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Hyperpolarized Carbon 13-Based Metabolic Imaging to Detect Radiation-Induced Cardiotoxicity

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ClinicalTrials.gov Identifier: NCT04044872
Recruitment Status : Recruiting
First Posted : August 5, 2019
Last Update Posted : August 20, 2020
Sponsor:
Information provided by (Responsible Party):
University of Texas Southwestern Medical Center

Brief Summary:
Patients enrolled in the study will receive standard of care adjuvant or definitive breast, chest wall or thoracic radiation therapy.Cardiac mitochondrial dysfunction is a hallmark of radiation-induced cardiac injury. Reactive oxygen species (ROS) produced by ionizing radiation cause oxidation of mitochondrial proteins and alter oxidative phosphorylation and pyruvate metabolism(5). The goal of this study is to detect early changes in the mitochondrial metabolism in situ as a marker for subclinical radiation-induced cardiotoxicity.

Condition or disease Intervention/treatment Phase
Thoracic Cancer Left Sided Breast Cancer Diagnostic Test: [1-13C]pyruvate along with MRI imaging Phase 1

Detailed Description:

The global burden of cancer continues to rise with an incidence of 17.5 million cancer cases worldwide. Approximately 50% of all cancer patients receive radiation therapy as a component of their cancer care. While radiation therapy has demonstrable benefit in improving survival in patients with many types of malignancies, cardiotoxicity is a major concern in patients receiving chest radiotherapy. The rates of major coronary events increased by 7.4% per gray of mean heart dose; the increased risk was noted within the first 5 years of radiotherapy and persisted into the third decade after treatment. With improvements in multi-disciplinary care of cancer patients, the long-term survival in patients with thoracic malignancies continues to improve and radiation-induced heart disease (RIHD) is now a major source of morbidity and mortality in such patients.In this study, the investigators will enroll five female patients (18 years of age to 100 years of age) with left-sided breast cancer who underwent lumpectomy or mastectomy without tissue expander placement and will receive adjuvant standard-of-care breast or chest wall radiation therapy. They will undergo baseline magnetic resonance spectroscopic imaging with [1-13C]pyruvate injection and a proton MRI/spectroscopy scan prior to receipt of adjuvant radiation therapy. Post-treatment imaging will be performed within 3 months of completion of radiation treatments. This study will investigate whether non-invasive MRI scanning approaches will detect damage to the heart from left-sided radiation treatments before structural changes and mechanical functional deficits become apparent. A first-in-human clinical study to evaluate the effect of cardiotoxic chemotherapy on [1-13C]Pyruvate metabolism is currently ongoing at UT Southwestern (ClinicalTrials.gov Identifier: NCT03685175; PI: Dr. Vlad Zaha). The proposed study employs the same technology and approach to study radiation-induced cardiac toxicity. The study will also test the prognostic value of decreased myocardial mitochondrial pyruvate flux in predicting clinically significant radiation induced cardiotoxicity. Towards this goal, study will measure myocardial mechanical functional parameters, including left ventricular global longitudinal strain and left ventricular myocardial deformation using cardiac MRI and correlate these changes with [1-13C]lactate/ [13C]bicarbonate ratio. Previous studies have demonstrated that strain rate imaging by MRI is a sensitive technique for dose-dependent decrease in myocardial function after breast radiotherapy. Although this pilot study is restricted to breast cancer patients, successful demonstration of feasibility will allow extension of the study to all patients receiving thoracic radiation (such as patients receiving radiation therapy for lung cancer, esophageal cancer and thoracic lymphomas). The lack of reliable technologies for early detection of sub-clinical radiation-induced cardiotoxicity limits early intervention in such patients. Thus, identification of early cardiac changes induced by radiation therapy at a stage that offers potential for reversibility remains a major unmet need in cancer care.

Concerns for sexually active men and women: Women should not become pregnant and men should not father a baby while taking part in this study because we do not know how the study drugs/procedures could affect a man's sperm (for some drugs/procedures, the concern may be that the sperm might be affected and in some cases, drugs could being carried by the semen into the vagina and cause harm) or a fetus, if a woman becomes pregnant during the study. It is important that you talk to your study doctor about avoiding pregnancy during this study. If you think you might have become pregnant or if you believe your female partner has become pregnant while you are in this study, you must tell one of the study doctors right away so that management of the pregnancy and the possibility of stopping the study can be discussed.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Single Institution Feasibility Study to Detect Radiation-Induced Cardiotoxicity in Receiving Thoracic Radiation Patients Using Hyperpolarized Carbon 13-Based Magnetic Resonance Spectroscopic Imaging
Actual Study Start Date : December 17, 2019
Estimated Primary Completion Date : October 2021
Estimated Study Completion Date : December 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Single Arm:Diagnosing Cardiotoxicity when on Radiation therapy Diagnostic Test: [1-13C]pyruvate along with MRI imaging
[1-13C]pyruvate: 0.1 mmol/kg dose will be injected at 5 mL/s followed by a 25 mL saline flush at 5 mL/s at the time of imaging performed at baseline (prior to radiation therapy), and 1 month after completion of radiation therapy.




