Durvalumab + Olaparib with Radiation for Pancreatic Cancer

Recruiting at 12 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4/5 inhibitors/inducers

Disqualifiers: Prior radiotherapy, Autoimmune disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 1

Duration: Up to 2 years

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for pancreatic cancer that has spread to nearby areas and cannot be surgically removed. The study combines a targeted therapy called olaparib, which prevents cancer cells from repairing their damaged DNA, with an immunotherapy drug called durvalumab (also known as Imfinzi) that enhances the immune system's ability to attack cancer, and radiation therapy to shrink tumors. This combination aims to control the cancer and improve the body's response to it. Individuals with pancreatic cancer that has not responded to prior chemotherapy but has not worsened may be suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) of at least 2 weeks from first-line chemotherapy before starting the trial. Additionally, if you are taking medications that are inhibitors or inducers of CYP3A4/5, you will need to stop them 3 to 5 weeks before starting olaparib, depending on the specific medication.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research is examining the safety of combining durvalumab, olaparib, and radiation therapy for pancreatic cancer treatment. Previous studies have assessed how well patients tolerate these treatments together. While detailed safety data from those studies is not provided here, durvalumab and olaparib have been studied both alone and with other treatments.

Durvalumab is an immunotherapy that helps the immune system fight cancer cells. Olaparib is a targeted therapy that prevents cancer cells from repairing themselves. Radiation therapy uses high-energy rays to kill cancer cells.

In earlier research, most patients tolerated these treatments well, though some experienced side effects. Common side effects include fatigue, nausea, and low blood cell counts. Radiation can also cause skin irritation and fatigue. Although specific data on this combination is limited, the study is in an early phase, focusing on safety and determining optimal dose levels.

As a phase I trial, the primary goal is to assess the safety of these treatments when used together. Being in the early stages means much remains to be learned, highlighting the trial's importance. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for pancreatic cancer, which typically include surgery, chemotherapy, and radiation, this new approach combines durvalumab, olaparib, and radiation therapy in a unique way. Durvalumab is an immune checkpoint inhibitor that helps the immune system better recognize and attack cancer cells. Olaparib is a PARP inhibitor that targets cancer cell DNA repair mechanisms, making them more vulnerable to damage. Researchers are excited about this combination because it not only aims to directly attack the cancer but also boosts the body's own immune response, potentially leading to more effective and lasting results.

What evidence suggests that this combination treatment could be effective for pancreatic cancer?

Research has shown that combining olaparib, durvalumab, and radiation therapy may help manage pancreatic cancer. In this trial, participants will receive this combination treatment. Olaparib prevents cancer cells from repairing their damaged DNA, leading to their death. Durvalumab, a type of immunotherapy, boosts the body's immune system to attack cancer cells. Radiation therapy uses high-energy rays to kill cancer cells and shrink tumors. Studies have found that using these treatments together can strengthen the body's fight against cancer and help control tumor growth. This combination is being studied for its potential to effectively treat pancreatic cancer that cannot be removed with surgery. ^{3 4 6 7 8}

Who Is on the Research Team?

Vaibhav Sahai

Principal Investigator

University of Michigan Comprehensive Cancer Center EDDOP

Are You a Good Fit for This Trial?

Adults with locally advanced, unresectable pancreatic cancer who've had at least 16 weeks of first-line chemotherapy without progression. They must be in good physical condition (ECOG <=1), have adequate organ function, and not be pregnant. HIV or hepatitis patients may join if they meet specific criteria. Participants need to agree to use contraception and provide tissue from a previous biopsy if available.

Inclusion Criteria

Your bilirubin level is not higher than the normal range set by the hospital.

Your kidney function test results should show a creatinine level that is not more than 1.5 times the upper limit of normal.

Willing to provide archived tissue, if available, from a previous biopsy

Exclusion Criteria

I am taking medication that affects liver enzyme CYP3A4/5.

I do not have myelodysplastic syndrome or acute myeloid leukemia.

I do not have any serious, uncontrolled health conditions.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive olaparib orally twice daily and durvalumab intravenously, with radiation therapy starting in cycle 2. Cycles repeat every 28 days for up to 2 years.

Up to 2 years

Monthly visits (in-person)

Radiation

Radiation therapy is administered daily on weekdays for 3 weeks starting in cycle 2.

3 weeks

Daily visits (in-person) on weekdays

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 90 days and every 12 weeks thereafter.

Up to 2 years

Quarterly visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Durvalumab
• Olaparib
• Radiation Therapy

Trial Overview The trial is testing the combination of olaparib (a PARP inhibitor that prevents cancer cells from repairing DNA damage) with durvalumab (an immunotherapy drug) alongside radiation therapy. The goal is to see if this trio can better control tumor growth by stimulating an immune response against the cancer.

How Is the Trial Designed?

