Peposertib + Radiation Therapy for Pancreatic Cancer

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

29 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests the combination of peposertib and lutetium Lu 177 dotatate in patients with neuroendocrine tumors. Peposertib blocks enzymes needed for tumor growth, while lutetium Lu 177 dotatate targets and kills tumor cells with radiation. Lutetium Lu 177 dotatate has been used to treat inoperable neuroendocrine tumors and has shown to improve patients' quality of life. The goal is to find the best dose and observe potential benefits and side effects.

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.

What data supports the effectiveness of the drug Peposertib + Radiation Therapy for Pancreatic Cancer?

The research shows that combining drugs with radiation therapy, like in the case of sorafenib and gemcitabine, can enhance the treatment's effectiveness against pancreatic cancer. This suggests that using Peposertib with radiation might also improve outcomes, although direct evidence for Peposertib is not provided. ^{1 2 3 4 5}

How is the drug Peposertib + Radiation Therapy for Pancreatic Cancer different from other treatments?

Peposertib combined with radiation therapy is unique because it includes Lutetium Lu 177 Dotatate, a radioactive drug that targets specific cancer cells, potentially enhancing the effectiveness of radiation therapy. This approach is different from standard treatments that typically use chemotherapy drugs like gemcitabine, which do not have this targeted radioactive component. ^{1 4 6 7 8}

Research Team

Lowell Anthony, MD, FACP

Principal Investigator

Ohio State University Comprehensive Cancer Center LAO

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

References

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

A phase I, dose-finding study of sorafenib in combination with gemcitabine and radiation therapy in patients with unresectable pancreatic adenocarcinoma: a Grupo Español Multidisciplinario en Cáncer Digestivo (GEMCAD) study. [2022]

2. Ireland pubmed.ncbi.nlm.nih.gov

Phase I trial of vorinostat added to chemoradiation with capecitabine in pancreatic cancer. [2018]

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

Phase I Clinical Trial to Determine the Feasibility and Maximum Tolerated Dose of Panitumumab to Standard Gemcitabine-Based Chemoradiation in Locally Advanced Pancreatic Cancer. [2022]

4. United States 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. [2022]

5. England 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. [2022]

6. Greece pubmed.ncbi.nlm.nih.gov

Capecitabine as a Radiosensitizer in Adjuvant Chemoradiotherapy for Pancreatic Cancer: A Retrospective Study. [2015]

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

The combination of epidermal growth factor receptor inhibitors with gemcitabine and radiation in pancreatic cancer. [2022]

8. China pubmed.ncbi.nlm.nih.gov

Phase Ib/II study combining tosedostat with capecitabine in patients with advanced pancreatic adenocarcinoma. [2022]