Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT06080841 |
| Other study ID # |
CEI/1598/21 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
April 19, 2023 |
| Est. completion date |
March 2025 |
Study information
| Verified date |
October 2023 |
| Source |
National Institute of Cancerología |
| Contact |
Denisse Castro-Eguiluz, RDN, PhD |
| Phone |
+525541940650 |
| Email |
adcastro[@]conahcyt.mx |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Brief Summary.
The goal of this pilot study is to learn about the effect of curcumin supplementation in
locally advanced cervical cancer patients. The main questions it aims to answer are:
- Does curcumin supplementation increase the levels of p53 and apoptosis in tumor cells
from cervical cancer patients?
- At which dose of curcumin supplementation is the broader effect observed for p53
expression and apoptosis in tumor cells from cervical cancer patients?
- Are all doses safe for supplementation?
Participants will be asked to take curcumin tablets throughout their cancer treatment.
Researchers will compare 6 different groups, each group will receive a different dose of
curcumin with or without piperin, to see the dose with the broader effect and safety of
curcumin supplementation:
1. 1 g of curcumin
2. 1 g of curcumin + piperine
3. 3 g of curcumin
4. 3 g of curcumin + piperine
5. 6 g of curcumin
6. 6 g of curcumin + piperine
Description:
BACKGROUND Cervical cancer (CC) continues to be a major public health problem in Mexico.
Today more than 4,000 women die each year from this disease, which requires implementing
strategies that can improve current treatments, particularly for locally advanced disease.
Today it is clear that persistent high-risk Human Papillomavirus infections are the main risk
factor for developing CC. At the National Cancer Institute of Mexico (INCan), 80% of patients
are diagnosed at locally advanced stages (IB3-IVA). The standard treatment for these stages
is concomitant chemoradiotherapy (CCRT) followed by brachytherapy (BT).
p53 restricts tumor growth, promoting cell death and decreasing cell viability. Activation of
p53 is vital for CCRT-induced cytotoxicity, while inactivation of p53 has been associated
with resistance or insensitivity to treatment. Different nutraceuticals such as berberine and
curcumin can reactivate endogenous p53 and exhibit its effects in CC. The E6 oncoprotein
inactivates the p53 pathway in CC; therefore, the restoration of p53 may be a promising
therapeutic strategy.
The health benefits associated with consuming fruits, vegetables, teas, and spices are due to
the presence of phytochemicals. Diets characterized by regular consumption of fruits and
vegetables have been associated with a decrease in the risk of CC. A particular group of
phytochemicals of interest is polyphenols. The polyphenol curcumin is considered safe and
non-toxic by the FDA (Food and Drug Administration), and its administration causes minimal
low-grade adverse effects (mainly grade 1 diarrhea). Based on clinical trials' safety and
toxicity profile, a dose of up to 8000 mg/day of curcumin can be considered safe.
The current information on the bioavailability of phytochemicals continues to be limited,
which places great importance on the exploration of polyphenols as possible new therapeutics.
However, the low bioavailability and complex metabolism linked to polyphenols make it
difficult to recommend a dose for daily consumption. The addition of piperine to curcumin
supplementation has been demonstrated to increase absorption in the intestine.
Different biological effects have been associated with curcumin supplementation in cancer
patients. Patients with pancreatic cancer received oral administration of curcumin at a dose
of 8 g/day for eight months in combination with gemcitabine, which was well tolerated and
showed an improvement in overall survival. Curcumin activity was evaluated in patients with
metastatic colon cancer, finding that it was safe and tolerable in combination with FOLFOX.
In locally advanced CC patients, the effect that curcumin has on the expression of p53 in
tumor cells has not been investigated, although in vitro studies have demonstrated its effect
on the inhibition of oncoproteins, such as E6, and the consequent stabilization of p53, which
makes CC cells more susceptible to being destroyed.
The present pilot study seeks to demonstrate that curcumin supplementation will regulate
molecular markers, such as p53 and apoptosis in tumor cells, which could provide the basis to
study further whether this modulation by curcumin leads to a greater susceptibility of the
tumor to standard cancer treatment and, therefore, a better response to treatment.
