Protective Effects of the Nutritional Supplement Sulforaphane on Doxorubicin-Associated Cardiac Dysfunction

NCT03934905 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: L19-065
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 1

Brief Summary

Cardiomyopathy is a major complication of doxorubicin (DOX) chemotherapy, and 10-21% of breast cancer patients receiving DOX experience compromised cardiac function. Recent advancements have increased cancer survivorship but it remains clinically challenging to mitigate the cardiotoxic side effects. Although there are several strategies used to reduce the occurrence and severity of DOX-induced cardiotoxicity, they are not particularly effective. Hence, there is an urgent need to develop new strategies that prevent the cardiotoxic effects of DOX but maintain its potency as a cancer therapy. Because the cellular events responsible for the antitumor activity of DOX and DOX-induced cardiotoxicity are distinctly different, it may be possible to develop therapies that selectively mitigate DOX-induced cardiotoxicity. Thus, the investigators propose to test an adjuvant therapy that combines the phytochemical sulforaphane (SFN) with DOX to attenuate DOX-induced cardiomyopathy. SFN activates the transcription factor Nrf2 and induces defense mechanisms in normal cells. Furthermore, SFN inhibits carcinogenesis and metastases and enhances cancer cell sensitivity to DOX, seemingly through Nrf2-independent mechanisms. SFN has also been tested in several clinical trials, although never together with DOX. Our early animal studies suggest that by activating Nrf2, SFN selectively protects the mouse and rat from DOX cardiotoxicity, enhances survival and enhances the effects of DOX on cancer growth in a rat breast cancer model. The investigators suspect that SFN affects DOX metabolism in cancer cells to enhance tumor regression, or it may synergistically activate other key antitumor mechanisms. Hence, SFN may improve the clinical outcome of cancer therapy by (1) attenuating DOX cardiotoxicity and (2) enhancing the effects of cancer treatment on the tumor. Our hypothesis is that SFN protects the heart from DOX-mediated cardiac injury without altering the antitumor efficacy of DOX. In Aim 1, the investigators will conduct an early-phase clinical trial to determine if SFN is safe to administer to breast cancer patients undergoing DOX chemotherapy. In Aim 2, the investigators will determine if SFN decreases DOX-induced inflammatory responses and enhances Nrf2- and SIRT1-target gene expression in breast cancer patients. Notably, transcript and protein signatures in peripheral blood mononuclear cells (PBMCs) can predict cardiac function in patients undergoing DOX chemotherapy for breast cancer. The investigators will also determine if SFN/DOX treatment activates Nrf2- and SIRT1-dependent gene expression, alters the levels of biomarkers for presymptomatic DOX-cardiotoxicity and mitigates the generation of cardiotoxic metabolites in PBMCs and plasma. These studies will facilitate the development of SFN co-treatment as a strategy to enhance the efficacy and safety of DOX cancer therapy.

Conditions

Anthracycline Related Cardiotoxicity in Breast Cancer

Keywords

doxorubicin; sulforaphane; cardiotoxicity; nrf2; heart

Outcome Measures

Primary Outcomes (1)

• Change in cardiac function after DOX therapy with or without sulforaphane through diagnostic studies

  2D Echo will be used to measure cardiac function amongst patients on DOX therapy who are exposed to sulforaphane or placebo.

  At baseline and 1 year from baseline assessment.

Secondary Outcomes (2)

• Elevation of troponin levels as a surrogate evidence of DOX related cardiotoxicity will be checked at baseline, prior to each DOX therapy and then at 1 year from baseline assessment (Each cycle is 14 days).

  At baseline, prior to each cycle of DOX, at completion of 4th cycle of DOX therapy and 1 year from baseline assessment.

• Tumor size in patients on DOX therapy with or without sulforaphane treatment will be assessed at baseline, at completion of DOX chemotherapy (4 cycles planned with each cycle being 14 days) and at 1 year from baseline assessment.

  2 days before first DOX treatment, 2 days after completion of 4th cycle of DOX therapy and 1 year from first DOX treatment

Study Arms (2)

sulforaphane

ACTIVE COMPARATOR

Processed SFN-rich extract will be purchased in form of caplets from Nutramax Laboratories, Inc. 2208 Lakeside Blvd Edgewood, MD 21040. Caplets containing SFN-rich broccoli sprout extracts from Nutramax Labs will be dispensed to participants in sealed bottles with instructions to keep them in a household freezer. Size of the caplet will be about 2 cm in length. Dosing will be based on weight and will be dosed daily for 12 weeks.

