Losartan to Reduce Radiation Induced Fibrosis in Breast Cancer Patients

October 13, 2023 updated by: Patricia Hardenbergh, Shaw Cancer Center

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Estimated)

40

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Breast Conservation Surgery with Losartan
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
Losartan 25 milligram oral capsule
Other Names:
  • losartan potassium
Placebo Comparator: Breast Conservation Surgery with Placebo
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
Placebo 25 milligram oral capsule
Experimental: Mastectomy with Losartan
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
Losartan 25 milligram oral capsule
Other Names:
  • losartan potassium
Placebo Comparator: Mastectomy with Placebo
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
Placebo 25 milligram oral capsule

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Fibrosis of the breast or reconstructed breast in irradiated breast cancer patients
Time Frame: Baseline, 3-, 6-, 12- and 18- month follow up visits
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
Time Frame: Baseline, 3- and 12- month follow up visits
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
Time Frame: Baseline, day of last radiation therapy fraction, 3- and 12- month follow up visits
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
Time Frame: Baseline, 6-, 12- and 18- month follow up visits
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
Time Frame: Baseline, 3-, 6-, 12- and 18- month follow up visits
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
Time Frame: Baseline, 3-, 6-, 12- and 18-month follow up visits

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
Time Frame: Anytime from completion of radiation therapy assessed at 6-, 12- and 18-month follow up visits
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

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of Reoperation
Time Frame: Two years following the completion of radiation therapy
Patients may chose to return to surgery to correct a poor outcome that could be associated with radiation induced fibrosis.
Two years following the completion of radiation therapy

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Shaw Cancer Center

Collaborators

Steadman Philippon Research Institute

Investigators

  • Principal Investigator: Patricia H Hardenbergh, MD, Medical Director

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 17, 2023

Primary Completion (Estimated)

August 17, 2027

Study Completion (Estimated)

August 17, 2027

Study Registration Dates

First Submitted

November 10, 2022

First Submitted That Met QC Criteria

November 23, 2022

First Posted (Actual)

December 5, 2022

Study Record Updates

Last Update Posted (Actual)

October 16, 2023

Last Update Submitted That Met QC Criteria

October 13, 2023

Last Verified

October 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2022-155

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

There is no plan to share individual participant data (IPD) with other researchers.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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