Peposertib + Radiation Therapy for Pancreatic Cancer

Not currently recruiting at 4 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP450 inhibitors, CYP450 inducers

Disqualifiers: Major surgery, Brain metastases, others

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

Compensation: Varies

Number of Visits: 8

Duration: 8 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose and potential benefits of combining peposertib, a new potential drug, with lutetium Lu 177 dotatate for treating neuroendocrine tumors, which can become cancerous. Peposertib may inhibit tumor growth by blocking certain enzymes, while lutetium Lu 177 dotatate delivers targeted radiation to tumor cells. This trial may suit individuals with a well-defined neuroendocrine tumor who have experienced disease progression despite previous treatment and have not yet tried peptide receptor radionuclide therapy. 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 treatment.

Will I have to stop taking my current medications?

The trial requires you to stop taking certain medications, such as strong inhibitors or inducers of specific liver enzymes (CYP3A4/5, CYP2C9, and CYP2C19) and proton-pump inhibitors, before starting the study. You should discuss with the study doctor to see if alternative medications can be used.

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

Research has shown that peposertib has been tested with radiation therapy in other studies. It was generally well-tolerated, with researchers focusing on finding the best dose while ensuring safety. Some patients experienced side effects, but these were mostly manageable.

Lutetium Lu 177 dotatate has also been tested in various situations. Studies indicate that it is mostly safe, though some people experienced side effects like tiredness, nausea, and diarrhea, which were usually mild. This drug is already approved for treating certain tumors, indicating a known safety profile.

In this trial, both peposertib and lutetium Lu 177 dotatate will be used together. Past evidence shows both are generally safe, but staying informed and discussing any concerns with the trial team is always important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Peposertib and Lutetium Lu 177 Dotatate for pancreatic cancer because it introduces a unique approach compared to current treatments. Unlike standard chemotherapy or surgery, Peposertib works by inhibiting DNA repair mechanisms in cancer cells, making them more vulnerable to radiation therapy. Meanwhile, Lutetium Lu 177 Dotatate is a targeted radiotherapy that delivers radiation directly to the cancer cells, potentially reducing damage to healthy tissue. This dual-action strategy could enhance the effectiveness of treatment while minimizing side effects, making it a promising option for patients with pancreatic cancer.

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

Research has shown that peposertib may be effective when combined with radiation therapy. Early studies demonstrated that adding peposertib to radiation treatment stopped pancreatic cancer cells from growing. Peposertib blocks enzymes that cancer cells need for growth. In this trial, participants will receive a combination of peposertib and lutetium Lu 177 dotatate. Lutetium Lu 177 dotatate, a radioactive drug, has successfully treated neuroendocrine tumors. Studies have shown that lutetium Lu 177 dotatate can significantly slow cancer progression and improve survival rates. Combining these two treatments in this trial might enhance their effectiveness in killing cancer cells. ^{6 7 8 9 10}

Who Is on the Research Team?

Lowell Anthony, MD, FACP

Principal Investigator

Ohio State University Comprehensive Cancer Center LAO

Are You a Good Fit for This Trial?

Adults with well-differentiated pancreatic neuroendocrine tumors, who've had a positive dotatate scan and failed at least one cancer treatment. They must have good organ function, no prior radionuclide therapy, be able to swallow pills, not pregnant or breastfeeding, and without serious infections or psychiatric issues that could affect participation.

Inclusion Criteria

Platelets >= 75,000/mcL

I have a heart condition and have been assessed using the NYHA classification.

White blood cell count >= 2,000/mcL

Exclusion Criteria

I have stopped taking long-acting somatostatin analogs for 4 weeks.

Patients receiving any other investigational agents

I cannot swallow pills or have a condition that affects how my body absorbs medication.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive peposertib orally once or twice daily and lutetium Lu 177 dotatate intravenously on day 1, repeated every 56 days for up to 4 cycles

8 months

4 cycles with multiple visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

24 months

Follow-up every 4 months

What Are the Treatments Tested in This Trial?

Interventions

• Lutetium Lu 177 Dotatate
• Peposertib

Trial Overview The trial is testing the combination of M3814 (Peposertib) with Lutetium Lu 177 Dotatate radiation therapy to determine the best dose and assess potential benefits and side effects in treating neuroendocrine tumors. Peposertib blocks enzymes needed for cell growth while the radioactive drug targets tumor cells.

How Is the Trial Designed?

Group I: Treatment (peposertib, lutetium Lu 177 dotatate) Experimental Treatment 5 Interventions

Patients receive peposertib PO QD or BID on days 1-21 and lutetium Lu 177 dotatate IV over 30 minutes on day 1. Treatment repeats every 56 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT/MRI throughout the trial and undergo collection of blood samples on study.

