To determine the potential pharmacokinetic interaction between CBD and endoxifen.Secondary objective: To investigate side effects of CBD and to determine the pharmacokinetic profile of CBD
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary study endpoint is the Area Under the plasma concentration time
Curve (AUC0-24h) of endoxifen.
Secondary outcome
The secondary endpoints are pharmacokinetic parameters of tamoxifen, other
pharmacokinetic parameters of endoxifen, toxicity of tamoxifen measured by
Quality of Life questionnaires (EORTC-QLQ-BR23; FACT-B/FACT-ES), potential
toxicity of CBD based on the CTCAE version 5.0 and the AUC0-24h of CBD.
Background summary
Cannabidiol (CBD) is widely used among breast cancer patients. CBD is one of
the chemical components of Cannabis, also called Marijuana. It can induce
pharmacological effects through binding on cannabinoids receptors (CB).There
are two receptors, CB1 mainly located in the nervous system and CB2 most
abundantly found in tissues of the immune system (exerting pro- and
anti-inflammatory effects). CBD acts as an negative modulator of CB1 and CB2.
It exerts analgesic, anxiolytic, sleep inducing and antiemetic properties
without causing psychoactive side-effects. Cannabis-associated psychoactive
effects only occur by using cannabis containing tetrahydrocannabinol (THC).
Interestingly, preclinical evidence shows the presence of both CB1 and CB2 in
breast cancer tissue. The expression of CB2 was found to be correlated with the
aggressiveness of the tumor. Cannabinoids were found to have several
anti-cancer effects in breast cancer models. They block cell cycle progression
and cell growth and are able to induce apoptosis. Despite significant in vitro
and animal model evidence supporting the anti-cancer activity of individual
cannabinoids - particularly THC and CBD - clinical evidence is absent.
Standard adjuvant treatment of patients with breast cancer consists of
tamoxifen. Tamoxifen is a selective estrogen receptor modulator (SERM), which
is frequently used for long periods, up to several years. Treatment with
tamoxifen results in prolonged overall survival, but there are also some severe
downsides of this treatment regimen. Firstly, nearly 50% of patients on
tamoxifen do not complete the recommended five years of treatment due to
cumbersome side effects such as hot flashes, insomnia, arthralgia and mood
alterations. On top of that, tamoxifen is heavily prone to drug-drug
interactions (DDIs) with well described interactions with herbs.
CBD could also affect tamoxifen pharmacokinetics. It has already been shown
that CBD is able to modify the activity of several components of human
metabolism at clinically relevant concentrations. For example, a clinical study
showed significantly changed levels of several anti-epileptic drugs due to the
addition of CBD through modulation of cytochrome P450 (CYP) isoenzymes. CBD
inhibits several CYP isoenzymes, such as CYP2D6 and also shows in vitro
inhibition of phase II metabolism conjugating enzymes
UDP-glucuronosyltransferases (UGTs) 1A9 and 2B7.
Many patients with cancer -up to 24%- use cannabinoids next to their
anti-cancer treatment, because of their supposed efficacy against several
cancer-related side effects as well as tumor growth. Therefore, we aim to
investigate the influence of CBD on endoxifen pharmacokinetics in patients with
breast cancer. We have chosen for CBD as cannabinoid of interest since it does
not elicit any psychoactive effects. The CBD to be used originates from a
manufacturer regulated by the Dutch government. Finally, in this study we will
also address potential (beneficial) effects of CBD on tamoxifen side-effects.
Study objective
To determine the potential pharmacokinetic interaction between CBD and
endoxifen.
Secondary objective: To investigate side effects of CBD and to determine the
pharmacokinetic profile of CBD
Study design
This is a one-way cross-over pharmacokinetic study.
Intervention
Twenty-six patients on steady-state tamoxifen treatment will start with
tamoxifen alone for 7 days (in order for participants to get acquainted with
filling out the patient diary) followed by tamoxifen with 5 drops 10% CBD three
times daily sublingually for 28 consecutive days. Five drops 10% CBD is
equivalent to 18 mg CBD. Fifteen atients will be admitted to the hospital for
24-hour blood sampling on days 7 and 35 of the study for pharmacokinetic
analysis. The other eleven patients, included for analysing the effect of CBD
on tamoxifen-related side effects, will use the CBD drops according to protocol
and will be asked to fill in the EORTC-QLQ-BR23 and FACT-ES questionnaire
before start of CBD and after 4 weeks of CBD. They visit the hospital two times
for blood withdrawal and toxicity assessment.
Study burden and risks
Patients with breast cancer will be treated with tamoxifen as standard of care.
Patients enrolled in this study will start with tamoxifen monotherapy in phase
A and continue in phase B with tamoxifen concomitantly with CBD for 28
consecutive days. Fifteen patients will be admitted to the hospital twice for
an overnight stay (2 times 24 hours), during which 13 blood withdrawals of 6 mL
for pharmacokinetic analysis will be performed. Major risks are not expected
for tamoxifen, as tamoxifen is registered as standard of care. Since CBD is
given for a short period of time (28 days), no major risks are to be expected.
CBD and its metabolites show dose-proportional PK over a clinically relevant
dose range and a mild toxicity profile. We will only use CBD of which the
production has been legally approved and of which the specifications meet the
conditions as demanded by the government. Nonetheless, we will carefully
observe all included patients using a patient diary and perform a two-weekly
phone or clinical appointment with the patient, during the whole study period.
Dr. Molewaterplein 40
Rotterdam 3015GD
NL
Dr. Molewaterplein 40
Rotterdam 3015GD
NL
Listed location countries
Age
Inclusion criteria
1. Age >= 18 years
2. WHO performance <= 1
3. Patients with primary breast cancer, who are on adjuvant tamoxifen treatment
and are willing to be treated with tamoxifen for at least 2 more months
4. Patients need to be on a steady state endoxifen level of at least 16 nmol/l
5. Patients need to experience at least one of the following tamoxifen-related
side effects (based on the CTCAE version 5.0)
a. Hot flashes: at least >10 hot flashes during 24 hours and moderate (limited
instrumental ADL) or severe (limited self-care ADL)
b. Insomnia: difficulty falling asleep, staying asleep or waking up early
c. Arthralgia: moderate (i.e. limited instrumental ADL) or severe (i.e. limited
self-care ADL)
d. Mood alterations: moderate or severe, as distinguished by CTCAE version 5.0.
6. Able and willing to sign the informed consent form prior to screening
evaluations
7. Willing to abstain from strong CYP3A4, CYP2D6, CYP2C9/2C19, UGT and p-Gp
inhibitors or inducers, herbal or dietary supplements or other over-the-counter
medication besides paracetamol.
Exclusion criteria
1. Patients with known impaired drug absorption (e.g. gastrectomy and
achlorhydria)
2. Known serious illness or medical unstable conditions that could interfere
with this study requiring treatment (e.g. HIV, hepatitis, Varicella zoster or
herpes zoster, organ transplants, kidney failure (GFR<30 ml/min/1.73 m2),
serious liver disease (e.g. severe cirrhosis), cardiac and respiratory diseases)
3. Use of cannabinoids in the last 3 months.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| CCMO | NL74240.078.20 |
| OMON | NL-OMON27716 |