Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT03934905 |
| Other study ID # |
L19-065 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 1/Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
June 1, 2022 |
| Est. completion date |
June 1, 2026 |
Study information
| Verified date |
August 2023 |
| Source |
Texas Tech University Health Sciences Center |
| Contact |
sharda p singh |
| Phone |
8067431540 |
| Email |
sharda.singh[@]ttuhsc.edu |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
Description:
Determine whether nutritional supplement sulforaphane (SFN) is safe to administer to breast
cancer patients undergoing doxorubicin (DOX) chemotherapy. The investigators have identified
biomarkers for presymptomatic detection of DOX cardiotoxicity in breast cancer patients and
reported that SFN alleviates DOX-induced cardiac toxicity while maintaining its anti-tumor
activity in an animal model of breast cancer. SFN is in various stages of preclinical and
clinical trials against different types of cancer but its safety and effects on identified
markers have never been tested in patients treated with DOX. Sulforaphane is a generally
recognized as a safe (GRAS) compound and this compound is currently in 61 different clinical
trials including, Cystic Fibrosis, COPD, Melanoma, Breast and prostate cancer etc.
(https://clinicaltrials.gov/ct2/results?term=sulforaphane&pg=1). Avmacol Extra Strength,
(Nutramax Laboratories Consumer Care, Inc. Edgewood, MD 21040) an over-the-counter dietary
supplement containing broccoli seed and sprout extracts that is rich with sulforaphane, will
be used in this study. This is an FDA regulated trial using an investigational drug under IND
141682. Dose considerations were made on the basis of the ongoing clinical trial "Effects of
Avmacol Extra Strength® in the Oral Mucosa of Patients Following Curative Treatment for
Tobacco-related Head and Neck Cancer" (https://clinicaltrials.gov/ct2/show/NCT03268993).
Furthermore, Avmacol Extra Strength has never been tested as an adjuvant to try and protect
the heart from DOXs harmful effects. . Therefore, the investigators are proposing to do an
early-clinical trial to assess SFN safety in DOX-treated patients and possibly prevent
DOX-cardiotoxicity in breast cancer patients.
Our hypothesis is that SFN protects the heart from DOX-mediated cardiac injury without
affecting its antitumor efficacy. Here, the investigators will test SFN in combination with
DOX-based chemotherapy for breast cancer; the investigators will assess its safety,
cardio-protective properties, and anti-cancer efficacy. The investigators will also examine
the effect of SFN on the expression of several biomarkers that indicate when a patient cannot
tolerate DOX.1 To test our hypothesis, the investigators propose the following Specific Aims.
Aim 1: Demonstrate that co-administration of SFN protects the heart and is not associated
with toxicity or reduced tumor response in breast cancer patients undergoing DOX
chemotherapy.
The investigators propose a pilot clinical trial to assess the safety of SFN as a
co-treatment with DOX chemotherapy. Strategy: Up to seventy breast cancer patients prescribed
DOX chemotherapy will be consented then randomly assigned to receive either SFN or placebo
during DOX chemotherapy. This sample size includes an additional 10 participants to allow for
potential attrition. There will be a 50-50 chance of receiving SFN. The patients will be
recruited from the Breast Cancer Clinic (Dr. Jones and Philipovskiy) in the Southwest Cancer
Center at TTUHSC/UMC Lubbock. Cardiac function with echocardiography will be assessed and
compared between arms for evidence of substantive decrease in DOX cardiotoxicity with SFN
compared to placebo. Tumor size will also be compared (based on RECIST criteria) between
treatment arms. The investigators will monitor treatment-emergent symptoms, hematological
parameters of cancer therapy toxicity, and renal and hepatic function. Blood samples will be
collected to assay markers of cardiotoxicity, including B-type natriuretic peptide and
troponin.
Aim 2: Determine if SFN alters the levels of known biomarkers of DOX cardiotoxicity and
affects the expression of SIRT1- and Nrf2-target genes.
The investigators will measure changes in transcript and protein biomarkers of
pre-symptomatic DOX-cardiotoxicity in response to SFN, and will determine if SFN promotes
SIRT1- and Nrf2-dependent gene expression. Because Nrf2 upregulates certain detoxifying
enzymes, the investigators will measure the plasma levels of cardiotoxic metabolites,
doxorubicinol (DOXol). Strategy: Blood will be collected before the start of DOX chemotherapy
and after each treatment cycle to isolate peripheral blood mononuclear cells (PBMCs) and
prepare plasma. In lieu of tissue biopsies, PBMCs will be used to examine SIRT1 and Nrf2
activity and target gene expression. Multiplex arrays will be used to measure plasma cytokine
levels, and plasma DOX metabolites will be assessed with ultrahigh performance liquid
chromatography-tandem mass spectrometry. These experiments will provide initial evidence to
indicate that SFN activates SIRT1 and Nrf2 pathways in non-cancer tissue of breast cancer
patients.
Impact: This will be the first clinical study to assess the safety of SFN as a co-treatment
with DOX to mitigate cardiotoxicity in breast cancer patients. Positive findings will be used
to justify a larger randomized controlled trial. Subjects will be randomized at a 1:1 ratio.
