Pembrolizumab + Olaparib for Pancreatic Cancer

Recruiting at 377 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Immunodeficiency, Pneumonitis, Autoimmune disease, 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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 7

Duration: Up to 18 cycles of 21 days, then 42 days per cycle

88 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies whether adding pembrolizumab to olaparib (standard of care) works better than olaparib alone in treating patients with pancreatic cancer with germline BRCA1 or BRCA2 mutations that has spread to other places in the body (metastatic). BRCA1 and BRCA2 are human genes that produce tumor suppressor proteins. These proteins help repair damaged deoxyribonucleic acid (DNA) and, therefore, play a role in ensuring the stability of each cell's genetic material. When either of these genes is mutated, or altered, such that its protein product is not made or does not function correctly, DNA damage may not be repaired properly. As a result, cells are more likely to develop additional genetic alterations that can lead to some types of cancer, including pancreatic cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Olaparib is an inhibitor of PARP, a protein that helps repair damaged DNA. Blocking PARP may help keep tumor cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. The addition of pembrolizumab to the usual treatment of olaparib may help to shrink tumors in patients with metastatic pancreatic cancer with BRCA1 or BRCA2 mutations.

Will I have to stop taking my current medications?

The trial requires that you stop taking strong or moderate CYP3A inhibitors or inducers at least 2 to 5 weeks before starting olaparib. Check with your doctor to see if your current medications fall into these categories.

What data supports the effectiveness of the drugs Pembrolizumab and Olaparib for pancreatic cancer?

Some evidence suggests that Pembrolizumab and Olaparib may help certain patients with advanced pancreatic cancer, especially those with specific genetic markers like dMMR or BRCA2 mutations. In a few cases, patients treated with these drugs showed no cancer progression for several months to years. ^{1 2 3 4 5}

Is the combination of Pembrolizumab and Olaparib safe for humans?

Olaparib has been studied for safety in various cancers, including ovarian and breast cancer, and is generally considered safe, though it may have side effects like nausea and fatigue. Pembrolizumab, also known as KEYTRUDA, is used in many cancer treatments and is generally safe, but can cause side effects like fatigue and skin reactions. ^{1 3 6 7 8}

How is the drug combination of Pembrolizumab and Olaparib unique for treating pancreatic cancer?

The combination of Pembrolizumab and Olaparib is unique because it combines an immune checkpoint inhibitor (Pembrolizumab) with a PARP inhibitor (Olaparib), which targets cancer cells with specific genetic mutations, offering a novel approach compared to traditional chemotherapy for pancreatic cancer. ^{1 2 7 8 9}

Research Team

Vincent Chung

Principal Investigator

SWOG Cancer Research Network

Eligibility Criteria

This trial is for adults with metastatic pancreatic cancer who have inherited BRCA mutations. They must have completed first-line platinum-based chemotherapy, show stable or responding disease, and not be on certain drugs that affect olaparib. People with HIV or hepatitis C can join if treated and virus-free. Those with a history of severe lung inflammation, active infections, autoimmune diseases needing recent treatment, or other cancers that could interfere are excluded.

Inclusion Criteria

I am 18 years old or older.

Your immune system's white blood cell count is at least 1.5 x 10^3 per microliter of blood.

I understand this study is experimental and I (or my legal representative) have signed the consent form.

Exclusion Criteria

I have another cancer type, but it won't affect this trial's treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive olaparib orally twice daily and pembrolizumab intravenously on day 1 of each cycle. Treatment repeats every 21 days for up to 18 cycles, then every 42 days starting cycle 19.

Up to 18 cycles of 21 days, then 42 days per cycle

1 visit per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-ups every 6 months for 3 years.

3 years

Every 6 months

Treatment Details

Interventions

• Olaparib
• Pembrolizumab

Trial Overview The study is testing if adding pembrolizumab (an immunotherapy drug) to olaparib (a PARP inhibitor used as standard care) is more effective in treating patients whose pancreatic cancer has spread and have BRCA1/2 mutations. It's a phase II trial where the effectiveness of this combination will be compared to using olaparib alone.

Participant Groups

Group I: Arm A (olaparib, pembrolizumab) Experimental Treatment 6 Interventions

Patients receive olaparib PO BID on days 1-21 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Beginning in cycle 19, patients receive olaparib PO BID on days 1-42 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI, tumor biopsy and blood sample collection throughout the study.

Group II: Arm B (olaparib) Active Control 5 Interventions

Patients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI, tumor biopsy and blood sample collection throughout the study.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

The combination of cediranib and olaparib did not show clinically meaningful activity in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who do not have a known BRCA mutation, as no objective responses were observed in the study of 19 patients.

Despite some patients experiencing stable disease for a median of 3.1 months, the overall survival was only 3.4 months, indicating limited efficacy of this treatment combination in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Activity and Safety of Cediranib and Olaparib Combination in Patients with Metastatic Pancreatic Ductal Adenocarcinoma without BRCA Mutation. Kim, JW., Cardin, DB., Vaishampayan, UN., et al.[2022]

In a study of 41 pancreas cancer patients treated with pembrolizumab, the median overall survival was 7.2 months, which is considered favorable compared to the benchmark of over 4 months.