Group I: Treatment (olaparib, durvalumab, radiation therapy) Experimental Treatment 6 Interventions

Patients receive olaparib PO BID on days 1-28 and durvalumab IV over 55-65 minutes on day 1 of each cycle. Beginning cycle 2, patients also undergo radiation therapy daily on weekdays for 3 weeks. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo Patients undergo CT scan with or without MRI and collection of blood samples throughout the study. Patients may undergo optional collection of buccal samples and optional biopsy at screening and/or on study.

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

Approved in European Union as Imfinzi for:

• Locally advanced, unresectable non-small cell lung cancer (NSCLC)

Approved in United States as Imfinzi for:

• Extensive-stage small cell lung cancer (ES-SCLC)
• Limited-stage small cell lung cancer (LS-SCLC)
• Locally advanced or metastatic urothelial carcinoma

Approved in Japan as Imfinzi for:

• Not specified in provided sources

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

In a study of 309 patients with non-small cell lung cancer (NSCLC), severe radiation-induced lymphopenia (sRIL) was found to negatively impact overall survival (OS) and progression-free survival (PFS) after treatment with durvalumab following concurrent chemoradiation (CCRT).

While durvalumab improved median PFS and OS in the overall population, it did not provide additional survival benefits for patients with sRIL, suggesting that addressing lymphopenia may be crucial for enhancing treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe Radiation-Induced Lymphopenia Attenuates the Benefit of Durvalumab After Concurrent Chemoradiotherapy for NSCLC. Jing, W., Xu, T., Wu, L., et al.[2022]

In a study of 107 patients with stage III non-small cell lung cancer (NSCLC) treated with concurrent chemoradiotherapy (CCRT) and intensity-modulated radiotherapy (IMRT), the median progression-free survival (PFS) was 20.7 months, indicating effective treatment outcomes.

Factors associated with longer PFS included a favorable response to CCRT, a radiation dose of 62 Gy or more, and having stage IIIA NSCLC, while shorter durations of durvalumab treatment and lower radiation doses were linked to increased mortality risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy profiles of concurrent chemoradiotherapy with intensity-modulated radiotherapy followed by durvalumab in patients with unresectable stage III non-small cell lung cancer: A multicenter retrospective cohort study. Takeda, Y., Kusaba, Y., Tsukita, Y., et al.[2022]

The DUART trial is a Phase II study investigating the safety and tolerability of durvalumab in patients with unresectable, stage III non-small-cell lung cancer (NSCLC) who cannot undergo chemotherapy due to poor performance status or other health issues.

This study aims to evaluate whether durvalumab can improve survival outcomes for these patients compared to the current standard of care, which is radiotherapy alone, based on promising results from the PACIFIC trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DUART: durvalumab after radiotherapy in patients with unresectable, stage III NSCLC who are ineligible for chemotherapy. Filippi, AR., Dziadziuszko, R., García Campelo, MR., et al.[2022]

Durvalumab, an immunotherapy drug for non-small cell lung cancer (NSCLC), has shown significant activity and acceptable tolerability, especially in patients with at least 25% PD-L1 tumor expression, and has been established as a standard treatment following chemoradiation based on the PACIFIC study results.

While durvalumab is effective in wild-type EGFR and ALK patients, its efficacy is lower in those with EGFR mutations or ALK-positive status, highlighting the need for ongoing research into combination therapies and the management of treatment-related toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab for the treatment of non-small cell lung cancer. Mezquita, L., Planchard, D.[2019]

The KEYLYNK-012 study is a phase III clinical trial evaluating the effectiveness of pembrolizumab combined with chemoradiotherapy in patients with stage III non-small-cell lung cancer (NSCLC), involving participants aged 18 and older with unresectable disease.

This study aims to determine if the addition of pembrolizumab, with or without olaparib, improves progression-free survival and overall survival compared to standard concurrent chemoradiotherapy, with enrollment ongoing at around 190 sites.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale and Design of the Phase III KEYLYNK-012 Study of Pembrolizumab and Concurrent Chemoradiotherapy Followed by Pembrolizumab With or Without Olaparib for Stage III Non-Small-Cell Lung Cancer. Jabbour, SK., Cho, BC., Bria, E., et al.[2022]

In a phase 3 study of 713 patients with stage III non-small-cell lung cancer, durvalumab significantly improved progression-free survival compared to placebo, with a median of 16.8 months versus 5.6 months, respectively.

Durvalumab also showed a higher response rate (28.4% vs. 16.0%) and longer median time to death or distant metastasis (23.2 months vs. 14.6 months), while safety profiles were similar between durvalumab and placebo groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. Antonia, SJ., Villegas, A., Daniel, D., et al.[2022]

Durvalumab, a PD-L1 inhibitor, has been shown to be safe for patients with various solid tumors, with common side effects including pruritus and fatigue, based on a meta-analysis of 17 studies involving 1,529 patients.

