Peposertib + Avelumab + Radiation for Hepatobiliary Cancer

Recruiting at 48 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immune checkpoint inhibitors, PPIs

Disqualifiers: Uncontrolled CNS disease, Active autoimmune, 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: 12

Duration: 28 days per cycle

103 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose and assess the effects of combining peposertib (a potential new drug) and avelumab (an immunotherapy drug) with a specialized radiation therapy for treating advanced solid tumors and hepatobiliary cancers that have spread. Peposertib may inhibit tumor growth by blocking certain enzymes, while avelumab aids the immune system in targeting cancer cells. The radiation delivers higher doses in a shorter time, potentially reducing side effects. This trial may suit those with solid tumors that have worsened after standard treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering patients the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before starting the study. Specifically, you must discontinue medications that are strong inhibitors or inducers of certain liver enzymes (CYP3A4/5 or CYP2C19) and proton-pump inhibitors (PPIs) before starting the trial drugs. It's important to discuss your current medications with the trial team to see if any need to be stopped.

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

Research has shown that the combination of peposertib, avelumab, and radiation is generally well-tolerated by patients. Studies have found that taking peposertib up to 200 mg twice a day with avelumab, and up to 250 mg once a day with both avelumab and radiation, was manageable for most people, indicating that side effects were not too severe for most participants.

While side effects can occur, evidence suggests that the treatment is safe enough for continued testing in humans. Each person's experience may vary, so discussing potential risks with a healthcare provider can provide more personalized information. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine innovative approaches to target hepatobiliary cancer. Unlike standard treatments like surgery, chemotherapy, and conventional radiation, this trial uses hypofractionated radiation therapy, which delivers larger doses over fewer sessions, potentially enhancing effectiveness and convenience. Avelumab is an immune checkpoint inhibitor that helps the immune system attack cancer cells more effectively. Additionally, Peposertib is a novel agent that targets DNA damage response pathways, possibly enhancing the cancer-killing effects of radiation. This combination could offer a more potent attack on cancer cells, leading to better outcomes for patients.

What evidence suggests that this trial's treatments could be effective for hepatobiliary cancer?

This trial will evaluate the combination of peposertib, avelumab, and hypofractionated radiation therapy for hepatobiliary cancer. Studies have shown that peposertib effectively blocks certain enzymes that cancer cells need to grow by preventing tumor cells from repairing damaged DNA, which is especially beneficial when combined with radiation therapy. Avelumab, an immunotherapy drug, helps the immune system attack cancer cells and has shown positive results in patients with advanced cancers, such as bladder cancer. Hypofractionated radiation therapy delivers high doses of radiation in a short time and is particularly effective for liver cancer, helping to control tumor growth. Together, these treatments show promise in stopping cancer from spreading and reducing tumor size in advanced cancers. Participants in this trial will receive different combinations of these treatments to assess their effectiveness. ^{6 7 8 9 10}

Who Is on the Research Team?

Kristen Spencer, MD

Principal Investigator

Laura and Isaac Perlmutter Cancer Center at NYU

Are You a Good Fit for This Trial?

Adults with advanced/metastatic solid tumors or hepatobiliary malignancies, who have tried standard treatments without success or declined them. They must be in relatively good health (ECOG <=2), have measurable cancer lesions, and agree to biopsies if needed. Pregnant women, those with certain psychiatric illnesses, uncontrolled diseases, recent live vaccinations, or on strong immune system drugs can't join.

Inclusion Criteria

I can swallow and keep down pills.

I can take care of myself but may not be able to do heavy physical work.

I have an advanced tumor that has not responded to or cannot be treated by standard therapies.

Exclusion Criteria

I have not had a serious infection in the last 4 weeks.

I do not have any uncontrolled illnesses.

I have received immunotherapy before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Radiation

Patients undergo 8 fractions of hypofractionated radiation therapy every day on days -17 to -7

2 weeks

8 visits (in-person)

Treatment

Patients receive peposertib orally twice daily on days 1-28 and avelumab intravenously on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle

2 visits (in-person) per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

Up to 12 months

1 visit at 30 days, then every 3 months for 1 year, every 6 months for year 2, then annually

What Are the Treatments Tested in This Trial?

Interventions

• Avelumab
• Hypofractionated Radiation Therapy
• Peposertib

Trial Overview The trial is testing Peposertib combined with Avelumab and hypofractionated radiation therapy against advanced cancers. It aims to find the best dose of Peposertib and see how well it works alongside an immunotherapy drug (Avelumab) and a type of intense short-term radiation treatment.

How Is the Trial Designed?

Group I: Phase I (hypofractionated RT, peposertib, avelumab) Experimental Treatment 6 Interventions

Patients with advanced/metastatic malignant solid tumors undergo 8 fractions of hypofractionated RT QD on days -17 to -7. Patients also receive peposertib PO BID on days 1-28, and avelumab IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, biopsy, and collection of blood samples during screening and on study.