Lutetium Lu 177 Dotatate is already approved in European Union, United States for the following indications:

Approved in European Union as Lutathera for:

• Gastroenteropancreatic neuroendocrine tumors

Approved in United States as Lutathera for:

• Gastroenteropancreatic neuroendocrine tumors

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 maximum tolerated dose (MTD) of vorinostat in combination with capecitabine and radiation for non-metastatic pancreatic cancer was determined to be 400 mg daily, with manageable side effects including lymphopenia and nausea.

Nineteen out of twenty-one patients (90%) experienced stable disease, and the treatment regimen led to a median overall survival of 1.1 years, indicating promising efficacy for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of vorinostat added to chemoradiation with capecitabine in pancreatic cancer. Chan, E., Arlinghaus, LR., Cardin, DB., et al.[2018]

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 II trial involving 69 treatment-naive patients with locally advanced pancreatic cancer, the combination of cetuximab, gemcitabine, and oxaliplatin followed by chemoradiotherapy showed a median overall survival of 19.2 months, meeting the primary endpoint of a 1-year survival rate greater than 45%.

The treatment was associated with manageable toxicity, with the most common side effects being gastrointestinal issues and acneiform rash, the latter of which correlated with improved survival outcomes, suggesting it may serve as a potential biomarker for treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of cetuximab, gemcitabine, and oxaliplatin followed by chemoradiation with cetuximab for locally advanced (T4) pancreatic adenocarcinoma: correlation of Smad4(Dpc4) immunostaining with pattern of disease progression. Crane, CH., Varadhachary, GR., Yordy, JS., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11137281/

Long-term clinical outcomes of [177Lu]Lu-DOTATATE in ... The disease control rate was 92%, comprising 9 patients with a partial response (PR) and 14 patients with stable disease (SD). The objective ...

2. cancer.gov cancer.gov/news-events/cancer-currents-blog/2024/lutathera-neuroendocrine-tumor-initial-treatment

Lutathera Delays Growth of Advanced Neuroendocrine ... Those who received Lu 177-dotatate plus octreotide (Sandostatin) lived almost three times as long without their cancer getting worseExit ...

3. lutathera-hcp.com lutathera-hcp.com/1l-netter-2-efficacy

1L: NETTER-2 | LUTATHERA® (lutetium Lu 177 dotatate) | HCP 43% overall response rate for LUTATHERA plus 30 mg octreotide, which is 4x greater. Duration of Response ...

4. jnm.snmjournals.org jnm.snmjournals.org/content/early/2025/06/05/jnumed.124.269416

Cost-Effectiveness of [177Lu]Lu-DOTATATE for the Treatment ... The NETTER-2 trial found superior median progression-free survival (22.8 mo vs. 8.5 mo) and similar adverse events and quality-of-life measures ...

5. novartis.com novartis.com/news/media-releases/novartis-lutathera-significantly-reduced-risk-disease-progression-or-death-72-first-line-treatment-patients-advanced-gastroenteropancreatic-neuroendocrine-tumors

Novartis Lutathera® significantly reduced risk of disease ... Novartis Lutathera® significantly reduced risk of disease progression or death by 72% as first-line treatment for patients with advanced ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40310018/

Post-marketing Safety Evaluation of Lutathera ( 177 Lu- ... This study aims to conduct a comprehensive analysis of the adverse events (AEs) associated with Lutathera using FDA Adverse Event Reporting System (FAERS) data.

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.4131

Safety and time to response of [ 177 Lu]Lu-DOTATATE in ... With a median TTR of 5.7 months, most responses to 177 Lu-DOTATATE occurred during scheduled treatment. Overall, the study confirmed the safety profile of 177 ...

8. frontiersin.org frontiersin.org/journals/oncology/articles/10.3389/fonc.2024.1393317/full

Long-term clinical outcomes of [ 177 Lu]Lu-DOTATATE in ... The most frequently reported (>15%) nonhematologic treatment-related adverse events were fatigue, nausea, vomiting, and diarrhea. Clinically ...

9. nature.com nature.com/articles/s41698-025-00938-1

Emerging innovations in theranostics for pancreatic ... The trial demonstrated that 177Lu-DOTATATE reduced the risk of progression or death by 79% compared to high-dose octreotide LAR, with a 20-month ...

10. onclive.com onclive.com/view/lutetium-lu-177-dotatate-yields-partial-responses-in-metastatic-bronchopulmonary-neuroendocrine-tumors

Lutetium Lu 177 Dotatate Yields Partial Responses in ... Lutetium Lu 177 dotatate demonstrated antitumor activity in metastatic BP-NETs, with partial responses in 17% of patients and stable disease in ...