Drug: sulforaphane

Placebo

PLACEBO COMPARATOR

Placebo caplets will comprise of microcrystalline cellulose from Nutramax Labs and will be dispensed to participants in sealed bottles with instructions to keep them in a household freezer. Placebo pills will be identical in appearance to the sulforaphane pills and will be dosed in a similar manner (identical number of pills based on weight, daily dosing and for 12 weeks)

Drug: Placebo Oral Tablet

Interventions

sulforaphane DRUG

The participants will be dosed, based on weight, in a double-blind fashion with identical appearing placebo or sulforaphane caplets in a daily dose for 12 weeks of: two caplets for individuals \<100 lb., four caplets for individuals 100-200 lb. and eight caplets for individuals \>200 lb. Avmacol or placebo will be prescribed by Dr. Awasthi and will be dispensed by local pharmacy or study coordinators at TTUHSC/UMC Lubbock. We will be doing pill counts to make sure that volunteers have used as directed. We will measure the Sulforaphane level in plasma by well-established method.

sulforaphane

Placebo Oral Tablet DRUG

The participants will be dosed, based on weight, in a double-blind fashion with identical appearing placebo or sulforaphane caplets in a daily dose for 12 weeks of: two caplets for individuals \<100 lb., four caplets for individuals 100-200 lb. and eight caplets for individuals \>200 lb. Avmacol or placebo will be prescribed by Dr. Awasthi and will be dispensed by local pharmacy or study coordinators at TTUHSC/UMC Lubbock. We will be doing pill counts to make sure that volunteers have used as directed. We will measure the Sulforaphane level in plasma by well-established method.

Placebo

Eligibility Criteria

• Age: 18 Years - 89 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 to 89 years
• No prior diagnosis of coronary artery, carotid artery or peripheral artery disease
• Not pregnant or breastfeeding (urine pregnancy test will be done if female of childbearing potential)
• Breast cancer requiring treatment with DOX-containing regimen above
• Women in child bearing age group (18-50 years) will agree to use birth control for duration of study
• Study subjects must be willing and able to swallow caplets, up to 8 daily.

You may not qualify if:

• Currently on a research study with an investigational drug, or has been on one in the previous 30 days
• Pregnant (by urine pregnancy test)
• Baseline ejection fraction of less than 50%, evidence of left ventricular hypertrophy or baseline EKG reported as abnormal per cardiologist.
• Inability to provide informed consent.
• Prior history of chest radiation therapy
• Diabetes or Hypertension or prior Myocardial infarction
• Trastuzumab patients
• Routinely taking vegetable or fruit-containing supplement pills (antioxidant phytochemicals) (daily vitamin pills ok)
• Inability to follow up for safety monitoring
• Prisoners
• Previous or current use of cocaine or any illicit drug
• Unable or unwilling to provide blood samples
• Taking medications known to have cardiac effects, such as but not limited to, beta blockers, anti-arrhythmic agents, non dihydropyridine calcium channel blockers, ace inhibitors, NSAIDS, diuretic agents.
• Unable to follow the protocol
• Inability to receive anthracycline due to any reason (underlying baseline cardiac dysfunction due to other reasons, with an EF under 50%)

Sponsors & Collaborators

• Texas Tech University Health Sciences Center: lead

Study Sites (1)

Texas Tech University Health Sciences Center

Lubbock, Texas, 79430, United States

RECRUITING

MeSH Terms

Conditions

Cardiotoxicity

Interventions

sulforaphane

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders; Radiation Injuries; Wounds and Injuries

Central Study Contacts

sharda p singh

CONTACT

8067431540; sharda.singh@ttuhsc.edu

Catherine Jones, MD

CONTACT

7855504533; catherine.jones@ttuhsc.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: We plan to include 70 DOX-naïve women with breast cancer undergoing neoadjuvant chemotherapy, with no prior cardiac disease and who will receive DOX without Her-2 receptor antagonists as part of their clinical care. Potential subjects will be recruited in a randomized, controlled; double blinded pilot study comparing SFN to placebo. Study will be conducted at the TTUHSC and UMC. The trial is approved by the institutional IRB and will be registered at clinicaltrials.gov. UMC cancer center pharmacist Ajoke A. Tijani, RPh. will receive placebo and test compound from supplier and will dispense them to test subjects. Randomization will be done with assignment of a subject ID to the study subject. The list of subject IDs will be subsequently assigned to either study drug or placebo using a randomizer software.

Study Record Dates

• First Submitted: March 29, 2019
• First Posted: May 2, 2019
• Study Start: June 1, 2022
• Primary Completion: November 1, 2025
• Study Completion (Estimated): June 1, 2026
• Last Updated: November 20, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: one year after completion of the study
• Access Criteria: data will be provided upon request

Locations

US (1)