Group II: Arm B (hypofractionated RT, peposertib, avelumab) Experimental Treatment 5 Interventions

Patients undergo 8 fractions of hypofractionated RT QD on days -17 to -7. Patients also receive peposertib PO BID on days 1-28, and avelumab IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy, CT, and collection of blood on the trial.

Group III: Arm A (hypofractionated RT, avelumab) Active Control 5 Interventions

Patients undergo 8 fractions of hypofractionated RT QD on days -17 to -7. Patients also receive avelumab IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy, CT, and collection of blood on the trial.

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

Approved in European Union as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Approved in United States as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Approved in Japan as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

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 96 patients with locally advanced pancreatic adenocarcinoma, the combination of nab-paclitaxel, gemcitabine, anti-PD-1 immunotherapy, and radiotherapy significantly improved overall survival (22.3 months) and progression-free survival (12.0 months) compared to chemotherapy alone (18.6 months and 10.5 months, respectively).

The combination treatment did not result in a higher incidence of severe adverse events compared to chemotherapy alone, indicating that it is both effective and safe for patients with LAPC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nab-paclitaxel and gemcitabine plus camrelizumab and radiotherapy versus nab-paclitaxel and gemcitabine alone for locally advanced pancreatic adenocarcinoma: a prospective cohort study. Chen, S., Li, J., Dong, A., et al.[2023]

In a phase II trial involving 30 patients with advanced hepatocellular carcinoma previously treated with sorafenib, avelumab demonstrated moderate efficacy with an objective response rate of 10% and a disease control rate of 73.3%.

Avelumab was well tolerated, with only seven grade 3 adverse events reported and no grade 4 adverse events, indicating a favorable safety profile for patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Avelumab in Patients with Advanced Hepatocellular Carcinoma Previously Treated with Sorafenib. Lee, DW., Cho, EJ., Lee, JH., et al.[2022]

In a study of 84 patients with refractory metastatic pancreatic cancer, the combination of stereotactic body radiotherapy (SBRT) with nivolumab and ipilimumab showed a clinical benefit rate of 37.2%, indicating a significant improvement compared to 17.1% for SBRT with nivolumab alone.

The treatment was associated with a manageable safety profile, with 24.4% of patients experiencing grade 3 or higher adverse events in the SBRT/nivolumab group and 30.2% in the SBRT/nivolumab/ipilimumab group, suggesting that this combination therapy may be a viable option for patients despite the unknown contribution of SBRT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Phase II Study of Nivolumab With or Without Ipilimumab Combined With Stereotactic Body Radiotherapy for Refractory Metastatic Pancreatic Cancer (CheckPAC). Chen, IM., Johansen, JS., Theile, S., et al.[2023]

In a study of 133 advanced melanoma patients who had previously failed anti-PD-1 therapy, adding hypofractionated radiotherapy to the treatment resulted in a 31% complete response rate and a 35% abscopal effect, indicating potential enhanced efficacy of the anti-PD-1 therapy.

The median progression-free survival was 15.2 months and melanoma-specific survival was 35.3 months, suggesting that this combination treatment may provide significant benefits, although the study's retrospective nature and small sample size highlight the need for further controlled trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of late concurrent hypofractionated radiotherapy in advanced melanoma patients failing anti-PD-1 monotherapy. Funck-Brentano, E., Baghad, B., Fort, M., et al.[2021]

In a phase 2 trial involving 33 patients with locally advanced unresectable hepatocellular carcinoma, the combination of transarterial chemoembolisation (TACE) and stereotactic body radiotherapy followed by the anti-PD-L1 drug avelumab resulted in 55% of patients being deemed amenable to curative treatment, indicating promising efficacy for this approach.

The treatment was associated with some safety concerns, as 33% of patients experienced grade 3 or worse adverse events, primarily related to liver enzyme increases and immune-related effects, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sequential transarterial chemoembolisation and stereotactic body radiotherapy followed by immunotherapy as conversion therapy for patients with locally advanced, unresectable hepatocellular carcinoma (START-FIT): a single-arm, phase 2 trial. Chiang, CL., Chiu, KWH., Chan, KSK., et al.[2023]

In a phase 2 trial involving 147 patients with post-operative locally recurrent pancreatic cancer, combining high-dose stereotactic body radiation therapy (SBRT) with pembrolizumab and trametinib showed a significant improvement in progression-free survival (PFS) compared to gemcitabine, particularly in patients receiving higher radiation doses (BED10 ≥65Gy).

