Durvalumab + Olaparib with Radiation for Pancreatic Cancer

Recruiting in Palo Alto (17 mi)

+12 other locations

Overseen by Michael D. Green

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4/5 inhibitors/inducers

Disqualifiers: Prior radiotherapy, Autoimmune disease, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This phase I trial tests the safety and tolerability of olaparib in combination with durvalumab and radiation therapy in patients with pancreatic cancer that has spread to nearby tissue or lymph nodes (locally advanced) and cannot be removed by surgery (unresectable). Olaparib is an inhibitor of PARP, an enzyme that helps repair deoxyribonucleic acid (DNA) when it becomes damaged. Blocking PARP may help keep cancer cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. The combination of targeted therapy with olaparib, immunotherapy with durvalumab and radiation therapy may stimulate an anti-tumor immune response and promote tumor control in locally advanced unresectable pancreatic cancer.

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.

What data supports the effectiveness of the treatment Durvalumab + Olaparib with Radiation for Pancreatic Cancer?

Research shows that Durvalumab, when used with radiotherapy, has provided additional survival benefits in patients with non-small cell lung cancer, suggesting potential effectiveness in other cancers like pancreatic cancer. ^{1 2 3 4 5}

Is the combination of Durvalumab and Olaparib with Radiation Therapy safe for humans?

Durvalumab has shown acceptable safety and tolerability in patients with non-small cell lung cancer (NSCLC) when used after chemoradiotherapy, although treatment-related toxicity is an important consideration. Olaparib's safety profile is not detailed in the provided research, but it is often used in combination with other treatments, suggesting it is generally considered safe in clinical settings. ^{1 3 6 7 8}

How is the treatment of Durvalumab + Olaparib with Radiation for Pancreatic Cancer different from other treatments?

This treatment combines Durvalumab, an immunotherapy drug that helps the immune system attack cancer cells, with Olaparib, a drug that targets cancer cell DNA repair, and radiation therapy, which uses high-energy rays to kill cancer cells. This combination is unique because it integrates different mechanisms to potentially enhance the overall effectiveness against pancreatic cancer, a condition with limited standard treatment options. ^{1 2 8 9 10}

Research Team

Michael D. Green

Principal Investigator

University of Michigan Comprehensive Cancer Center EDDOP

Eligibility Criteria

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 active infections like TB, hepatitis B, or C.

Trial Timeline

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)

Treatment Details

Interventions

• Durvalumab (PD-L1 Inhibitor)
• Olaparib (PARP Inhibitor)
• Radiation Therapy (Radiation)

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.

Participant Groups

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 radiologic evaluation 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 Japan for the following indications:

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+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

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]

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]

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]

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]

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]

References

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

DUART: durvalumab after radiotherapy in patients with unresectable, stage III NSCLC who are ineligible for chemotherapy. [2022]

2. Ireland 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. [2022]

3. England 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. [2022]

4. England 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. [2022]

5. England 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. [2023]

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

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Durvalumab for the treatment of non-small cell lung cancer. [2019]

8. United States 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. [2022]

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

Severe Radiation-Induced Lymphopenia Attenuates the Benefit of Durvalumab After Concurrent Chemoradiotherapy for NSCLC. [2022]

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

Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. [2022]