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

22 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the treatment Losartan + Radiation Therapy for Pancreatic Cancer?

Research shows that adding losartan to chemotherapy and radiation therapy improved surgical outcomes in pancreatic cancer patients, with a 61% success rate in removing tumors completely. Additionally, losartan has been found to enhance the effects of radiation therapy in prostate cancer, suggesting it may help make cancer cells more sensitive to treatment. ^{1 2 3 4 5}

Is the combination of Losartan and hypofractionated radiation therapy safe for treating pancreatic cancer?

Studies on hypofractionated radiation therapy for pancreatic cancer show that it is generally well-tolerated, with early mild side effects and no severe late side effects observed. This suggests that the treatment is safe for use in humans, although specific data on Losartan combined with this therapy is not detailed. ^{6 7 8 9 10}

How is the treatment of Losartan combined with Hypofractionated Radiation Therapy unique for pancreatic cancer?

This treatment is unique because it combines losartan, a drug that can enhance the effects of radiation by making cancer cells more sensitive to it, with hypofractionated radiation therapy, which delivers higher doses of radiation over fewer sessions, potentially improving treatment outcomes for pancreatic cancer. ^{1 2 5 11 12}

What is the purpose of this trial?

This phase I trial studies the side effects of losartan and hypofractionated radiation therapy after chemotherapy in treating patients with pancreatic cancer that may or may not be removed by surgery (borderline resectable) or has spread from its original site of growth to nearby tissues or lymph nodes and is not amenable to surgical resection (locally advanced unresectable). Losartan may improve blood flow and allows for better tissue oxygenation. Hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. Giving losartan and hypofractionated radiation therapy may work better in treating patients with pancreatic cancer compared to hypofractionated radiation therapy alone.

Research Team

Shane Lloyd

Principal Investigator

Huntsman Cancer Institute/ University of Utah

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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 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 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 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 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]

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]

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]

References

1. Singapore pubmed.ncbi.nlm.nih.gov

Association of losartan with outcomes in metastatic pancreatic cancer patients treated with chemotherapy. [2022]

2. France pubmed.ncbi.nlm.nih.gov

Losartan sensitizes selectively prostate cancer cell to ionizing radiation. [2016]

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

Antitumor effect of angiotensin II type 1 receptor blocker losartan for orthotopic rat pancreatic adenocarcinoma. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Stereotactic body radiation therapy for reirradiation of localized adenocarcinoma of the pancreas. [2022]

5. United States 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. [2023]

6. United States 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. [2023]

7. Ireland pubmed.ncbi.nlm.nih.gov

Dosimetric and clinical predictors of toxicity following combined chemotherapy and moderately hypofractionated rotational radiotherapy of locally advanced pancreatic adenocarcinoma. [2023]

8. United States 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. [2023]

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

Hypofractionated intensity-modulated radiotherapy in locally advanced unresectable pancreatic cancer: A pilot study. [2020]

10. England pubmed.ncbi.nlm.nih.gov

Tolerance and efficacy of palliative radiotherapy for advanced pancreatic cancer: A retrospective analysis of single-institutional experiences. [2020]

11. England pubmed.ncbi.nlm.nih.gov

No association between losartan use and acute pancreatitis in hypertensive patients. [2022]

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

Effects of angiotensin II receptor antagonist, Losartan on the apoptosis, proliferation and migration of the human pancreatic stellate cells. [2022]