Losartan for Radiation-Induced Fibrosis in Breast Cancer

Recruiting at 1 trial location

Overseen By Katie Hess, BS

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Shaw Cancer Center

Must not be taking: Losartan, RAS agents, Lithium, others

Disqualifiers: Recurrent breast cancer, Connective tissue disorder, Uncontrolled illness, Pregnancy, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: 1 year

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether losartan, a medication approved for other uses, can reduce scarring in the breast and lungs caused by radiation therapy for breast cancer. Researchers believe losartan might lower inflammation and improve recovery after radiation. Participants will take either losartan or a placebo (a pill with no active drug) during radiation therapy. Women who have had breast cancer surgery and are scheduled for radiation therapy may be suitable for this study. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I have to stop taking my current medications for this trial?

The trial does not specify if you must stop all current medications, but you cannot take Losartan, other renin-angiotensin system agents, agents to increase serum potassium, lithium, or aliskiren for diabetes.

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

Research has shown that losartan is generally safe for use. The FDA has approved it to treat high blood pressure. In studies with breast cancer patients, losartan reduced fibrosis, which is the thickening or scarring caused by radiation therapy.

Reports from these studies indicate that side effects are usually mild, with common ones including dizziness, stuffy nose, or back pain. Serious side effects are rare. Since losartan is already approved for other uses, extensive safety information is available, confirming its safety for many people.

Consult a doctor if there are any concerns or questions before joining a trial. They can help determine if this medication is suitable. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for radiation-induced fibrosis?

Losartan is unique because it targets radiation-induced fibrosis in breast cancer patients, a condition typically managed through physical therapy, steroids, or surgery. Unlike these options, losartan is an angiotensin receptor blocker, which means it works by reducing inflammation and fibrosis at the cellular level. Researchers are excited about losartan because it offers a potential new approach to preventing fibrosis, potentially improving the quality of life for patients undergoing radiation therapy. By addressing the root cause rather than just managing symptoms, losartan could offer a more effective long-term solution.

What evidence suggests that losartan could be an effective treatment for radiation-induced fibrosis in breast cancer?

Research has shown that losartan, a drug approved by the FDA, might help reduce radiation-induced fibrosis (RIF), a condition where tissue becomes stiff after radiation treatment. Losartan blocks a protein called TGF-β1, which contributes to tissue stiffness and inflammation. In this trial, some participants will receive losartan to evaluate its effectiveness in reducing stiffness in breast cancer patients undergoing radiation therapy. Studies suggest that losartan might reduce stiffness and has also shown promise in reducing heart tissue stiffness, supporting its potential in managing fibrosis overall. These findings offer hope that losartan could improve outcomes for patients with RIF. ^{1 3 4 6 7}

Who Is on the Research Team?

Patricia H. Hardenbergh

Principal Investigator

Vail Health Shaw Cancer Center

Are You a Good Fit for This Trial?

This trial is for women over 18 with stage 0-IV breast cancer who've had surgery and are set for radiation therapy. They must have normal kidney and liver function, not be pregnant or breastfeeding, and can't have autoimmune diseases, a history of certain conditions, or be on conflicting medications.

Inclusion Criteria

I am a woman eligible for this trial.

Your kidney function, measured by eGFR, is normal or higher than 60.

I have been diagnosed with breast cancer at any stage.

Exclusion Criteria

I have specific genetic mutations related to cancer.

My breast cancer has come back or I've had radiation therapy for it before.

I do not have any uncontrolled illnesses like heart failure, unstable angina, kidney disease, uncontrolled diabetes, cystic fibrosis, or fibromyalgia.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Participants undergo radiation therapy as per local clinic procedures

Varies based on individual treatment plans

Treatment

Participants receive 25mg of Losartan or placebo daily starting from the first day of radiation therapy until one year after completion of radiation therapy

1 year

Follow-up

Participants are monitored for fibrosis, cosmetic outcomes, and incidence of reoperation

18 months

Follow-up visits at 3, 6, 12, and 18 months

What Are the Treatments Tested in This Trial?

Interventions

• Losartan
• Placebo

Trial Overview The study tests if Losartan, a drug that blocks TGF-β1 involved in fibrosis, can reduce scarring in the lung and breast from radiation treatment in breast cancer patients compared to a placebo.

How Is the Trial Designed?

Group I: Mastectomy with Losartan Experimental Treatment 1 Intervention

Participants who underwent a mastectomy will take losartan in a 25 milligram oral capsule once daily starting day one of radiation therapy until one year following the completion of radiation therapy.

Group II: Breast Conservation Surgery with Losartan Experimental Treatment 1 Intervention

Participants who underwent breast conservation surgery will take losartan in a 25 milligram oral capsule once daily starting day one of radiation therapy until one year following the completion of radiation therapy.

Group III: Mastectomy with Placebo Placebo Group 1 Intervention

Participants who underwent a mastectomy will take placebo in a 25 milligram oral capsule once daily starting day one of radiation therapy until one year following the completion of radiation therapy.

Group IV: Breast Conservation Surgery with Placebo Placebo Group 1 Intervention

Participants who underwent breast conservation surgery will take placebo in a 25 milligram oral capsule once daily starting day one of radiation therapy until one year following the completion of radiation therapy.

Who Is Running the Clinical Trial?