Study Design and Procedures Study Design. The investigators intend to include up to 70
DOX-naïve women diagnosed with breast cancer undergoing neoadjuvant chemotherapy with no
prior cardiac disease and who will receive DOX without Her-2 receptor antagonists (to
eliminate possibility of secondary side effects) as part of their clinical care. These
potential subjects will be recruited in a randomized, controlled, double blinded pilot study
comparing SFN to placebo. The study will be conducted at the Texas Tech University Health
Sciences Center, and University Medical Center. The trial will be approved by our local IRB
and registered at clinicaltrials.gov. UMC cancer center pharmacist Ajoke A. Tijani, RPh.
(Tijani@umchealthsystem.com) will receive placebo and test compound from supplier and will
dispense them to test subjects.
Randomization will be achieved with assignment of a subject ID to the study subject. The list
of subject IDs will be subsequently assigned either study drug or placebo using a randomizer
software such as (www.randomizer.org). The pharmacist dispensing the medication will be aware
of the study IDs in relation to the patient identity, in order to be able to dispense the
test drug or the placebo per their assigned status as test or control subjects.
Study Drug and Placebo. 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 or microcrystalline cellulose (placebo) also 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 the size of a 1000 mg Vit C pill (about 2
cm in length). The participants will be dosed, based on weight, in a double-blind fashion
with identical appearing placebo or SFN caplets in a daily dose for 12 weeks of: two caplets
for individuals <100 lb., three caplets for individuals 100-200 lb. and four caplets for
individuals >200 lb. Avmacol Extra Strength or placebo will be prescribed by Dr. Jones and
Philipovskiy and will be dispensed by local pharmacy or study coordinators at TTUHSC/UMC
Lubbock. The investigators will be doing pill counts to make sure that volunteers have used
as directed. The investigators will measure the Sulforaphane level in plasma by
well-established method. 26 The drug and the placebo will be stored at the South West Cancer
Center pharmacy based on manufacturer based guidelines and dispensed to each participant at
their baseline visit then at DOX infusion visits 1, 2, and 3. Patients will be expected to
maintain at least an 80% adherence to the medication regimen, in the absence of prohibitive
toxicity. Adherence will be monitored through therapeutic drug level (Plasma sulforaphane
levels of 120 ng/ml) monitoring as mentioned above and pill counts. For subjects who do not
meet 80% compliance, they will be instructed on the importance of taking the pills as
directed, but if their next visit demonstrates less than 80% compliance, they will be
withdrawn from the study. As long as participants complete their 4th cycle of DOX
chemotherapy treatment the investigators will still use their study data during analysis. If
side effects are noted, patient will be asked to notify the study team of the same and will
be evaluated within a suitable time frame based on severity of side effects.
SFN is a safe natural isolate. Above doses (30mg/caplet) are considered adequate to maintain
intended therapeutic drug levels, while maintaining a simple study design and without
significant concerns for drug toxicity It has been used in several clinical trials from doses
ranging from 2-200 µmol/day for 2-28 weeks in 25-80 years old subjects without significant
side-effects or toxicity
(https://clinicaltrials.gov/ct2/results?term=sulforaphane&Search=Search), yet never in
combination with DOX.
Statistical Considerations Data for the primary endpoint (DOX cardiotoxicity) and other
binary outcomes will be summarized by treatment arm as number and proportion per arm. The
change in DOX-cardiotoxicity rate with SFN compared to placebo will be assessed with a
1-sided Z-test (see Sample-size justification). Tumor size, plasma cardiac biomarkers,
cardiac ejection fraction, DOX metabolite levels will be summarized by treatment arm and time
point as means and standard deviations and graphed as box plots and profile plots. The
investigators will adhere to ANOVA distributional assumptions so that appropriate data
transformations can be applied. Data for each continuous variable will be analyzed for
differences in group means at each time point with ANOVA or Mann-Whitney-Wilcoxon
non-parametric tests at each time point. These tests will employ a more-stringent alpha =
0.02 significance level to adjust for the multiple comparisons without overinflating type II
error. For subjects withdrawn from the study or do not complete the study for any reason, as
long as they completed their 4th cycle of DOX chemotherapy treatment the investigators will
still use their study data during analysis.
Sample-size justification. The number of subjects (35 per treatment arm; 70 total; the
investigators expect some attrition, which this sample size addresses) is based on the
primary endpoint of DOX-induced cardiac dysfunction, the rate of which was recently observed
at our previous institution (UAMS) to be ~25%1. The investigators expect that SFN will
decrease this to 5%. The cardiotoxicity rates for each arm will be compared via 1-sided
pooled-variance Z-test at an alpha = 0.10. The statistical power of this test, conducted as
described, needs to exceed 80% in order for our study to be generally recognized as having
adequate statistical power. Our sample size provides the 1-sided pooled-variance Z-test with
83.2% power at 10% alpha to detect the expected 20-point decrease in DOX-toxicity rates from
25% in the placebo arm to 5% in the SFN arm.
The formal consent of each subject, using the IRB-approved consent form, will be obtained
before that subject is submitted to any study procedure.
