Clinical trial NCT05637216: Losartan to Reduce Radiation Induced Fibrosis in Breast Cancer Patients
Official title: A Pilot Study of Losartan to Reduce Radiation Induced Fibrosis in Breast Cancer Patients
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Radiation Induced Fibrosis
Keywords: 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)
Lead sponsor: Shaw Cancer Center
Sponsor class: OTHER
Collaborators: name: Steadman Philippon Research Institute
First posted: 2022-12-05
Enrollment: 40
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: PREVENTION

Brief summary: 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: This single site study will be conducted at the Vail Health 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.

Eligibility criteria: 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 and history of prior breast radiation therapy
* Breast cancer requiring bilateral breast/chest wall radiation therapy
* Undergoing concurrent chemotherapy treatment
* Documented fall risk
* Active known diagnosis of a connective tissue disorder, rheumatoid arthritis, or systemic lupus erythematosus (SLE)
* Any known uncontrolled intercurrent illness including, but not limited to:

  * Hyperkalemia
  * Impaired renal function
  * 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
* A medical history of interstitial lung disease or evidence of interstitial lung disease
* 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

Primary outcomes:
measure: Fibrosis of the breast or reconstructed breast in irradiated breast cancer patients
timeFrame: Baseline, 3-, 6-, 12- and 18- month follow up visits
measure: Radiographic lung fibrosis in the radiation field of irradiated breast cancer patients
timeFrame: Baseline, 3- and 12- month follow up visits
measure: Average levels of cellular senescence, transforming growth factor beta-1 (TGF-β1) and senescence-associated secretory phenotype (SASP) serum biomarkers
timeFrame: Baseline, day of last radiation therapy fraction, 3- and 12- month follow up visits
Secondary outcomes:
measure: Change in breast volume
timeFrame: Baseline, 6-, 12- and 18- month follow up visits
measure: Cosmesis
timeFrame: Baseline, 3-, 6-, 12- and 18- month follow up visits
measure: Patient reported outcomes
timeFrame: Baseline, 3-, 6-, 12- and 18-month follow up visits
measure: Reoperation notation
timeFrame: Anytime from completion of radiation therapy assessed at 6-, 12- and 18-month follow up visits
Other outcomes:
Locations:
city: Edwards
country: United States
facility: Vail Health Shaw Cancer Center
state: Colorado
Study officials:
affiliation: Vail Health Shaw Cancer Center
name: Patricia H Hardenbergh, MD
role: PRINCIPAL_INVESTIGATOR
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