Losartan + Radiation Therapy for Pancreatic Cancer

(SHAPER Trial)

Overseen By Mitchell Shea

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Utah

Must not be taking: Angiotensin blockers, Renin inhibitors

Disqualifiers: Metastases, Prior radiation, Heart failure, HIV, Hepatitis, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if combining losartan (a medicine that may improve blood flow) with hypofractionated radiation therapy can more effectively treat pancreatic cancer than using the radiation therapy alone. It targets patients with pancreatic cancer that cannot be fully removed by surgery or has spread locally. Suitable candidates have doctor-confirmed pancreatic cancer, have undergone specific chemotherapy treatments, and do not have distant cancer spread. 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 that you stop taking certain medications, specifically angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, and direct renin inhibitors like aliskiren, before starting the study treatment. If you are taking more than 50mg of losartan daily, you may need to adjust your dosage.

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

Previous studies have shown that losartan, a common medication for high blood pressure, is generally safe for people with cancer. Some research suggests it might even improve survival rates. No major safety concerns arose when losartan was combined with other cancer treatments.

Research indicates that hypofractionated radiation therapy, which involves higher doses of radiation over a shorter period, is well-tolerated. Studies have found that this type of radiation therapy can effectively control tumors without causing many serious side effects.

Overall, both losartan and hypofractionated radiation therapy have demonstrated a good safety record in past research. This suggests they might be safe options for people with pancreatic cancer, but discussing any concerns with doctors remains important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for pancreatic cancer, which typically involve surgery, chemotherapy, or conventional radiation therapy, this new approach combines losartan with hypofractionated radiation therapy. Researchers are excited about this because losartan, a blood pressure medication, may increase blood flow to the tumor, potentially enhancing the effectiveness of the radiation therapy. Hypofractionated radiation therapy is also different because it delivers higher doses of radiation over a shorter period, which might improve patient outcomes and reduce treatment time. This combination could offer a more effective and faster treatment option for pancreatic cancer patients.

What evidence suggests that losartan and hypofractionated radiation therapy might be an effective treatment for pancreatic cancer?

Research has shown that losartan, which participants in this trial will receive, might help treat pancreatic cancer by reducing blood flow to tumors. Some studies suggest it can slow tumor growth, but its effect on survival remains uncertain. Losartan may work by altering the cancer's support structure.

Hypofractionated radiation therapy, also part of this trial, uses higher doses of radiation over a shorter period and has shown promising results. Studies have found it can improve survival by effectively controlling the main tumor. This trial combines these treatments to enhance outcomes for pancreatic cancer patients. ^{1 4 6 7 8}

Who Is on the Research Team?

Shane Lloyd

Principal Investigator

Huntsman Cancer Institute/ University of Utah

Are You a Good Fit for This Trial?

This trial is for patients with pancreatic cancer that's borderline resectable or locally advanced and unresectable. They must have had at least one round of specific chemotherapy, be within certain blood and organ function parameters, not pregnant, willing to use effective contraception, and able to consent. Exclusions include those on high-dose losartan, other trials, prior malignancies affecting safety assessments, previous radiation or surgery for pancreatic cancer, uncontrolled ulcers or chronic coughs among others.

Inclusion Criteria

My cancer is confirmed as pancreatic ductal adenocarcinoma.

I have tried FOLFIRINOX or gemcitabine chemotherapy.

I am enrolling within 3 months after my last chemotherapy session.

Exclusion Criteria

My cancer has spread to distant parts of my body, but may also be in nearby lymph nodes.

I don't have another cancer that could affect this trial's safety or results.

I take more than 50mg of losartan daily and cannot reduce it.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Chemotherapy

Participants receive induction chemotherapy to stabilize or manage locally progressive pancreatic ductal adenocarcinoma

Varies

Treatment

Participants receive losartan potassium orally once daily starting on day 1. Beginning day 14, they also undergo hypofractionated radiation therapy over 15 fractions, 5 days a week for up to 3 weeks. Losartan continues during radiation and for 28 days after completion.

6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment. Follow-up occurs at 28 and 84 days, every 3 months for 12 months, and then every 6 months for up to 36 months.

36 months

What Are the Treatments Tested in This Trial?

Interventions

• Hypofractionated Radiation Therapy
• Losartan Potassium

Trial Overview The SHAPER trial is testing the combination of losartan (a drug that may improve blood flow) with hypofractionated radiation therapy (which delivers higher doses in a shorter period), following chemotherapy. The goal is to see if this combo is more effective than just radiation alone in treating pancreatic cancer by killing more tumor cells with fewer side effects.

How Is the Trial Designed?

Group I: Treatment (losartan, hypofractionated radiation therapy) Experimental Treatment 5 Interventions

Beginning on day 1, patients receive losartan potassium PO QD. Beginning day 14, patients also undergo hypofractionated radiation therapy over 15 fractions 5 days a week for up to 3 weeks. Patients continue to receive losartan potassium PO QD during radiation therapy and for 28 days after completion of radiation therapy. Patients may begin additional anti-cancer therapy per investigator discretion after the last dose of HRT. Losartan can be given concurrently with additional therapy and Losartan dosing can continue until 28 days after last dose of HRT, regardless of when additional therapy is started.

