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Target Dosing of Docetaxel Through Pharmacokinetic/Pharmacodynamic Optimisation of the First Chemotherapeutic Cycle

Phase 1/Phase 2
18 Years
Not Enrolling
Solid Tumors

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Trial Information

Target Dosing of Docetaxel Through Pharmacokinetic/Pharmacodynamic Optimisation of the First Chemotherapeutic Cycle


Poor tolerance of standard docetaxel dosage regimens used as a single agent in Asians has
been clearly demonstrated by our group in 2 separate studies. Neutropenia emerged as the
most prominent manifestation of chemotherapy toxicity [12, 20]. While this has been
attributed to the lower docetaxel CL derived in our Asian patients, an optimal dosage
regimen taking into account the extensive genetic polymorphisms associated with CYP3A4 has
yet to be established. The use of ketoconazole as a potent CYP3A4 modulator to reduce
pharmacokinetic variability of docetaxel did show >2-fold reduction in docetaxel dosage, but
inter-individual variability in CL was not significantly reduced. There was also poor
correlation of docetaxel CL to midazolam phenotyping of CYP3A4 with the addition of
ketoconazole to the regimen [23]. Since the use of an additional modulator failed to achieve
the desired reduction in pharmacokinetic variability, the idea of using low-dose docetaxel
to predict its own pharmacokinetic parameters appeared feasible, safe and an appealing

The more acute toxicities of docetaxel, such as neutropenia, stomatitis, neurological
toxicities and fluid retention are more frequently associated with the 3 weekly than weekly
dosing schedule. This study is designed so that the less toxic weekly schedule is used for
PK/PD correlation. This information would be utilized to derive an optimal dosage for the 3
weekly regimen that follows since cumulative myelosuppression was not observed with previous
weekly docetaxel for metastatic breast cancer [31].

Currently patients with impaired liver function manifested by elevated baseline ALT/AST more
than 1.5 more than the institutional limits of normal are not treated with the recommended
dose of docetaxel because of impaired clearance of docetaxel. Theoretically, these patients
may benefit from docetaxel treatment, but the dose will need to be individualized based on
hepatic drug clearance to avoid toxicity. To determine the clinical usefulness of our
strategy of predicting docetaxel clearance and individualised dosing based on clearance and
a PD model, patients with a certain extent of liver dysfunction will be included into the
study. They will be divided into 3 groups according to the level of AST/ALT and SAP, total
bilirubin, and initial weekly doses as well as q3weekly doses will be lower than the
recommended doses for patients with normal liver function. Previous investigators have
reported the feasibility of using the erythromycin breath test as an in vivo probe for CYP3A
activity and docetaxel clearance in patients with liver dysfunction (Baker SD et al
Evaluation of CYP3A activity as a predictor covariate for docetaxel clearance Proceedings of
ASCO 2004; 128: 2006abs).

2.4 Hypothesis

The hypothesis for this study is that PK/PD guided dosing of docetaxel will reduce the
variability in docetaxel PK while achieving the maximum exposure desired within acceptable
limits of toxicity. At this juncture, this is a novel approach in oncology to fully exploit
the potential of using low-dose docetaxel as its own probe drug to individualise and
optimise dosage for subsequent chemotherapy treatment without having to use other agents to
modulate or predict drug metabolism and clearance.

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
(see Appendix A) grade < 1.

4. Patients must have ECOG performance status < 2 (Karnofsky >60%, see Appendix B).

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 ≤ 10 x institutional upper
limits of normal; SAP < 5x ULN; total bilirubin ≤ 1.5x ULN) will be eligible for

8. Women of child-bearing 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 7days 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.

9. 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 other agents used in study.

5. Patients who have prior medications known to be metabolized by or induce/inhibit
CYP3A4 within 1 week (see appendix C).

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: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

change in neutrophil counts and docetaxel AUC

Outcome Description:

. Based on maximal acceptable toxicity, expressed as the reduction in neutrophil count, the corresponding breakpoint for AUC will be identified as the PK target. Both linear regression and nonlinear mixed effects modeling will be employed to establish a relationship between docetaxel CL and demographic, phenotypic and pathophysiological factors.

Outcome Time Frame:

3 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:

May 2006

Completion Date:

February 2012

Related Keywords:

  • Solid Tumors