METHODS The work will be carried out at the National Cancer Institute of Mexico (INCan) in
patients with locally advanced CC. Six supplementation groups will be included; in three
groups, curcumin will be administered in tablets in oral doses of 1, 3, and 6 g / day
respectively, and in the other three groups, curcumin will be administered in tablets in oral
doses of 1, 3, and 6 g / day respectively plus 5 mg of piperine/g of curcumin (to facilitate
the absorption of curcumin).
Invitation to the study protocol: Diagnosis will be confirmed in the INCan Functional
Gynecology Oncology Unit. The corresponding studies are carried out to corroborate that the
patient meets the inclusion criteria. On the day of the invitation to the patient, the
patient will be explained what the study consists of, and the Informed Consents will be read.
If the patient agrees to participate and signs the consent, she will be assigned to the
corresponding curcumin dose group.
The patients will be followed for four visits throughout the study: (1) 2 weeks before the
beginning of treatment; (2) at the beginning of CRT; (3) at the third cycle of CRT; and (4)
at BT.
Patients will be evaluated in 4 visits:
- Visit 1: Indications for a standard diet will be given according to the patient's
requirements. Curcumin will be provided to the patient, and instructions for its use
will be given according to the group to which she has been assigned. Urine and serum
samples will be collected. A cervical swab sample will be obtained.
- Visit 2: The day of initiation of treatment with concomitant CRT. Feces, urine, and
serum samples will be collected. A cervical swab sample will be obtained.
- Visit 3: Once the 3 CRT cycles have been completed. Feces, urine, and serum samples will
be collected. A cervical swab sample will be obtained.
- Visit 4: When starting treatment with BT. Urine and serum samples will be collected.
Biological samples:
Cervicovaginal cytologies will be taken at each visit. The samples will be analyzed by flow
cytometry to quantify p53 positive cells and annexin will be used to identify apoptosis.
Adherence to supplementation will be monitored, bioavailability will be investigated,
gastrointestinal toxicity determined, and the safety of supplementation evaluated.
Gastrointestinal symptoms will be classified at each visit during treatment according to
common toxicity criteria (CTCAE v. 5). Liver function tests, renal function tests, blood
chemistry, and hematic biometry will be monitored to assess curcumin supplementation safety.
Stool, urine, and serum samples will be taken, from which the bioavailability of curcumin
will be assessed by liquid chromatography-electrospray ionization-mass spectrometry. A
comparative analysis of these variables will be made between the different supplementation
groups to establish the dose in which an impact on the expression of p53 and apoptosis is
observed.
Analysis of data:
Data will be analyzed using Statistica software, and graphs will be made in GraphPad Prism. A
single-factor repeated measures analysis will be performed with repeated measures across all
treatments. The analysis plan will consist of:
- Normality test. The Shapiro-Wilk test will be performed to know if the variables'
distribution is normal.
- Descriptive analysis. The distribution of the quantitative independent variables will be
determined using the Kolmogorov-Smirnov test. The mean ± standard deviation will be
reported for variables with normal distribution or median with 25th and 75th percentiles
for variables with free distribution.
- One-way or two-way ANOVA will be performed to determine the significance of differences
between groups, followed by Tukey's test for the significance of differences. Confidence
intervals will be constructed at 95%, and a value will be declared statistically
significant when p is <0.05.
- Multivariate analysis. The following tests will be used to determine if there are
differences between the patients who were supplemented with the different doses of
curcumin and those who also received piperine:
- Student's T test for quantitative variables with normal distribution.
- Mann Whitney U test for quantitative variables with free distribution or ordinal
variables.
- Chi-square test for dichotomous and polytomous variables.
EXPECTED RESULTS AND PERSPECTIVES The investigators expect that curcumin supplementation will
stabilize the expression of p53 and increase the apoptosis of tumor cells. The investigators
also expect that piperine will increase its absorption. In addition, a dose in humans
associated with the expression of p53 has not been reported, so this study will allow the
identification of the dose that favors said expression in humans. In addition to its
molecular effect, due to its antioxidant properties, the investigators expect that patients
will improve gastrointestinal symptoms associated with treatment with CCRT.