Hypofractionated Radiation Therapy is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Hypofractionated Radiotherapy for:

• Soft tissue sarcoma
• Extremity soft tissue sarcoma

Approved in European Union as Hypofractionated Radiotherapy for:

• Soft tissue sarcoma
• Extremity soft tissue sarcoma

Approved in Canada as Hypofractionated Radiotherapy for:

• Soft tissue sarcoma
• Extremity soft tissue sarcoma

Who Is Running the Clinical Trial?

University of Utah

Lead Sponsor

Trials

1,169

Recruited

1,623,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 61 patients with locally advanced pancreatic adenocarcinoma, hypofractionated radiotherapy resulted in a 33% incidence of acute gastrointestinal grade 2 toxicity, highlighting the need to manage side effects during treatment.

Dosimetric analysis revealed that higher doses to the stomach (V20[%]) and duodenum (V40[%] and V45[%]) were significant predictors of both acute and late anatomical toxicity, suggesting that careful planning of radiation doses can help minimize these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dosimetric and clinical predictors of toxicity following combined chemotherapy and moderately hypofractionated rotational radiotherapy of locally advanced pancreatic adenocarcinoma. Cattaneo, GM., Passoni, P., Longobardi, B., et al.[2023]

In a pilot study involving 10 patients with unresectable pancreatic adenocarcinoma, hypofractionated intensity modulated radiotherapy (H-IMRT) demonstrated a high local control rate, with tumor response observed in 9 out of 10 patients.

The treatment was associated with manageable gastrointestinal toxicity, which correlated with the dose received by the duodenum, and resulted in promising 1-year overall and disease-free survival rates of 83.3% and 68.6%, respectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypofractionated intensity-modulated radiotherapy in locally advanced unresectable pancreatic cancer: A pilot study. De Felice, F., Benevento, I., Bulzonetti, N., et al.[2020]

In a study of 28 patients with pancreatic cancer who received hypofractionated stereotactic body radiation therapy (SBRT) after prior radiation, 85.7% were free from local progression, indicating that SBRT can effectively control local disease.

The treatment was generally well-tolerated, with only mild to moderate side effects reported, but the overall survival rate remained low, with a median survival of 5.9 months, highlighting the challenges in treating pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic body radiation therapy for reirradiation of localized adenocarcinoma of the pancreas. Lominska, CE., Unger, K., Nasr, NM., et al.[2022]

Losartan, an AT1 receptor antagonist, effectively induces apoptosis in human pancreatic stellate cells (hPSCs) in a dose- and time-dependent manner, without promoting cell proliferation.

The study suggests that Losartan may have anti-fibrotic effects by reducing the migration and type I collagen production of hPSCs, indicating its potential therapeutic role in pancreatic fibrosis associated with cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of angiotensin II receptor antagonist, Losartan on the apoptosis, proliferation and migration of the human pancreatic stellate cells. Liu, WB., Wang, XP., Wu, K., et al.[2022]

In a study of 170 patients with unresectable non-metastatic pancreatic cancer, hypofractionated radiotherapy combined with full-dose gemcitabine resulted in significantly better overall survival (52% at 1 year) and distant metastasis-free survival (41% at 1 year) compared to standard fractionation radiotherapy with 5-fluorouracil (36% and 24%, respectively).

Both treatment regimens showed similar rates of gastrointestinal toxicities, indicating that the hypofractionated RT with gemcitabine is not only more effective but also has a comparable safety profile to the standard treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypofractionated Conformal Radiotherapy with Concurrent Full-Dose Gemcitabine Versus Standard Fractionation Radiotherapy with Concurrent Fluorouracil for Unresectable Pancreatic Cancer: a Multi-Institution Experience. Rakhra, S., Strauss, JB., Robertson, J., et al.[2023]

In a phase II study involving 54 patients with resectable pancreatic cancer, neoadjuvant chemoradiotherapy using moderately hypofractionated intensity-modulated radiation therapy (NACIMRT) demonstrated a median overall survival of 40.0 months, indicating its potential efficacy as a treatment option.

The study achieved a high R0 resection rate of 95.2% among patients who underwent surgery after NACIMRT, with no intervention-related deaths, suggesting that this approach is safe and effective in preparing patients for surgical resection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of neoadjuvant chemoradiotherapy with moderately hypofractionated intensity-modulated radiotherapy for resectable pancreatic cancer: A prospective, open-label, phase II study. Masui, T., Nagai, K., Anazawa, T., et al.[2023]

In a study of 114 patients with metastatic pancreatic ductal adenocarcinoma, the use of losartan during chemotherapy did not show significant differences in overall survival (OS) or progression-free survival (PFS) compared to patients not using losartan.

