Pembrolizumab + Olaparib for Pancreatic Cancer

Not currently recruiting at 606 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether adding pembrolizumab, an immunotherapy drug, to the usual treatment of olaparib, a targeted therapy drug, enhances effectiveness for individuals with metastatic pancreatic cancer who have specific genetic mutations (BRCA1 or BRCA2). These mutations can hinder cells from repairing DNA damage, leading to cancer. Pembrolizumab aids the immune system in targeting cancer cells, while olaparib blocks a protein (PARP) that cancer cells use for self-repair. The trial seeks participants with pancreatic cancer who have these genetic mutations and have previously received certain types of chemotherapy. As a Phase 2 trial, the 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 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.

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

Research has shown that the combination of pembrolizumab and olaparib is generally safe. Common side effects include low red blood cell count (anemia), nausea, and fatigue. Importantly, no new safety issues have emerged with this combination.

For olaparib alone, studies have found it can cause nausea and lower hemoglobin levels, a protein in red blood cells. In some cases, about 40% of people experienced more serious side effects. However, olaparib has been used safely for other conditions, indicating a well-understood safety profile.

Overall, both treatments are usually well-tolerated according to past studies, but like any treatment, side effects can occur. It's always important to discuss any concerns with a healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they introduce a novel combination approach to fighting pancreatic cancer. Unlike most treatments that focus solely on chemotherapy, this study combines olaparib, a PARP inhibitor, with pembrolizumab, an immune checkpoint inhibitor. Olaparib targets cancer cells by preventing them from repairing DNA damage, while pembrolizumab enhances the immune system's ability to attack cancer cells. This dual-action strategy could potentially increase effectiveness and provide a new avenue for patients who do not respond to traditional therapies.

What evidence suggests that pembrolizumab and olaparib might be an effective treatment for metastatic pancreatic cancer?

Research has shown that combining pembrolizumab with olaparib may help shrink tumors in people with advanced pancreatic cancer, particularly those with BRCA1 or BRCA2 gene changes. In this trial, some participants will receive this combination, which previous studies have found safe and effective for treating advanced tumors with these genetic changes. Other participants will receive olaparib alone, which has slowed disease progression and extended time without cancer growth for some patients. Specifically, nearly one in four patients responded well to olaparib after chemotherapy. These findings suggest that the combination might be more effective than olaparib alone for some patients. ^{1 6 7 8 9}

Who Is on the Research Team?

Vincent Chung

Principal Investigator

SWOG Cancer Research Network

Are You a Good Fit for This Trial?

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

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.

I have never been treated with immune checkpoint inhibitors.

Exclusion Criteria

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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 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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8208637/

The Role of Olaparib in Metastatic Pancreatic Cancer - PMC Although the study met its primary endpoint, median OS was not statistically significant (18.9 months in Olaparib arm versus 18.1 months in placebo arm, HR 0.91 ...

2. lynparza.com lynparza.com/pancreatic-cancer/results.html

Pancreatic Cancer Treatment Results 32 out of 92 adults with an inherited BRCA mutation did not have disease progression or death with LYNPARZA compared with 18 out of 62 adults with placebo.

3. lynparzahcp.com lynparzahcp.com/pancreatic-cancer/efficacy/polo.html

LYNPARZA Metastatic Pancreatic Cancer POLO Trial Efficacy ... Almost 1 in 4 patients in the LYNPARZA group with measurable disease after first-line platinum-based chemotherapy achieved a response (vs almost 1 in 8 in the ...

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa1903387

Maintenance Olaparib for Germline BRCA-Mutated ... Among patients with a germline BRCA mutation and metastatic pancreatic cancer, progression-free survival was longer with maintenance olaparib than with placebo.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10896473/

Olaparib in Patients With Pancreatic Cancer With BRCA1/2 ... The collective results from these three studies along with this TAPUR cohort demonstrate that treatment with a PARPi achieves an OR rate of 16%-42% in patients ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10476841/

Overall Survival Results From the POLO Trial: A Phase III ... The phase III POLO study demonstrated significant progression-free survival (PFS) benefit for active olaparib maintenance therapy versus placebo.

7. lynparzahcp.com lynparzahcp.com/pancreatic-cancer/safety-tolerability/polo.html

LYNPARZA Safety and Tolerability Data from POLO Trial Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients who received LYNPARZA for PROfound were: decrease in hemoglobin (98%), decrease in ...

8. lynparzaarguide.com lynparzaarguide.com/clinical-trials/onset-and-duration/clinical-trials-onset-and-duration-pancreatic-cancer

Pancreatic Cancer Clinical Trial Onsets and Duration Most common adverse reactions (Grades 1-4) in ≥20% of patients who received LYNPARZA in the metastatic setting for OlympiAD were: nausea (58%), ...

9. ascopubs.org ascopubs.org/doi/abs/10.1200/JCO.21.01604

Overall Survival Results From the POLO Trial: A Phase III ... The phase III POLO study demonstrated significant progression-free survival (PFS) benefit for active olaparib maintenance therapy versus placebo.