Solid TumorsPhase 1/2NCT00703378
Target Dosing of Docetaxel Through Pharmacokinetic/Pharmacodynamic Optimisation of the First Chemotherapeutic Cycle
A Phase 1/2 study testing Docetaxel (Taxotere®) in people with Solid Tumors, run by National University Hospital, Singapore at 1 site in Singapore.
Trial summary
Primary Objective 1. To develop a pharmacokinetic-pharmacodynamic (PD) model for optimisation of docetaxel dosing Secondary Objectives 1. To establish an exposure-toxicity (neutropenia) relationship for docetaxel 2. To determine the exposure breakpoint for docetaxel toxicity based on a neutropenia PD model 3. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Solid Tumors
- What is being tested?
- Docetaxel (Taxotere®)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 33 participants
- Where
- 1 siteSingapore
- Study dates
- May 2006to Feb 2012
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which docetaxel is indicated.
- Patients must have measurable or evaluable disease.
- 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.
- Patients must have ECOG performance status < 2 (Karnofsky >60%, see Appendix B).
- Patients must have a life expectancy of greater than 3 months.
- Patients must have normal renal and marrow function as defined below:
Show all 14Show fewer
- 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
- 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 enrolment.
- 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.
- Ability to understand and the willingness to sign a written informed consent document.
Who cannot join
- 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.
- Patients may not be receiving any other investigational agents.
- Patients who have rapidly progressive intracranial or spinal metastatic disease (including patients who require corticosteroid for CNS disease).
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to docetaxel or other agents used in study.
- Patients who have prior medications known to be metabolized by or induce/inhibit CYP3A4 within 1 week (see appendix C).
- 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.
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Primary Objective
- To develop a pharmacokinetic-pharmacodynamic (PD) model for optimisation of docetaxel dosing
Secondary Objectives
- To establish an exposure-toxicity (neutropenia) relationship for docetaxel
- To determine the exposure breakpoint for docetaxel toxicity based on a neutropenia PD model
- To identify demographic, pathophysiological and/or phenotypic covariates predicting docetaxel clearance
- To prospectively validate this PK-PD model for optimisation of docetaxel dosage and determination PK variability and toxicity
Read the detailed description
Rationale
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 approach.
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.
- Conditions
- Solid Tumors
- Being tested
- Docetaxel (Taxotere®)
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Docetaxel (Taxotere®)Drug
Also called Taxotere®
Phase 1 Cycle 1 and 2 Patients in group 1 receive 40mg/m2/week of docetaxel in a 1-hour infusion. Patients in group 2 receive 30mg/m2/week of docetaxel in a 1-hour infusion. Patients in group 3 receive 20mg/m2/week of docetaxel in a 1-hour infusion.
| Study group | Role | What they receive |
|---|---|---|
| Group 1 | Experimental | Group 1: normal liver function Receives: Drug: Docetaxel (Taxotere®) |
| Group 2 | Experimental | Group 2: AST and/or ALT up to 1-5 x upper limit of normal; SAP 1- 5x upper limit of normal, total bilirubin within normal limits Receives: Drug: Docetaxel (Taxotere®) |
| Group 3 | Experimental | Group 3: Any SAP and AST/ALT >5-10 x upper limit of normal and/or total bilirubin 1-1.5 x upper limit of normal Receives: Drug: Docetaxel (Taxotere®) |
What is being measured
The primary outcome is the main question the study is designed to answer.
change in neutrophil counts and docetaxel AUC
. 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.
Measured: 3 weeks
Secondary outcomes (1)
Pharmacokinetic sampling of docetaxel serum concentrations
Pharmacokinetic sampling of docetaxel serum concentrations will be carried out around the first course of docetaxel administration of both cycles 1a and 1b of the chemotherapy regimen. The time points elected for docetaxel sampling are: 0h (baseline), 15mins, 1.5h, 3h, 4h, 6h and 24h.
Measured: 7 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Jun 2008 (estimated)
- Study startMay 2006
- Primary completionFeb 2011
- Study completionFeb 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Solid TumorsStudies of the same condition, open and under way.
- More trials run by National University Hospital, SingaporeThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 33 participants (actual)
Sponsor and investigators
- Lead sponsor
- National University Hospital, Singapore
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Haematology-Oncology, National University Hospital, Singapore
- Investigators
- Boon Cher Goh, MBBS, MRCP, Principal investigator, National University Hospital, Singapore
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00703378
- Sponsor's protocol ID
- PK01/06/05
- Other IDs
- 2005/00082, 2005
- Status last verified
- Mar 2012
- First submitted
- 20 Jun 2008
- Last updated
- 28 Mar 2012
- Results posted
- No
Publications
Goh BC, Lehnert M, Lim HL, Ng AW, Chan CC, Kong HL, Lee SC, Wee J, Chua ET, Wong JE. Phase II trial of docetaxel in Asian patients with inoperable stage III non-small cell lung cancer. Acta Oncol. 2000;39(2):225-9. doi: 10.1080/028418600430824.
PubMed 10859016Goh BC, Lee SC, Wang LZ, Fan L, Guo JY, Lamba J, Schuetz E, Lim R, Lim HL, Ong AB, Lee HS. Explaining interindividual variability of docetaxel pharmacokinetics and pharmacodynamics in Asians through phenotyping and genotyping strategies. J Clin Oncol. 2002 Sep 1;20(17):3683-90. doi: 10.1200/JCO.2002.01.025.