While there was a trend towards longer PFS in patients treated with losartan and FOLFIRINOX, this did not reach statistical significance, suggesting that further research is needed to explore the potential benefits of losartan in metastatic pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of losartan with outcomes in metastatic pancreatic cancer patients treated with chemotherapy. Kasi, A., Allen, J., Mehta, K., et al.[2022]

Losartan, an angiotensin II receptor blocker, effectively reduces the survival of prostate cancer cells, showing a significant antitumor effect at a concentration of 1 µM.

When combined with ionizing radiation, losartan enhances the treatment's effectiveness, further reducing prostate cancer cell proliferation without causing toxicity to non-malignant fibroblast cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Losartan sensitizes selectively prostate cancer cell to ionizing radiation. Yazdannejat, H., Hosseinimehr, SJ., Ghasemi, A., et al.[2016]

A study involving 1449 hypertensive patients with acute pancreatitis and 2479 controls found no significant association between losartan use and the risk of developing acute pancreatitis, with adjusted odds ratios of 0.96 for current use and 1.05 for late use, indicating no increased risk.

The findings suggest that losartan does not significantly impact the likelihood of acute pancreatitis in hypertensive patients, but further research is needed to explore any potential links.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

No association between losartan use and acute pancreatitis in hypertensive patients. Lai, SW., Lin, HF., Lin, CL., et al.[2022]

In a phase II trial, adding losartan (LOS) to FOLFIRINOX (FFX) chemotherapy and chemoradiation (CRT) led to a 61% rate of R0 surgical resection in patients with locally advanced pancreatic cancer, indicating improved surgical outcomes.

LOS treatment was associated with reduced immunosuppression and pro-invasion gene expression, as well as changes in immune cell populations, suggesting that LOS enhances the effectiveness of FFX+CRT by modifying the tumor microenvironment favorably.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of Losartan to FOLFIRINOX and Chemoradiation Reduces Immunosuppression-Associated Genes, Tregs, and FOXP3+ Cancer Cells in Locally Advanced Pancreatic Cancer. Boucher, Y., Posada, JM., Subudhi, S., et al.[2023]

In a study of 31 patients with locally advanced or metastatic pancreatic adenocarcinoma, hypofractionated radiotherapy was well-tolerated, with no late high-grade toxicity observed and early mild toxicity reported.

The treatment provided significant pain relief, with 55% of patients achieving good pain control without medication, and it also contributed to an average survival time of 9 months, with a 1-year overall survival rate of 16%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerance and efficacy of palliative radiotherapy for advanced pancreatic cancer: A retrospective analysis of single-institutional experiences. Wolny-Rokicka, E., Sutkowski, K., Grządziel, A., et al.[2020]

In a study using a rat model of pancreatic cancer, the combination of gemcitabine and losartan significantly improved survival rates, extending life expectancy to 102.6 days compared to 59.6 days in the control group.

Both gemcitabine and losartan reduced cancer cell proliferation and inhibited the expression of vascular endothelial growth factor, suggesting that targeting the AT1 receptor with losartan enhances the effectiveness of gemcitabine in treating advanced pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor effect of angiotensin II type 1 receptor blocker losartan for orthotopic rat pancreatic adenocarcinoma. Kim, S., Toyokawa, H., Yamao, J., et al.[2022]

Citations

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Hypofractionated radiotherapy followed by rhGM-CSF ... Hypofractionated radiotherapy followed by rhGM-CSF enhances immunogenic cell death in a murine model of pancreatic cancer · ABSTRACT.

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Evaluation of hypofractionated adaptive radiotherapy using ... The aim of the trial is to assess safety of extreme hypofractionation of SABR using MRgRT in pancreatic cancer. The five-fraction, three- ...

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Hypofractionated radiotherapy concomitant to capecitabine ... One- and two-year survival were 85.2 % and 36 %, respectively. Conclusions. The present schedule of hypofractionated RT after induction CHT is feasible with ...

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A Propensity Score-Matched Analysi Conclusion: For patients with intact, pancreatic ductal carcinoma, modern. CRT is well tolerated with minimal decline in quality of life during treatment.

5. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2777063

Association of Ablative Radiation Therapy With Survival ... Hypofractionated ablative radiation therapy was associated with durable control of the primary tumor leading to favorable survival outcomes.

6. redjournal.org redjournal.org/article/S0360-3016(24)01022-8/fulltext

Safety and Efficacy Results of a Phase II Clinical Trial ... The purpose of this clinical trial is to evaluate the safety and efficacy of moderately-hypofractionated CRT.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11795415/

Multi‐Institutional Phase II Study on the Efficacy and Safety ... DTT moderately hypofractionated IMRT shows preferable locoregional control without significant toxicity in patients with LAPC.

8. sciencedirect.com sciencedirect.com/science/article/pii/S0360301623074527

Outcomes of Moderately Dose Escalated Hypofractionated ... We found MDE is a simple, safe, and effective strategy associated with improved local control, higher R0 resection rates, and similar toxicity to SD CRT for ...