Shaw Cancer Center

Lead Sponsor

Trials

1

Recruited

40+

Steadman Philippon Research Institute

Collaborator

Trials

11

Recruited

700+

Published Research Related to This Trial

Topical losartan significantly reduced corneal opacity and the generation of myofibroblasts after photorefractive keratectomy (PRK) in rabbits, indicating its potential efficacy in preventing late haze scarring fibrosis.

Losartan, an angiotensin II receptor inhibitor, appears to work by inhibiting TGF-β signaling, leading to decreased production of non-basement membrane collagen type IV, which is associated with scarring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Losartan Inhibition of Myofibroblast Generation and Late Haze (Scarring Fibrosis) After PRK in Rabbits. Sampaio, LP., Hilgert, GSL., Shiju, TM., 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 murine model of metastatic HER2/neu-positive breast cancer, combining losartan with radiation therapy significantly increased tumor growth delay by an additional 5 to 8 days compared to radiation alone, indicating enhanced treatment efficacy.

Losartan treatment also reduced lung metastasis and improved animal survival, likely by increasing tumor vascularity and decreasing hypoxia, suggesting it could be a promising strategy for improving outcomes in HER2-positive breast cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combining losartan with radiotherapy increases tumor control and inhibits lung metastases from a HER2/neu-positive orthotopic breast cancer model. Li, W., Li, S., Chen, IX., et al.[2021]

Losartan, an angiotensin system inhibitor, enhances the effectiveness of the chemotherapy drug paclitaxel in ovarian cancer by normalizing the tumor microenvironment, which improves drug delivery and blood vessel perfusion.

Patients with ovarian cancer who received angiotensin system inhibitors alongside standard treatments had a significantly longer overall survival (30 months) compared to those on other antihypertensives, suggesting a potential benefit of this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Losartan treatment enhances chemotherapy efficacy and reduces ascites in ovarian cancer models by normalizing the tumor stroma. Zhao, Y., Cao, J., Melamed, A., et al.[2020]

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 rat model of radiation-induced heart disease (RIHD), treatment with losartan significantly reduced left ventricular hypertrophy (LVH) and fibrosis after 15 weeks, indicating its potential efficacy in managing heart damage caused by thoracic radiotherapy.

The beneficial effects of losartan were linked to the suppression of specific proteins and signaling pathways associated with heart remodeling, suggesting a mechanism of action that involves the repression of chymase and components of the TGF-β/SMAD pathway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigation of the Antihypertrophic and Antifibrotic Effects of Losartan in a Rat Model of Radiation-Induced Heart Disease. Kovács, MG., Kovács, ZZA., Varga, Z., et al.[2021]

Losartan, an approved medication, can reduce collagen production in tumor-associated fibroblasts, which may help improve the delivery of nanotherapeutics in dense tumors.

In mouse models of breast, pancreatic, and skin tumors, losartan not only decreased stromal collagen but also enhanced the effectiveness of both intratumoral oncolytic herpes simplex viruses and intravenous pegylated liposomal doxorubicin (Doxil).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. Diop-Frimpong, B., Chauhan, VP., Krane, S., et al.[2023]

Telmisartan, an angiotensin II type 1 receptor blocker, significantly improved blood flow and stabilized perfusion in solid tumours, leading to reduced transient hypoxia, which is known to make tumour cells resistant to radiation.

Tumours treated with telmisartan showed enhanced responsiveness to radiation therapy, suggesting that it can effectively modify the tumour microenvironment to improve treatment outcomes by targeting hypoxic tumour cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin II type 1 receptor blocker telmisartan inhibits the development of transient hypoxia and improves tumour response to radiation. Wadsworth, BJ., Cederberg, RA., Lee, CM., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05637216

Losartan to Reduce Radiation Induced Fibrosis in Breast ... This study will evaluate the efficacy of losartan (LOS), an FDA-approved transforming growth factor beta-1 blocker, to decrease radiation induced fibrosis ...

2. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-07202

Losartan for Reducing Radiation Therapy-induced Cardiac ... Losartan may be effective in reducing cardiac fibrosis among breast cancer patients undergoing radiation therapy. Eligibility Criteria. Inclusion Criteria.

3. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/391175

Losartan to Reduce Radiation Induced Fibrosis in Breast ... This study will evaluate the efficacy of losartan (LOS), an FDA-approved transforming growth factor beta-1 blocker, to decrease radiation induced fibrosis ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12250197/

Losartan as a mechanotherapeutic adjuvant: Remodeling the ... Losartan therapy markedly suppressed the tumor cell population in our model. In untreated simulations, the viable cancer cell concentration ...

5. centerwatch.com centerwatch.com/clinical-trials/listings/NCT05637216/losartan-to-reduce-radiation-induced-fibrosis-in-breast-cancer-patients

Losartan to Reduce Radiation Induced Fibrosis in Breast ... This study will evaluate the efficacy of losartan (LOS), an FDA-approved transforming growth factor beta-1 blocker, to decrease radiation ...

6. clinicaltrial.be clinicaltrial.be/en/details/82638?per_page=100&only_recruiting=0&only_eligible=0&only_active=0

Losartan in Prevention of Radiation-Induced Heart Failure... This is a pilot study examining whether losartan prevents radiation therapy-induced myocardial fibrosis (thickening of the heart tissue), ...

7. clinconnect.io clinconnect.io/trials/NCT05637216

Losartan to Reduce Radiation Induced Fibrosis in Breast This clinical trial is studying the effects of a medication called losartan on women with breast cancer who are experiencing radiation-induced fibrosis, a ...