PubMed 12202670Syn NL, Wang L, Wong AL, Soe MY, Chuah B, Chan D, Tan SH, Soo RA, Lee SC, Goh BC, Yong WP. Dose modifications in Asian cancer patients with hepatic dysfunction receiving weekly docetaxel: A prospective pharmacokinetic and safety study. Cancer Sci. 2016 Feb;107(2):173-80. doi: 10.1111/cas.12856. Epub 2016 Feb 8.
PubMed 26663719
Study at a glance
From the registry record, last updated by the sponsor on 28 Mar 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Target Dosing of Docetaxel Through Pharmacokinetic/Pharmacodynamic Optimisation of the First Chemotherapeutic Cycle
- ClinicalTrials.gov ID
- NCT00703378
- Acronym / sponsor ID
- PK01/06/05
- Conditions
- Solid Tumors
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 33 participants (actual)
- Lead sponsor
- National University Hospital, SingaporeUniversity, hospital or other
- Study start
- May 2006
- Primary completion
- Feb 2011 (actual)
- Study completion
- Feb 2012 (actual)
- First posted
- 23 Jun 2008 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Primary Objective
- To develop a pharmacokinetic-pharmacodynamic (PD) model for optimisation of docetaxel dosing
Secondary Objectives
- To establish an exposure-toxicity (neutropenia) relationship for docetaxel
- To determine the exposure breakpoint for docetaxel toxicity based on a neutropenia PD model
- To identify demographic, pathophysiological and/or phenotypic covariates predicting docetaxel clearance
- To prospectively validate this PK-PD model for optimisation of docetaxel dosage and determination PK variability and toxicity
Detailed description
Rationale
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 approach.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Group 1 | Experimental | Drug: Docetaxel (Taxotere®)Group 1: normal liver function |
| Group 2 | Experimental | Drug: Docetaxel (Taxotere®)Group 2: AST and/or ALT up to 1-5 x upper limit of normal; SAP 1- 5x upper limit of normal, total bilirubin within normal limits |
| Group 3 | Experimental | Drug: Docetaxel (Taxotere®)Group 3: Any SAP and AST/ALT >5-10 x upper limit of normal and/or total bilirubin 1-1.5 x upper limit of normal |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which docetaxel is indicated.
- Patients must have measurable or evaluable disease.
- 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.
- Patients must have ECOG performance status < 2 (Karnofsky >60%, see Appendix B).
- Patients must have a life expectancy of greater than 3 months.
Key exclusion criteria (7 listed)
- 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.
- Patients may not be receiving any other investigational agents.
- Patients who have rapidly progressive intracranial or spinal metastatic disease (including patients who require corticosteroid for CNS disease).
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to docetaxel or other agents used in study.
- Patients who have prior medications known to be metabolized by or induce/inhibit CYP3A4 within 1 week (see appendix C).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Docetaxel (Taxotere®)Also: Taxotere®Phase 1 Cycle 1 and 2 Patients in group 1 receive 40mg/m2/week of docetaxel in a 1-hour infusion. Patients in group 2 receive 30mg/m2/week of docetaxel in a 1-hour infusion. Patients in group 3 receive 20mg/m2/week of docetaxel in a 1-hour infusion. | Drug | Group 1, Group 2, Group 3 |
Primary outcome
change in neutrophil counts and docetaxel AUC
Time frame: 3 weeks
. 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.
1 secondary outcome
Pharmacokinetic sampling of docetaxel serum concentrations
Time frame: 7 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Mar 2012.
- Background: PubMed 10859016Goh BC, Lehnert M, Lim HL, Ng AW, Chan CC, Kong HL, Lee SC, Wee J, Chua ET, Wong JE. Phase II trial of docetaxel in Asian patients with inoperable stage III non-small cell lung cancer. Acta Oncol. 2000;39(2):225-9. doi: 10.1080/028418600430824.
- Background: PubMed 12202670Goh BC, Lee SC, Wang LZ, Fan L, Guo JY, Lamba J, Schuetz E, Lim R, Lim HL, Ong AB, Lee HS. Explaining interindividual variability of docetaxel pharmacokinetics and pharmacodynamics in Asians through phenotyping and genotyping strategies. J Clin Oncol. 2002 Sep 1;20(17):3683-90. doi: 10.1200/JCO.2002.01.025.
- Derived from this study: PubMed 26663719Syn NL, Wang L, Wong AL, Soe MY, Chuah B, Chan D, Tan SH, Soo RA, Lee SC, Goh BC, Yong WP. Dose modifications in Asian cancer patients with hepatic dysfunction receiving weekly docetaxel: A prospective pharmacokinetic and safety study. Cancer Sci. 2016 Feb;107(2):173-80. doi: 10.1111/cas.12856. Epub 2016 Feb 8.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Boon Cher Goh, MBBS, MRCP principal investigator
National University Hospital, Singapore
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Docetaxel (Taxotere®) in people with Solid Tumors, run by National University Hospital, Singapore at 1 site in Singapore.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 Mar 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Singapore. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
change in neutrophil counts and docetaxel AUC (time frame: 3 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00703378, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Mar 2012.