Primary objective: To determine pharmacokinetic interactions between milk thistle and docetaxel and between milk thistle and tolbutamide in patients with cancer.Secundary objective: To determine the safety of the use of milk thistle in combination…
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Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The most important parameter is the plasma concentration of docetaxel and
tolbutamide and the course of this concentration with time in the presence or
absence of milk thistle.
Secondary outcome
Secondary parameters are toxicities that patients experience from docetaxel in
the presence or absence of milk thistle.
Background summary
The use of complementary and alternative medicines (CAM) by cancer patients has
increased during the last years and we hypothesize that interactions between
CAM and anticancer drugs can explain unexpected clinical toxicities and
undertreatment of chemotherapy in cancer patients.
A CAM which is often used by cancer patients is milk thistle. Milk thistle is
used as a self-treatment for hepatitis, cirrhosis, mushroom poisoning and for
protection of the liver against toxicity of alcohol, acetaminophen and other
hepatotoxic drugs. Milk thistle is also investigated for its potential
anticancer effects.
In vitro assays, performed in our laboratory at Utrecht University, have shown
that milk thistle inhibits the activity of hepatic enzymes CYP2C9 and CYP3A4.
Thus, concomitant use of milk thistle could lead to significant interactions
with (anticancer) drugs metabolized by these enzymes. In fact, CYP2C9 and
CYP3A4 are involved in the metabolism of many anticancer drugs. However, there
are no anticancer drugs which are solely metabolized by CYP2C9. This explains
our choice for the well-studied CYP2C9 probe drug tolbutamide to assess the
influence of milk thistle on CYP2C9 activity. The clinical effect of milk
thistle on tolbutamide pharmacokinetics could also be of importance for
anticancer drugs that are partly metabolized by CYP2C9 and for concomitant
medication that is metabolized by this enzyme.
Docetaxel, which is mainly metabolized by CYP3A4, has been chosen to
investigate the effect of milk thistle on CYP3A4 activity. Inhibition of CYP2C9
and CYP3A4 by milk thistle is expected to increase plasma levels of tolbutamide
and docetaxel.
Until now, no studies have been performed to examine the pharmacokinetics of
docetaxel and tolbutamide with co-administration of milk thistle. To
investigate whether the inhibition of CYP2C9 and CYP3A4 by milk thistle
demonstrated in vitro, is of clinical importance, it is essential to perform
this pharmacokinetic interaction study.
Study objective
Primary objective:
To determine pharmacokinetic interactions between milk thistle and docetaxel
and between milk thistle and tolbutamide in patients with cancer.
Secundary objective:
To determine the safety of the use of milk thistle in combination with
docetaxel or tolbutamide;
To establish guidelines to prevent unwanted interactions between complementary,
alternative medicines (e.g. St. John*s wort, echinacea, milk thistle) and
anticancer drugs in patients.
Study design
This is a phase I, randomized, crossover, open-label interaction study.
Included patients will be randomized in cohort A or cohort B.
Cohort A:
Day 0 of cycle 1 starts in the morning with oral administration of the
officially registered milk thistle capsules in a dose of 1 capsule three times
daily. This dosage regimen will be continued for 4 days (until day 3).
At approximately 09.00 h on day 1 patients will receive a subtherapeutic dose
of 250 mg tolbutamide orally. Thereafter, at around 10.00 h, docetaxel will be
administered intravenously for 120 min. as an absolute dose of 135 mg. The dose
of 135 mg is based on a safe dose of 75 mg/m2 and a mean BSA of 1.8 m2.
Pharmacokinetics of docetaxel and tolbutamide will be monitored until 48 h (day
3) after the start of administration of docetaxel. Further, on day 1 one blood
sample will be drawn for CYP2C9 genotyping.
Day 3 will be followed by a wash out period from day 4 until day 21.
On day 1 of cycle 2, docetaxel (135 mg, IV) and tolbutamide (250 mg, PO) will
be administered for the second time under the same conditions as in cycle 1.
Cohort B:
Cycle 1 starts on day 1 at approximately 09.00 h with oral administration of
250 mg tolbutamide. At approximately 10.00 h docetaxel will be administered
intravenously for 120 min. as an absolute dose of 135 mg. The dose of 135 mg is
based on a safe dose of 75 mg/m2 and a mean BSA of 1.8 m2. Pharmacokinetics of
docetaxel and tolbutamide will be monitored until 48 h (day 3) after the start
of administration of docetaxel. Further, on day 1 one blood sample will be
drawn for CYP2C9 genotyping.
