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Interaction study of Docetaxel + Tolbutamide and Milk Thistle.


- candidate number13316
- NTR NumberNTR3611
- ISRCTNISRCTN wordt niet meer aangevraagd.
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR13-sep-2012
- Secondary IDsNL34285.031.10 CCMO
- Public TitleInteraction study of Docetaxel + Tolbutamide and Milk Thistle.
- Scientific TitlePhase I interaction study of Docetaxel and Tolbutamide with supplementation of Milk Thistle.
- ACRONYM
- hypothesisInhibition of CYP2C9 and CYP3A4 by milk thistle is expected to increase plasma levels of tolbutamide and docetaxel.
- Healt Condition(s) or Problem(s) studiedDocetaxel, Cancer, Milk thistle, Tolbutamide, Pharmacokinetic interaction
- Inclusion criteria1. 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 criteria1. Any treatment with investigation drugs within 30 days before the start of the study;
2. Patients with known alcoholism, drug addiction and/or a psychiatric or physiological condition which in the opinion of the investigator would impair study compliance;
3. Women who are pregnant or breast feeding;
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. Concomitant use of MDR, CYP2C9 and CYP3A modulating drugs such as amiodaron, fluconazole, ketoconazole, clarithromycin, rifampicin, Ca+-entry blockers (verapamil, dihydropyridines), cyclosporine, quinidine, quinine, tamoxifen, megestrol and grapefruit juice, concomitant use of HIV medications; other protease inhibitors, (non) nucleoside analogs, or St. John's wort;
7. Type I and II diabetes mellitus patients;
8. Uncontrolled infectious disease or known HIV-1 or HIV-2 type patients;
9. Unresolved (>grade 1) toxicities of previous chemotherapy;
10. Bowel obstruction or motility disorders that may influence the absorption of drugs;
11. Chronic use of H2-receptor antagonists or proton pump inhibitors;
12. Neurologic disease that may render a patient at increased risk for peripheral or central neurotoxicity;
13. Symptomatic cerebral or leptomeningeal metastases;
14. Use of herbal supplements, especially milk thistle, within 6 weeks prior to study treatment.
- mec approval receivedyes
- multicenter trialno
- randomisedyes
- masking/blindingNone
- controlNot applicable
- groupCrossover
- Type2 or more arms, randomized
- Studytypeintervention
- planned startdate 5-mrt-2012
- planned closingdate1-apr-2013
- Target number of participants10
- InterventionsDay 1 and day 22: 135 mg docetaxel (IV) + 250 mg tolbutamide (PO).

Cohort A: Three times daily one 180 mg capsule of milk thistle on day 0, 1, 2 and 3;
Cohort B: Three times daily one 180 mg capsule of milk thistle on day 21, 22, 23 and 24.
- Primary outcomePharmacokinetic parameters of docetaxel and tolbutamide on day 1 and 22: AUC, Cmax, t1/2.
- Secondary outcomeSafety parameters: (serious )adverse events.
- TimepointsDay 1 and 22: PK sampling docetaxel and tolbutamide.
End of treatment assessment on day 42.
- Trial web siteN/A
- statusopen: patient inclusion
- CONTACT FOR PUBLIC QUERIESMSc. A.K.L. Goey
- CONTACT for SCIENTIFIC QUERIESMSc. A.K.L. Goey
- Sponsor/Initiator Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI AVL)
- Funding
(Source(s) of Monetary or Material Support)
Dutch Cancer Society
- PublicationsN/A
- Brief summaryThe 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. In vitro assays have shown that milk thistle inhibits the activity of the hepatic enzymes CYP2C9 and CYP3A4. Thus, concomitant use of milk thistle could lead to significant interactions with (anticancer) drugs metabolized by these enzymes. In the present study the well-studied CYP2C9 probe drug tolbutamide has been selected to assess the influence of milk thistle on CYP2C9 activity. 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 coadministration 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.
- Main changes (audit trail)
- RECORD13-sep-2012 - 6-okt-2012


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