Losartan to Reduce Radiation Induced Fibrosis in Breast Cancer Patients

Study Overview
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Brief Summary
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This study will evaluate the efficacy of Losartan (LOS), an FDA-approved transforming growth factor beta-1 (TGF-β1) blocker, to decrease radiation induced fibrosis (RIF) in the breast and the lung of breast cancer patients, testing the hypothesis that Losartan will decrease RIF, TGF- β1 and cellular senescence/inflammation in the breast and the lung of irradiated breast cancer patients relative to placebo treatment and consequently improve clinical outcomes in breast cancer patients.

Detailed Description
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This single site study will be conducted at the Shaw Cancer Center in Edwards, Colorado. A block, double-blinded, placebo-controlled, randomized phase II design will be utilized . Study participants will be blocked by surgical intervention (breast conserving surgery vs. mastectomy) and then randomized, 1:1, into the treatment and control arms for a total of four study arms. The research team and study participants will be blinded to the study arm and a placebo will be used to reduce detection bias in the reporting of outcomes. Selection bias will be minimized through the randomization of study arms. Study participants will be prescribed 25mg capsules of placebo or the investigational drug, Losartan, to be taken by mouth once daily. The treatment start date will be the day that subject begins radiation therapy. Radiation therapy will continue to be prescribed in accordance with local clinic procedures. Treatment with the study intervention will continue for one year upon completion of radiation therapy. All participants will be assessed for fibrosis, cosmetic outcomes, and incidence of reoperation for 18 months following the completion of radiation therapy.

Official Title
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A Pilot Study of Losartan to Reduce Radiation Induced Fibrosis in Breast Cancer Patients

Conditions
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Radiation Induced Fibrosis

Intervention / Treatment
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* Drug: Losartan 25 milligram capsule
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Diagnosed with clinical or pathologic stage 0-IV invasive breast cancer to include ductal carcinoma in situ (Tis), primary tumor cannot be assessed (TX) and all other primary tumor stage categories (T1-T4) Has been treated with breast conserving surgery or mastectomy with reconstruction Is a candidate for unilateral post-surgery radiation therapy per National Comprehensive Cancer Network (NCCN) guidelines Age ≥ 18 Female Laboratory values Aspartate Aminotransferase (AST) ≤ 2.5 x Upper Limit Normal (ULN) Alanine Aminotransferase (ALT) ≤ 2.5 x ULN Creatine ≤ 1.5 x ULN Estimated Glomerular Filtration Rate (eGFR) ≥ 60 Inclusion of Women and Minorities - Women of any race/ethnicity are eligible for this trial. Exclusion Criteria Recurrent breast cancer or history of prior breast radiation therapy Breast cancer requiring bilateral breast/chest wall radiation therapy Undergoing concurrent chemotherapy treatment Documented fall risk Active known or suspected systemic autoimmune disease (except for vitiligo, residual auto-immune hypothyroidism requiring hormone replacement only, psoriasis not requiring systemic treatment for two years, conditions not expected to recur in the absence of an external trigger) or any history of a systemic inflammatory arthritis such as psoriatic, rheumatoid, systemic lupus, ankylosing spondylitis or reactive arthritis Uncontrolled intercurrent illness including, but not limited to: Symptomatic congestive heart failure Unstable angina pectoris Kidney disease Uncontrolled diabetes Cystic fibrosis Fibromyalgia based on American College of Rheumatology criteria Concomitant use of: Losartan Other renin-angiotensin system (RAS) agent Agents to increase serum potassium Lithium Aliskiren for diabetes Having a known allergy to any active or inactive ingredient in Losartan Unable to tolerate oral medication Pregnant or breast-feeding or planning pregnancy for the year following radiation The presence of interstitial lung disease on baseline CT scan Patients with any medical condition, including findings in laboratory or medical history or in the baseline assessments, that (in the opinion of the Principal Clinical Investigator or his/her designee), constitutes a risk or contraindication for participation in the study or that could interfere with the study conduct, endpoint evaluation or prevent the subject from fully participating in all aspects of the study Individuals known to possess deoxyribonucleic acid (DNA) gene mutations including: Ataxia-Telangiectasia Mutated (ATM) Double-strand-break repair protein rad21 homolog (RAD21) C-to-T single-nucleotide polymorphism (C-509T) in the Transforming growth factor β-1 gene

