Primary objective1. To compare the Area under the curve (AUC) of endoxifen in patients with breast cancer treated with tamoxifen with and without diclofenac.Secondary objectives1. To compare the Area under the Curve (AUC) of tamoxifen and endoxifen-…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To investigate the interaction between diclofenac and tamoxifen; by comparing
the Area under the curve (AUC) of endoxifen in patients with breast cancer
treated with tamoxifen with and without diclofenac.
Secondary outcome
1. To compare the Area Under the Curve (AUC) of tamoxifen and
endoxifen-glucuronide in patients with breast cancer treated with tamoxifen
with and without diclofenac.
2. To compare other tamoxifen, endoxifen-glucuronide and endoxifen
pharmacokinetic outcomes (i.e. clearance, maximum concentration (Cmax), minimal
concentration (Ctrough) and time until maximum concentration (Tmax) and
elimination half-life (T*)). Furthermore the endoxifen/endoxifen-glucuronide
ratio in patients with breast cancer treated with tamoxifen with and without
diclofenac.
3. To evaluate the incidence and severity of side-effects of treatment with
tamoxifen in absence and presence of diclofenac.
Background summary
Nowadays many (cancer) patients use additional medication next to their
anti-cancer therapy. Thereby increasing the risk of possible severe drug-drug
interactions ultimately leading to a suboptimal therapeutic outcome or an
increase in toxicity. One of the most commonly used class of drugs are the Non-
Steroid Anti-Inflammatory Drugs (NSAIDs). NSAIDs are used in the treatment of
fever, pain and inflammation. Approximately 18% of cancer patients use NSAIDs
for several conditions and therefore this class of drugs belong to one of the
most prescribed drugs in the Netherlands, with diclofenac as the most commonly
used NSAID. The drug-interaction potential of NSAIDs is considered low in
general, although most NSAIDs are substrates for CYP2C9 and therefore might not
be combined with strong CYP2C9 inhibitors or inducers. However several in vitro
studies show inhibitory potential of NSAIDs on phase II drug metabolism. Phase
II drug metabolism plays an important role in the metabolism of several drugs.
Through several conjugating enzymes (e.g. UDP-glucuronosyltransferases (UGT),
sulfotransferases (SULT), glutathione S-transferases) active drugs will be
transformed into pharmacologically mostly inactive excretable forms. UGT is one
of the main phase II metabolizing enzymes, with UGT2B7, UGT1A1 and UGT1A4 as
the most important enzymes. In contrast to drug-drug interactions regarding
phase I metabolism less is known about drug-drug interactions regarding phase
II drug metabolism. In theory, inhibition or induction of these phase II (e.g.
UGT) enzymes can lead to significantly altered plasma concentration of phase II
substrate drugs. For example, a clinical study with the NSAID mefenamic acid
showed a significant 51% increase in dapagliflozin exposure through UGT1A9
inhibition.5 One of the most potent and well known inhibitors of several UGT*s
(e.g. UGT1A4, UGT2B7, UGT1A3, UGT1A6, UGT1A1 and UGT1A9), according to in vitro
evidence, is diclofenac. Therefore making diclofenac a potential drug causing
severe drug-drug interactions.
Study objective
Primary objective
1. To compare the Area under the curve (AUC) of endoxifen in patients with
breast cancer treated with tamoxifen with and without diclofenac.
Secondary objectives
1. To compare the Area under the Curve (AUC) of tamoxifen and
endoxifen-glucuronide in patients with breast cancer treated with tamoxifen
with and without diclofenac.
2. To compare other tamoxifen, endoxifen-glucuronide and endoxifen
pharmacokinetic outcomes (i.e. clearance, maximum concentration (Cmax), minimal
concentration (Ctrough) and time until maximum concentration (tmax) and
elimination half-life (t*)). Furthermore the endoxifen/endoxifen-glucuronide
ratio will be determined in patients with breast cancer treated with tamoxifen
with and without diclofenac.
3. To evaluate the incidence and severity of side-effects of treatment with
tamoxifen in absence and presence of diclofenac.
Study design
This is an open label 2 period exploratory, randomized, single-center,
pharmacokinetic cross-over study in patients taking tamoxifen for the treatment
of breast cancer. This study will be performed in the Erasmus MC Cancer
Institute in Rotterdam, the Netherlands. It is anticipated that the study will
be performed within a 1 year period after approval by the ethical board. A
total of 14 evaluable patients need to be enrolled to reach the primary
endpoint. Before entering the study patients need to be on steady state
endoxifen plasma levels. To reach steady state patients have to use tamoxifen
(at the same dose) for at least three months (run-in phase). After reaching
steady-state patients will use tamoxifen (phase A) alone or tamoxifen
concomitantly with diclofenac (phase B) in this order or vice versa depending
on randomization. Patients must use diclofenac 75 mg twice daily concomitantly
with tamoxifen for 7 consecutive days. On the 7th and 14th day of the study
patients will be hospitalized for pharmacokinetic blood sampling depending on
the randomization sequence.
Intervention
Tamoxifen will be used as standard care of treatment (adjuvant and metastatic
setting). Tamoxifen is given in a dosage of 20-40 mg q.d. Dose modifications
are not allowed after the run-in phase of three months. Tamoxifen will be
administered for at least three months at the same dose to guarantee
steady-state of endoxifen. Patients will use the same brand of tamoxifen during
the whole study period. Tamoxifen will be administered daily at approximately
10.00AM. Diclofenac will be given in a dosage of 75 mg twice daily dose
concomitantly with tamoxifen at 10.00 AM and 10:00 PM. On PK-days a light meal
exactly 2 hours before tamoxifen treatment is permitted.
Study burden and risks
Patients will be invited to the hospital for a total of 2 days, during the
visits pharmacokinetic blood withdrawals will be performed.
Minor risks to be expected are side effects of tamoxifen or diclofenac for
which patients will be observed carefully.
Dr. Molewaterplein 40
Rotterdam 3015 GD
NL
Dr. Molewaterplein 40
Rotterdam 3015 GD
NL
Listed location countries
Age
Inclusion criteria
1. Age * 18 years
2. Patients with a confirmed diagnosis of primary or advanced breast cancer, who are on tamoxifen treatment for at least three months (steady state concentration).
3. WHO performance * 1 (see Appendix B)
4. Able and willing to sign the informed consent form prior to screening evaluations
5. 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.
6. Adequate organ function defined as:
- ALAT and ASAT <5.0 upper limit of normal (ULN)
- bilirubin <1.5 (ULN)
- GFR > 30 ml/min/1.73 m2
- Controlled thyroid dysfunction
Exclusion criteria
1. Pregnant or lactating patients
2. Patients with known impaired drug absorption (e.g. gastrectomy and achlorhydria)
3. Patients with a history of (stomach) ulcers or gastric bleeding or hypersensitivity to NSAIDs.
4. 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<60 ml/min/1.73 m2), serious liver disease (e.g. severe cirrhosis), cardiac and respiratory diseases)
5. A CYP2D6 poor metabolizer or ultra-rapid metabolizer phenotype based on CYP2D6 genotyping outcome.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-003482-33-NL |
| CCMO | NL68151.078.18 |