olaparib and pembrolizumab together has been safe in past studies for certain advanced cancers. These studies included patients with specific genetic changes in their tumors, known as HRR gene mutations. Most patients tolerated the treatment well. Common side effects included tiredness and nausea, typical for many cancer treatments.

Pembrolizumab, also called KEYTRUDA, has been widely studied in patients with melanoma. It has a well-known safety record, with common side effects like tiredness, itching, and rash. Serious side effects are rare but can occur.

In this study, researchers are testing both olaparib and pembrolizumab together for eye melanoma. This is a phase 2 trial, so the treatment's safety is still under careful observation. However, earlier research provides some confidence about its safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using Olaparib and Pembrolizumab for eye melanoma because this combination targets the cancer in a unique way. While most treatments focus on surgery, radiation, or chemotherapy, Olaparib is a PARP inhibitor, which disrupts cancer cell repair mechanisms, causing them to die. Pembrolizumab, on the other hand, is an immunotherapy drug that helps the immune system recognize and attack cancer cells more effectively. This combination not only has the potential to be more effective than current options but also offers a new approach by combining DNA repair disruption with enhanced immune response.

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

Research has shown that pembrolizumab, one of the treatments tested in this trial, has potential in treating advanced melanoma. In a study with 173 patients who did not respond to other treatments, pembrolizumab helped about 26% of them, with roughly a quarter experiencing tumor shrinkage or halted growth. Although less information exists on using olaparib and pembrolizumab together for uveal melanoma, this trial evaluates the combination of these two drugs. Olaparib, a PARP inhibitor, prevents cancer cells from repairing themselves, making them easier to attack. This combination approach aims to improve outcomes for patients with this challenging type of eye cancer. ^{1 2 4 5 6}

Who Is on the Research Team?

Nikhil Khushalani, MD

Principal Investigator

Moffitt Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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, 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]

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 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]

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 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]

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 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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05524935

Study Details | NCT05524935 | Olaparib in Combination ... This is a prospective phase II multi-center trial of the combination of the PARP inhibitor olaparib with the immune checkpoint inhibitor pembrolizumab in ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12295115/

Advances and Challenges in Immunotherapy for Metastatic ... Retrospective and prospective clinical studies were selected, provided they reported clearly distinguishable and complete data specific to mUM ...

3. withpower.com withpower.com/trial/phase-2-uveal-neoplasms-9-2022-4a2ef

Olaparib + Pembrolizumab for Eye Melanoma 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 ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12071000/

Current Treatment of Uveal Melanoma - PMC This review examines the current treatment landscape for uveal melanoma, highlighting effective local therapies such as enucleation and plaque brachytherapy.

5. merck.com merck.com/news/merck-announces-keylynk-008-trial-evaluating-keytruda-pembrolizumab-plus-lynparza-olaparib-for-patients-with-metastatic-squamous-non-small-cell-lung-cancer-to-stop-for-futility/

Merck Announces KEYLYNK-008 Trial Evaluating ... The most common adverse reactions (≥20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were ...

6. onclive.com onclive.com/view/olaparib-plus-pembrolizumab-shows-efficacy-in-hrr-gene-mutated-advanced-tumors-with-without-hrd-positivity

Olaparib Plus Pembrolizumab Shows Efficacy in HRR ... Olaparib plus pembrolizumab was safe and effective in HRR gene–mutated and/or HRD-positive advanced tumors.