Olaparib + Pembrolizumab for Melanoma

Not currently recruiting at 1 trial location

Overseen By Kevin B Kim, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: California Pacific Medical Center Research Institute

Must not be taking: PARP inhibitors, Steroids

Disqualifiers: Immunodeficiency, Active 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: 3

Duration: 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether the combination of two drugs, olaparib and pembrolizumab, can effectively treat advanced melanoma that has spread in patients with a specific genetic change. Olaparib (Lynparza) may stop cancer cells from growing by blocking certain enzymes, while pembrolizumab (KEYTRUDA) works with the immune system to fight cancer. The trial seeks patients whose melanoma has worsened despite previous treatments, including immunotherapy and, in some cases, BRAF inhibitors. Those with melanoma that has a specific genetic mutation (such as BRCA1/2 or others) and whose condition did not improve with other treatments might be suitable for this study. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on chronic systemic steroid therapy exceeding 10 mg daily of prednisone equivalent or any other form of immunosuppressive therapy within 7 days before starting the study drug.

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

Research has shown that using olaparib and pembrolizumab together is safe for people with certain gene changes in advanced cancers. Studies have found that most patients tolerate this treatment well, experiencing side effects that are typically mild to moderate, which is common for cancer treatments.

This combination has been tested in other types of cancer and has proven safe. While side effects can occur, they are usually manageable. Anyone considering joining a trial should discuss the potential risks and benefits with their doctor. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for melanoma?

Researchers are excited about the combination of Olaparib and Pembrolizumab for treating advanced melanoma because it offers a novel approach by combining a PARP inhibitor with an immune checkpoint inhibitor. Unlike standard treatments like chemotherapy or single-agent immunotherapies, Olaparib specifically targets cancer cells with genetic HR mutations, potentially making it more effective in patients with those alterations. Meanwhile, Pembrolizumab helps to unleash the immune system against cancer cells. By working together, these drugs might provide a more robust attack on melanoma, offering hope for better outcomes in patients with specific genetic profiles.

What evidence suggests that the combination of olaparib and pembrolizumab could be effective for advanced melanoma?

This trial will evaluate the combination of olaparib and pembrolizumab for patients with advanced melanoma who have specific genetic mutations. Research has shown that combining these drugs may help treat cancers with genetic changes, such as mutations in the BRCA1 and BRCA2 genes, which affect DNA repair. In patients with BRCA mutations, olaparib improved the time during which the cancer did not worsen, compared to a placebo. Pembrolizumab, a treatment that helps the immune system fight cancer, has effectively treated advanced melanoma, with 34% of patients surviving for five years. Together, these drugs might work better for patients whose cancers have certain genetic mutations. ^{1 2 5 6 7}

Who Is on the Research Team?

Kevin B Kim, MD

Principal Investigator

California Pacific Medical Center Research Institute

Are You a Good Fit for This Trial?

This trial is for adults with advanced melanoma that can't be removed by surgery or has spread, and have specific gene changes called HR mutations. They must have tried immunotherapy and, if they have a BRAF mutation, also BRAF inhibitors without success or couldn't tolerate them. Participants need to be fairly healthy overall and not on high-dose steroids.

Inclusion Criteria

My cancer has a specific genetic mutation.

I have had only one chemotherapy treatment but may have had multiple immunotherapy or targeted therapy treatments.

My melanoma cannot be removed by surgery and is in stage III or IV.

Exclusion Criteria

I have had lung inflammation from specific cancer treatment that needed steroids.

I have had an organ, bone marrow, or cord blood transplant for cancer.

My brain metastases are stable, and I haven't needed steroids for 14 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive olaparib 300 mg daily and pembrolizumab 200 mg every 3 weeks for up to 2 years

2 years

Every 3 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Olaparib
• Pembrolizumab

Trial Overview The study tests the combination of Olaparib, which blocks enzymes helping tumor growth, with Pembrolizumab, an immune system booster against cancer. It's for patients whose melanoma worsened after previous treatments. The goal is to see how effective and safe this drug combo is in these cases.

How Is the Trial Designed?

Group I: Olaparib + Pembrolizumab Experimental Treatment 2 Interventions

This arm will enroll patients who has advanced melanoma with a genetic HR mutation/ alteration including mutation/ deletion in ARID1A/B, ARID2, ATM, ATR, BARD1, BRCA1/2, BAP1, BRIP1, CHEK2, FANCA, FANCD2, MRN11A, PALB2, RAD50, RAD51, RAD54B.

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?

California Pacific Medical Center Research Institute

Lead Sponsor

Trials

44

Recruited

10,600+

M.D. Anderson Cancer Center

Collaborator

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

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]

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 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) 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 study of 67 advanced melanoma patients treated with pembrolizumab, the drug demonstrated a 27% overall response rate, with 6.5% achieving complete responses, indicating its efficacy even in heavily pretreated patients.

The median overall survival for cutaneous melanoma patients was 14 months, with an 18-month survival rate of 47.1%, and importantly, there were no serious adverse events reported, highlighting the safety of pembrolizumab in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for advanced melanoma: experience from the Spanish Expanded Access Program. González-Cao, M., Arance, A., Piulats, JM., et al.[2018]

In a study of 655 patients with advanced melanoma, pembrolizumab showed a 5-year overall survival rate of 34%, with even better outcomes (41%) for treatment-naive patients, indicating its long-term efficacy.

The treatment was generally well-tolerated, with 86% of patients experiencing treatment-related adverse events, but only 7.8% discontinued due to these effects, suggesting a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Hamid, O., Robert, C., Daud, A., et al.[2023]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04633902

NCT04633902 | Phase II Study of Olaparib and ... This open-label phase II trial studies how well olaparib in combination with pembrolizumab works in treating patients with advanced, metastatic melanoma ...

2. 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 and pembrolizumab showed promising efficacy in HRR mutation and HRD-positive advanced cancers, especially in BRCA1/2-mutated cases ...

3. withpower.com withpower.com/trial/phase-3-melanoma-2-2021-322c9

Olaparib + Pembrolizumab for Melanoma In a study of 655 patients with advanced melanoma, pembrolizumab showed a 5-year overall survival rate of 34%, with even better outcomes (41%) for treatment- ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12364676/

PARP inhibitors in melanoma treatment: potential, challenges ... The benefit was most prominent in the subgroup of patients with BRCA mutations, where the median PFS was 11.2 months for Olaparib versus 4.3 months for placebo ...

5. merck.com merck.com/news/merck-announces-phase-3-keylynk-001-trial-met-primary-endpoint-of-progression-free-survival-pfs-in-patients-with-advanced-epithelial-ovarian-cancer/

Merck Announces Phase 3 KEYLYNK-001 Trial Met ... The Phase 3 KEYLYNK-001 trial evaluating KEYTRUDA (pembrolizumab) plus chemotherapy followed by maintenance with LYNPARZA (olaparib), with or without ...

6. ascopubs.org ascopubs.org/doi/10.1200/PO-24-00658

Phase II Study of Niraparib in Patients With Advanced ... Our results indicate a promising signal for single agent niraparib in patients with pretreated nonuveal metastatic melanoma with HR gene mutations.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11374802/

Efficacy of PARP inhibitor therapy after targeted BRAF/MEK ... HR-DDR mutations in melanoma are common, with frequencies ranging from 18.1% to upwards of 41%. In general, patients with advanced melanoma ...