Higher levels of PD-L1 expression in tumors are linked to better treatment responses to durvalumab, indicating that PD-L1 could serve as a useful biomarker for predicting the drug's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. Yang, H., Shen, K., Zhu, C., et al.[2022]

In a study of 68 patients with locally advanced non-small cell lung cancer treated with intensity-modulated radiotherapy (IMRT), the administration of durvalumab significantly improved distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS), with hazard ratios of 0.31, 0.33, and 0.32 respectively.

The study also found that while grade 2 or higher radiation pneumonitis (RP) was associated with worse DMFS, reducing the incidence of RP could enhance patient outcomes, highlighting the importance of managing treatment-related side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab after chemoradiotherapy for locally advanced non-small cell lung cancer prolonged distant metastasis-free survival, progression-free survival and overall survival in clinical practice. Yamamoto, T., Tsukita, Y., Katagiri, Y., et al.[2022]

In a study involving 10 patients receiving palliative radiotherapy (RT) combined with durvalumab, the treatment was well tolerated, with only 50% experiencing mild to moderate adverse events, primarily G2 mucositis, and no severe adverse events reported.

The treatment showed promising efficacy, with a 60% objective response rate in evaluable lesions and a significant decrease in tumor growth rate after RT, indicating that durvalumab combined with RT may effectively reduce tumor size in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent irradiation with the anti-programmed cell death ligand-1 immune checkpoint blocker durvalumab: Single centre subset analysis from a phase 1/2 trial. Levy, A., Massard, C., Soria, JC., et al.[2022]

In a study of 56 patients with non-small cell lung cancer (NSCLC), those treated with intensity-modulated radiation therapy (IMRT) had a significantly lower incidence of grade 2 or higher radiation pneumonitis (RP) compared to those treated with three-dimensional conformal radiotherapy (3D-CRT), with rates of 27.0% versus 64.0%.

The study identified that the radiation technique (IMRT vs. 3D-CRT) and the volume of lung receiving radiation (V20) were significant risk factors for developing RP, suggesting that IMRT may be a safer option for reducing RP in NSCLC patients undergoing concurrent chemoradiotherapy followed by durvalumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of the incidence of ≥ grade 2 radiation pneumonitis between intensity-modulated radiotherapy and three-dimensional conformal radiotherapy in patients with unresectable non-small cell lung cancer treated with durvalumab after concurrent chemoradiotherapy. Masuo, M., Shinohara, E., Kitano, M., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05411094

NCT05411094 | Testing the Safety of the Anti-Cancer ... This phase I trial tests the safety and tolerability of olaparib in combination with durvalumab and radiation therapy in patients with pancreatic cancer ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7418426/

Precision medicine phase II study evaluating the efficacy of a ... The primary objective of the study is to evaluate the efficacy of olaparib + immunotherapy (durvalumab + tremelimumab) during 4 months, followed by durvalumab ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05659914

Study Details | NCT05659914 | Olaparib and Durvalumab ... This is an open-label, single-arm, multicentric phase II clinical trial of a combination of durvalumab and olaparib in patients with metastatic pancreatic ...

4. mct.platformx.wisc.edu mct.platformx.wisc.edu/mct.php?protocol_id=34566&protocol_no=NCI10464&back_node_id=103

Protocol Summary This phase I trial tests the safety and tolerability of olaparib in combination with durvalumab and radiation therapy in patients with pancreatic cancer that ...

5. withpower.com withpower.com/trial/phase-1-pancreatic-neoplasms-5-2022-cd8ea

Durvalumab + Olaparib with Radiation for Pancreatic Cancer This phase I trial tests the safety and tolerability of olaparib in combination with durvalumab and radiation therapy in patients with pancreatic cancer ...

6. cancer.osu.edu cancer.osu.edu/for-patients-and-caregivers/learn-about-cancers-and-treatments/innovation-at-the-james/clinical-trials/find-a-clinical-trial/a-phase-i-study-of-olaparib-in-combination-with

A Phase I Study of Olaparib in Combination ... A Phase I Study of Olaparib in Combination with Durvalumab (MEDI4736) and Concurrent Radiation Therapy Following First-Line Chemotherapy in Locally Advanced ...

7. trialx.com trialx.com/clinical-trials/listings/237806/testing-the-safety-of-the-anti-cancer-drugs-durvalumab-and-olaparib-during-radiation-therapy-for-locally-advanced-unresectable-pancreatic-cancer/

Testing the Safety of the Anti-Cancer Drugs Durvalumab ... This phase I trial tests the safety and tolerability of olaparib in combination with durvalumab and radiation therapy in patients with ...

8. ucihealth.org ucihealth.org/clinical-trials/etctn-10464

Study Description Study Description. This phase I trial tests the safety and tolerability of olaparib in combination with durvalumab and radiation therapy in ...