Patients with specific genetic markers (dMMR, MSI-H, TMB-H, or Lynch syndrome) had a significantly lower risk of death, indicating that these biomarkers may help identify patients who could benefit more from pembrolizumab treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab near the end of life in patients with metastatic pancreatic cancer: a multi-site consecutive series to examine survival and patient treatment burden. Storandt, MH., Tran, N., Martin, N., et al.[2023]

The combination of olaparib and durvalumab (O+D) showed a progression-free survival rate of 35% at 6 months in patients with advanced solid tumors, including rare cancers with homologous recombination repair (HRR) defects, indicating its efficacy in this challenging patient population.

O+D was found to be safe, with only 6% of patients experiencing serious adverse events, and it produced durable objective tumor responses in several rare cancer types, suggesting it could be a promising treatment option without new toxicity concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A signal-seeking Phase 2 study of olaparib and durvalumab in advanced solid cancers with homologous recombination repair gene alterations. Thavaneswaran, S., Kansara, M., Lin, F., et al.[2023]

In the BAROCCO trial involving 123 patients with recurrent platinum-sensitive ovarian cancer, the combination of cediranib and olaparib did not show superior progression-free survival (PFS) compared to paclitaxel chemotherapy, with median PFS of 5.6 months for the continuous cediranib-olaparib group and 3.1 months for the control group.

Despite not outperforming chemotherapy, the cediranib-olaparib combination was associated with a lower rate of treatment discontinuation due to adverse events (5% in the intermittent arm) and offers a potential non-chemotherapy treatment option for heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II trial of weekly paclitaxel vs. cediranib-olaparib (continuous or intermittent schedule) in platinum-resistant high-grade epithelial ovarian cancer. Colombo, N., Tomao, F., Benedetti Panici, P., et al.[2022]

Pembrolizumab, an FDA-approved treatment for advanced pancreatic cancer, showed promising results as a maintenance therapy in three patients with different stages of pancreatic ductal adenocarcinoma (PDAC), with one patient remaining progression-free for 4 years after treatment.

The cases suggest that pembrolizumab may be effective for patients with dMMR mutations or PD-1 expression, indicating a potential role in reducing recurrence and prolonging survival when used alone or in combination with other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival Benefit of Pembrolizumab for Patients With Pancreatic Adenocarcinoma: A Case Series. Zhao, L., Singh, V., Ricca, A., et al.[2022]

Olaparib significantly improves overall survival in patients with recurrent platinum-sensitive ovarian cancer, with a hazard ratio of 1.24 based on a meta-analysis of 7 randomized controlled trials involving 2406 patients.

However, the treatment is associated with a higher incidence of adverse events, particularly for grades 3 or higher, indicating that while olaparib is effective, it also carries a risk of significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic Review of Olaparib in the Treatment of Recurrent Platinum Sensitive Ovarian Cancer. Chen, Q., Li, X., Zhang, Z., et al.[2022]

In a phase 1 trial involving 18 patients with unresectable pancreatic ductal adenocarcinoma (PDAC), the maximum tolerated dose of olaparib combined with irinotecan and cisplatin was determined to be 100 mg twice daily, but the addition of mitomycin C was not tolerated due to high toxicity.

Despite significant toxicity, including a high rate of grade ≥3 adverse events in 89% of patients, one patient with a BRCA2 mutation experienced a durable response lasting over four years, suggesting that further investigation into PARP inhibitors for PDAC may be warranted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer. Yarchoan, M., Myzak, MC., Johnson, BA., et al.[2022]

Olaparib (Lynparza) is approved for treating adult patients with high-risk early breast cancer that has a germline BRCA mutation, following chemotherapy treatment.

This approval highlights Olaparib's role as an adjuvant therapy, which means it is used after initial treatments to help prevent cancer recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Adjuvant Treatment for High-Risk Early Breast Cancer. Aschenbrenner, DS.[2022]

Olaparib is an oral medication that inhibits poly (ADP-ribose) polymerase and is primarily developed for treating BRCA mutation-positive ovarian cancer, with its capsule formulation already approved in the EU and USA.

The drug is currently undergoing extensive clinical trials for various cancers, including breast, gastric, and pancreatic cancers, indicating its potential broad application in oncology beyond ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib: first global approval. Deeks, ED.[2020]

References

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

Clinical Activity and Safety of Cediranib and Olaparib Combination in Patients with Metastatic Pancreatic Ductal Adenocarcinoma without BRCA Mutation. [2022]

2. Germany pubmed.ncbi.nlm.nih.gov

Pembrolizumab near the end of life in patients with metastatic pancreatic cancer: a multi-site consecutive series to examine survival and patient treatment burden. [2023]

3. England pubmed.ncbi.nlm.nih.gov

A signal-seeking Phase 2 study of olaparib and durvalumab in advanced solid cancers with homologous recombination repair gene alterations. [2023]

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

Randomized phase II trial of weekly paclitaxel vs. cediranib-olaparib (continuous or intermittent schedule) in platinum-resistant high-grade epithelial ovarian cancer. [2022]

5. Canada pubmed.ncbi.nlm.nih.gov

Survival Benefit of Pembrolizumab for Patients With Pancreatic Adenocarcinoma: A Case Series. [2022]

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

Systematic Review of Olaparib in the Treatment of Recurrent Platinum Sensitive Ovarian Cancer. [2022]

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

Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer. [2022]

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

New Adjuvant Treatment for High-Risk Early Breast Cancer. [2022]

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

Olaparib: first global approval. [2020]