In the morning of day 0 of cycle 2 patients in this cohort start with oral
administration of the officially registered milk thistle capsules in a dose of
1 capsule three times daily. This dosage regimen will be continued for 4 days
(until day 3 of cycle 2).
On day 1 of cycle 2, docetaxel (135 mg, IV) and tolbutamide (250 mg, PO) will
be administered under the same conditions as in cycle 1.
Collected blood samples will be stored not longer than the duration of the
study. After the end of the study, the blood samples will be destroyed.
Intervention
- Administration of 135 mg docetaxel and 250 mg tolbutamide on day 1 of cycle 1
and 2.
- Administration of 3 times daily 1 milk thistle capsule for 4 days.
- 2 times 24 h-hospital admission with bloodsampling for pharmacokinetics
(including 1 blood sample for CYP2C9 genotyping).
- 6 times hospital visit for physical examination and bloodsampling for safety
and/or pharmacokinetics.
Study burden and risks
- Administration of 135 mg docetaxel and 250 mg tolbutamide on day 1 of cycle 1
and 2.
- Administration of 3 times daily 1 milk thistle capsule for 4 days.
- 2 times 24 h-hospital admission with bloodsampling for pharmacokinetics
(including 1 blood sample for CYP2C9 genotyping).
- 6 times hospital visit for physical examination and bloodsampling for safety
and/or pharmacokinetics.
Toxiciteities of docetaxel will also be experienced by patients when they do
not participate in the study and receive standard docetaxel therapy. No
toxicities of milk thistle and a subtherapeutic dose of 250 mg tolbutamide are
to be expected. There is a small risk of bruising by blood sampling.
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Age
Inclusion criteria
1. Patients for whom treatment with docetaxel is considered to be of therapeutic benefit, e.g. advanced breast, gastric, esophagus, bladder, ovarian cancer and non-small cell lung cancer, head and neck cancer and prostate cancer
2. Histological or cytological proof of cancer
3. Age >= 18 years
4. WHO performance status of 0, 1 or 2
5. Patient is able and willing to give written informed consent
6. Patient is able and willing to swallow and retain oral medication
7. Patient is able and willing to undergo blood sampling for pharmacokinetics
8. Patient is willing to comply to the protocol and to follow dietary restrictions
9. Life expectancy > 3 months allowing adequate follow up of toxicity evaluation and antitumor activity
10. Minimal acceptable safety laboratory values
a. ANC of >= 1.5 x 10^9 /L
b. Platelet count of >= 100 x 10^9 /L
c. Hepatic function as defined by serum bilirubin <= 1.5 x ULN, ALAT and ASAT <= 2.5 x ULN
d. Renal function as defined by serum creatinine <= 1.5 x ULN or creatinine clearance >= 50 ml/min (by Cockcroft-Gault formula).
11. No radio- or chemotherapy within the last 4 weeks prior to study entry, except for pain palliation.
Exclusion criteria
1. Any treatment with investigation drugs within 30 days before the start of the study
2. Women who are pregnant or breast feeding
3. Concomitant use of MDR, CYP2C9 and CYP3A modulating drugs, food or drinks such as amiodaron, fluconazole, ketoconazole, clarithromycin, rifampicin, Ca2+-entry blockers (verapamil, dihydropyridines), cyclosporine, quinidine, quinine, tamoxifen, megestrol, grapefruit juice, concomitant use of HIV medications; other protease inhibitors, (non) nucleoside analogs, or St. John*s wort;
4.Unreliable contraceptive methods. Both men and women enrolled in this trial must agree to use a reliable contraceptive method throughout the study (adequate contraceptive methods are: condom, contraceptive pill (female partner), abstinence from sexual intercourse, sterilisation of man or woman).
5. Legal incapacity
6. Type I and II diabetes mellitus patients
7. Chronic use of H2-receptor antagonists or proton pump inhibitors
8. Unresolved (>grade 1) toxicities of previous chemotherapy
9. Bowel obstruction or motility disorders that may influence the absorption of drugs
10. Neurologic disease that may render a patient at increased risk for peripheral or central neurotoxicity
11. Symptomatic cerebral or leptomeningeal metastases
12. Uncontrolled infectious disease or known HIV-1 or HIV-2 type patients
13. Use of herbal supplements, especially milk thistle, within 6 weeks prior to study treatment.
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
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-023415-34-NL |
| CCMO | NL34285.031.10 |
| OMON | NL-OMON27803 |