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Effect of Ketoconazole Inhibition of CYP3A on Urinary Excretion of Docetaxel

Phase 2
18 Years
Open (Enrolling)
Solid Tumors

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Trial Information

Effect of Ketoconazole Inhibition of CYP3A on Urinary Excretion of Docetaxel

Introduction: This is a follow-up protocol to an earlier study entitled "A phase I study of
docetaxel with ketoconazole modulation in solid tumors" (PH14/01) which showed 2-fold
reduction in docetaxel clearance and a clear correlation with renal function.

Aims: The aim of this study is to confirm that ketoconazole inhibition of CYP3A activity
changes the urinary excretion profile of docetaxel.

Methodology: This is a single-centre, crossover study. Ten patients (calculated sample size
=5, α=0.05, β=0.8, difference in means=5%, within group standard deviation=3) will be
accrued and randomly assigned to receive docetaxel at either 75mg/m2 q3w x 1 dose or 70mg
q3w x 1 dose with ketoconazole 200mg bid x q3d at cycle 1 of chemotherapy. This will be
followed by a 20-day washout period before receiving the other regimen of docetaxel at cycle
2. Blood samples of 5mls each will be drawn at times 0, 0.5h, 1h, 1.5h, 3h, 4h, 6h and 24h
after the onset of docetaxel infusion for pharmacokinetics analysis. A 24-hour urine
collection commencing on the same day as docetaxel infusion will be required of the
patients. All urine over the next 24 hours must be collected and returned to the study
coordinator on Day 2 of each study cycle for docetaxel analysis and creatinine clearance
determination. The amount of docetaxel excreted by each patient with and without
ketoconazole modulation will be determined by a LCMSMS method and compared.

Clinical Relevance: This is to ensure the safe advocation of a dose-sparing strategy
established in an earlier study for the costly agent docetaxel by confirming if changes in
excretion profile occurs once its major route of hepatic metabolism is blocked.

Inclusion Criteria:

1. Patients must have histologically confirmed malignancy that is metastatic or
unresectable and for which docetaxel is indicated.

2. Patients must have measurable or evaluable disease.

3. With the exception of alopecia, fatigue, nausea and asthenia, patients must have
resolution of all acute toxic effects of any prior surgery' radiotherapy or
chemotherapy to National Cancer Institute (NCI) Common Toxicity Criteria version 3.0
grade < 1.

4. Patients must have ECOG performance status ≤ 2 (Karnofsky ≥ 60%).

5. Patients must have a life expectancy of greater than 3 months.

6. Patients must have normal renal and marrow function as defined below:

- leukocytes ≥ 3,000/μl

- absolute neutrophil count ≥ 1,500/μl

- platelets ≥ 100,000/μl

- haemoglobin ≥ 7g/dL

- creatinine ≤ 1.5 X institutional upper limit of normal

7. Patients with abnormal liver function tests (AST/ALT ≤ 3 x institutional upper limits
of normal; ALP ≤ 5x ULN; total bilirubin ≤ 2x ULN) will be eligible for enrollment.

8. Patients must have adequate renal functions (serum creatinine within normal
laboratory limits).

9. Women of childbearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control) prior to study entry and for the
duration of study participation. Females with childbearing potential must have a
negative serum pregnancy test within 7 days prior to study enrollment. Should a woman
become pregnant or suspect she is pregnant while participating in this study, she
should inform her treating physician immediately.

10. Ability to understand and the willingness to sign a written informed consent

Exclusion Criteria:

1. Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering
the study or those who have not recovered from adverse events due to agents
administered more than 4 weeks earlier.

2. Patients may not be receiving any other investigational agents.

3. Patients who have rapidly progressive intracranial or spinal metastatic disease
(including patients who require corticosteroid for CNS disease).

4. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to docetaxel or ketoconazole used in study.

5. Patients who have prior medications known to be metabolized by or induce/inhibit
CYP3A4 within 1 week of each treatment cycle.

6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

7. Pregnant women are excluded from this study because docetaxel is
embryotoxic/fetotoxic with the potential for abortifacient effects. Because there is
an unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with docetaxel, breastfeeding should be discontinued if the
mother is treated with docetaxel. These potential risks may also apply to other
agents used in this study.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To confirm if ketoconazole inhibition of CYP3A activity affects fractional excretion of docetaxel in the urine.

Outcome Time Frame:

9 weeks

Safety Issue:


Principal Investigator

Boon Cher Goh, MBBS, MRCP

Investigator Role:

Principal Investigator

Investigator Affiliation:

National University Hospital, Singapore


Singapore: Domain Specific Review Boards

Study ID:




Start Date:

October 2006

Completion Date:

October 2013

Related Keywords:

  • Solid Tumors