Although the combination treatment did not significantly extend overall survival (OS) compared to gemcitabine, the results suggest that further research is needed to explore the potential synergy of high-dose SBRT with immunotherapy and targeted therapy in larger phase 3 trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of stereotactic body radiotherapy dose escalation plus pembrolizumab and trametinib versus stereotactic body radiotherapy dose escalation plus gemcitabine for locally recurrent pancreatic cancer after surgical resection on survival outcomes: A secondary analysis of an open-label, randomised, controlled, phase 2 trial. Zhu, X., Liu, W., Cao, Y., et al.[2022]

In a phase 2 study involving 26 patients with refractory pancreatic cancer, the combination of ipilimumab, nivolumab, tocilizumab, and stereotactic body radiotherapy (SBRT) did not result in any objective responses, indicating limited efficacy for this treatment regimen.

While 19% of patients achieved stable disease, the median overall survival was only 5.3 months, and 73% experienced treatment-related adverse events, highlighting safety concerns associated with this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 study of ipilimumab, nivolumab, and tocilizumab combined with stereotactic body radiotherapy in patients with refractory pancreatic cancer (TRIPLE-R). Chen, IM., Donia, M., Chamberlain, CA., et al.[2023]

In a study of 25 advanced melanoma patients treated with both radiotherapy and anti-PD-1 therapy, hypo-fractionated radiotherapy showed promising results, with 24% of radiated lesions achieving a complete response and 12% a partial response.

The study suggests a potential 'abscopal effect,' where responses in non-radiated lesions were correlated with those in radiated lesions, indicating that radiotherapy may enhance the overall efficacy of anti-PD-1 therapy without unusual adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of combined hypo-fractionated radiotherapy and anti-PD-1 monotherapy in difficult-to-treat advanced melanoma patients. Roger, A., Finet, A., Boru, B., et al.[2021]

Combining radiation therapy with inhibition of the ephrinB2-EphB4 signaling pathway significantly reduces the infiltration of immunosuppressive cells and stromal fibrosis in pancreatic ductal adenocarcinoma (PDAC), leading to enhanced tumor control.

This study provides evidence that targeting the ephrinB2-EphB4 interaction can mitigate the immunosuppressive tumor microenvironment, suggesting a novel therapeutic strategy for improving treatment outcomes in PDAC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pancreatic Tumor Microenvironment Modulation by EphB4-ephrinB2 Inhibition and Radiation Combination. Lennon, S., Oweida, A., Milner, D., et al.[2020]

Citations

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Clinical Study Results | BAVENCIO® (avelumab) Efficacy Among those patients whose tumors got smaller​​ BAVENCIO is not a cure. The data represent patients in the clinical trial, and not all patients will experience ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12223640/

Survival and Safety Outcomes of Avelumab Maintenance ... Avelumab maintenance therapy demonstrated favorable survival outcomes and tolerability in patients with advanced UC in daily practice.

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Real-World Data Confirms Safety of Bavencio and Inlyta in ... Bavencio and Inlyta combination therapy demonstrated high six- and 12-month OS rates in advanced RCC patients in real-world settings. The AVION ...

4. onclive.com onclive.com/view/real-world-data-support-the-frontline-use-of-avelumab-plus-axitinib-in-advanced-rcc

Real-World Data Support the Frontline Use of Avelumab ... The AVION study confirmed the real-world effectiveness and safety of avelumab plus axitinib in advanced RCC, with a 12-month OS rate of 82.7%.

5. emdgroup.com emdgroup.com/en/news/asco-gu-2024-avelumab-updates-22-01-2024.html

Multiple New Analyses Reinforce the Role of BAVENCIO® ... Patients who received BAVENCIO first-line maintenance treatment following chemotherapy achieved a median OS of 30.5 months measured from the ...

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Study Details | NCT04068194 | Testing the Combination of ... This phase I/II trial studies the best dose and side effects of peposertib and to see how well it works with avelumab and hypofractionated radiation therapy.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10937199/

Phase I study of peposertib and avelumab with or without ... Peposertib doses up to 200 mg bid in combination with avelumab and up to 250 mg qd in combination with avelumab and radiotherapy were tolerable in patients ...

8. withpower.com withpower.com/trial/phase-2-cholangiocarcinoma-11-2019-6de89

Peposertib + Avelumab + Radiation for Hepatobiliary Cancer This phase I/II trial studies the best dose and side effects of peposertib and to see how well it works with avelumab and hypofractionated radiation therapy ...

9. app.1104health.com app.1104health.com/start/physician/NCT04068194/

Phase I/II Study of Peposertib and Avelumab ... This study investigates the safety, tolerability, and efficacy of combining peposertib, a DNA-dependent protein kinase inhibitor, with avelumab and ...

10. ucihealth.org ucihealth.org/clinical-trials/etctn-10276

A Phase I/II Study of Peposertib (M3814) and Avelumab in ... This phase I/II trial studies the best dose and side effects of peposertib and to see how well it works with avelumab and hypofractionated radiation therapy.