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be blocked by surgical type (breast conservation surgery/mastectomy) and then randomized 1:1 in a parallel design into treatment and control arms. All participants will take an oral 25 milligram tablet once daily of either losartan or placebo. Assessments of fibrosis will include provider assessments and participant reported outcomes of fibrosis and cosmesis, the participant's decision for reoperation, laboratory assessments of inflammatory biomarkers, a CT scan and bilateral mammograms.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Breast Conservation Surgery with Losartan<br>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. | Drug: Losartan 25 milligram capsule<br>* Losartan 25 milligram oral capsule<br>* Other names: losartan potassium;|
| Placebo Comparator: Breast Conservation Surgery with Placebo<br>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. | Drug: Placebo<br>* Placebo 25 milligram oral capsule<br>|
| Experimental: Mastectomy with Losartan<br>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. | Drug: Losartan 25 milligram capsule<br>* Losartan 25 milligram oral capsule<br>* Other names: losartan potassium;|
| Placebo Comparator: Mastectomy with Placebo<br>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. | Drug: Placebo<br>* Placebo 25 milligram oral capsule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fibrosis of the breast or reconstructed breast in irradiated breast cancer patients | Fibrosis will be assessed by a radiation oncology provider using the Late Effects Normal Tissue Task Force (LENT)-Subjective, Objective, Management, Analytic (SOMA) (LENT-SOMA) scale. 0=Fibrosis absent, not detectable. 1=Fibrosis is Barely Palpable; 2=Definite increased density; 3=Very marked density, retraction and firmness and fixation | Baseline, 3-, 6-, 12- and 18- month follow up visits | 
| Radiographic lung fibrosis in the radiation field of irradiated breast cancer patients | Radiographic lung fibrosis will be assessed with high resolution CT scans of the thorax. Thorax CT scans will be fused to the radiation planning CT scan for confirmation of the overlap of fibrosis with the radiation field. | Baseline, 3- and 12- month follow up visits | 
| Average levels of cellular senescence, transforming growth factor beta-1 (TGF-β1) and senescence-associated secretory phenotype (SASP) serum biomarkers | Cellular senescence, and senescence-associated secretory phenotype (SASP) including TGF-β and inflammation will be quantified in the treatment and control group. A novel and expert approach to measure senescent cells in serum will be utilized. | Baseline, day of last radiation therapy fraction, 3- and 12- month follow up visits | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in breast volume | Bilateral mammographic determination of breast volume will be calculated at routine follow-up intervals. Breast shrinkage associated with radiation-induced fibrosis will be assessed by monitoring the change in the breast volume of the treated breast from baseline to 18 months following completion of radiation therapy. Measurement of breast volume on both breasts will use breast height in centimeters (cm) (H), breast width in cm (W) and compression thickness in cm (C), from a craniocaudal projection. Volume in milliliters (mL) = (π/4) x H x W x C. Mammograms will also provide a distance measurement, in centimeters, on the nipple line from nipple to pectoralis muscle and a length measurement, in centimeters, from the superior to inferior margin that bisects the Posterior to Nipple Line (PNL) at a 90° angle. | Baseline, 6-, 12- and 18- month follow up visits | 
| Cosmesis | Cosmesis will be assessed using a clinician assessment The Harvard Cosmesis Scale: 1=Excellent (Treated breast nearly identical to untreated breast); 2=Good (Treated breast slightly different from untreated breast); 3=Fair (Treated breast clearly different from untreated breast but not distorted); 4=Poor Treated breast seriously distorted. | Baseline, 3-, 6-, 12- and 18- month follow up visits | 
| Patient reported outcomes | Self-reported participant quality of life will be assessed by Breast-Q Reconstruction Module. The Breast-Q, Version 2.0 tool was developed to assess participant's perception of clinical outcomes in both psychological and satisfaction domains will be used. Psychosocial Well-Being module: measures psychological well being Physical Well-Being Chest module: measures pain or tightness and difficulty with mobility Satisfaction with Breasts (Post-Op) module: satisfaction with breast size, how bras fit, and appearance in mirror clothed or unclothed, as well as how breasts feel when they are touched. Adverse Effects of Radiation module: measures physical changes such as soreness of skin. | Baseline, 3-, 6-, 12- and 18-month follow up visits | 
| Reoperation notation | The participant's decision to have corrective surgery on either breast after radiation will be recorded at each time-point. Post-mastectomy patients will be considered to have been reoperated if corrective surgery occurred after permanent implant placement. | Anytime from completion of radiation therapy assessed at 6-, 12- and 18-month follow up visits | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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losartan, radiation, fibrosis, cosmesis, reoperation, TGFB1, Transforming growth factor beta 1 (TGF-β1), Angiotensin II Receptor Blockers, ace inhibitor, Angiotensin-converting enzyme (ACE) inhibitors, TGF-β1, antifibrotic, signaling pathway, breast cancer, TGF beta, radiation induced fibrosis, irradiation fibrosis, Radiation injury with fibrosis, Transforming growth factor beta 1, Inflammation, Biomarker, Suppressor of Mothers against Decapentaplegic (SMAD)