Primary Outcome Measures :
  1. To determine if radiation-induced cardiac injury [ Time Frame: at 1 month before the radiation ]
    To determine if radiation-induced cardiac injury causes myocardial mitochondrial dysfunction as measured by increase in [1-13C]lactate/ [13C]bicarbonate ratio and a decrease in [5-13C]glutamate formation in patients receiving radiotherapy to the thorax


Secondary Outcome Measures :
  1. Determination of the prognostic value decreased of myocardial mitochondrial pyruvate flux in predicting clinically significant radiation induced cardiotoxicity. [ Time Frame: At 1 month after the radiation ]
    As a secondary outcome, we will measure if decreased myocardial mitochondrial pyruvate flux results in changes in myocardial mechanical functional parameters. Towards this goal, we will measure myocardial mechanical functional parameters, including left ventricular global longitudinal strain and left ventricular myocardial deformation using cardiac MRI and correlate them with [1-13C] lactate/ [13C] bicarbonate ratio. Prior studies that cardiac MRI can detect changes in myocardial strain in patients who received whole breast radiotherapy for treatment of breast cancer.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Tissue diagnosis of benign or malignant tumor of the breast (left-sided only) or thorax

    1. Stage I to III
    2. ECOG performance status 0-1
    3. The patient must be deemed an appropriate candidate for adjuvant ordefinitive radiation therapy with or without regional nodal irradiation
    4. Radiation therapy planning should be CT scan-based using 3D conformal radiotherapy (3D-CRT), intensity modulated radiotherapy (IMRT) or volumetric arc therapy (VMAT).
    5. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

      5.1 A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

      • Has not undergone a hysterectomy or bilateral oophorectomy; or
      • Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).

      5.2. A female of postmenopausal status is defined as patients over 60 or greater OR patients age 50-59 who meet the following criteria:

      • s/p bilateral oophorectomy, OR
      • with intact uterus without menses in the past 12 months OR,
      • with biochemical confirmation of post-menopausal status (estradiol in the menopausal range based on local laboratory criteria)
    6. Ability to understand and the willingness to sign a written informed consent.

Exclusion Criteria:

  1. Prior thoracic radiation therapy
  2. Neoadjuvant, adjuvant or prior HER-2 directed therapy
  3. Subjects may not be receiving any investigational agents for the treatment of the cancer under study.
  4. Tissue expander placement after mastectomy
  5. Diagnosis of connective tissue disorders, including systemic lupus erythematosis, scleroderma, or dermatomyositis
  6. Known metastases
  7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with study requirements
  8. eGFR <30
  9. Any contraindication to MRI (including, but not limited to metal implants and devices contraindicated at 3T, breast tissue expanders, non-MR compatible IV port, claustrophobia)
  10. History of psychiatric or addictive disorders that would preclude obtaining informed consent
  11. Subjects must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04044872


Contacts
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Contact: Sarah Hardee, MS 2146458525 sarah.hardee@utsouthwestern.edu
Contact: Kajal Desai, MS 2146458525 kajal.desai@utsouthwestern.edu

Locations
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United States, Texas
Department of Radiation Oncology; UT Southwestern Medical Center Recruiting
Dallas, Texas, United States, 75390
Contact: Prasanna Alluri, MD, PhD    214-648-8941    Prasanna.Alluri@UTSouthwestern.edu   
Contact: Vlad Zaha, MD, PhD         
Principal Investigator: Prasanna Alluri, MD, PhD         
Sponsors and Collaborators
University of Texas Southwestern Medical Center
Investigators
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Principal Investigator: Prasanna Alluri, MD, PhD UTSW Radiation Oncology
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Responsible Party: University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier: NCT04044872    
Other Study ID Numbers: STU 2019-1099
First Posted: August 5, 2019    Key Record Dates
Last Update Posted: August 20, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Product Manufactured in and Exported from the U.S.: No
Keywords provided by University of Texas Southwestern Medical Center:
Cardiotoxicity
Cardiac injury
Radiation induced heart disease (RIHD)
Additional relevant MeSH terms:
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Unilateral Breast Neoplasms
Cardiotoxicity
Pathologic Processes
Drug-Related Side Effects and Adverse Reactions
Chemically-Induced Disorders
Radiation Injuries
Wounds and Injuries
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases