Antineoplastic Agents

All Drugs and Chemicals

Hematinics

Docetaxel

Liver Extracts

Bilirubin

Tubulin Modulators

Antimitotic Agents

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: Any SAP and AST/ALT \>5-10 x upper limit of normal and/or total bilirubin 1-1.5 x upper limit of normal

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.

Docetaxel (Taxotere®)

Boon Cher Goh, MBBS, MRCP

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. To identify demographic, pathophysiological and/or phenotypic covariates predicting docetaxel clearance
4. To prospectively validate this PK-PD model for optimisation of docetaxel dosage and determination PK variability and toxicity

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.

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

. 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.

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.

National University Hospital, Singapore

Dr. Goh Boon Cher

Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Pleural Effusion, Malignant

Pleural Effusion

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Amino Acids

Gefitinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Patients will receive Taxotere at 75 mg/m2 given IV over 60 minutes on day 1 of a three week cycle.

ZD1839 will be administered orally at 250mg daily starting on day one, concurrently with the Taxotere.

Taxotere® will be administered to patients a maximum of 2 cycles, after a maximal response is achieved, and then discontinued.

docetaxel (Taxotere®)

ZD1839 will be continued until progression, or until trial closure, whichever comes first.

ZD1839

Alberto Chiappori, MD

This is a Phase II, open-label trial of Taxotere® + ZD1839 in elderly patients with Stage III-b or IV NSCLC who have received no prior chemotherapy for metastatic disease. Patients with prior adjuvant chemotherapy were allowed to enroll on this trial.

This trial is designed to test the efficacy and tolerability of a standard chemotherapy agent, Docetaxel, in combination with an oral agent, Iressa, in elderly patients with advanced stage lung cancer. Current practices utilize two chemotherapeutic medications that may result in increased toxicities and poor outcomes in the elderly population. Treatment consists of an infusion of docetaxel every 21 days for four doses while taking Iressa every day. A computed tomography (CT) scan will measure disease response after two cycles. Response determines continuation of treatment. Lab work will be collected before every treatment. Side effect information will also be collected at every visit. Once the infusion phase of the study is completed, a maintenance phase of taking just the Iressa begins and disease assessment occurs every two months. This period will last until disease progression is demonstrated.

Phase II Study of Docetaxel + ZD1839 in Elderly Patients With Non-Small Cell Lung Cancer

Phase II Study of Taxotere® (Docetaxel) + ZD1839 (IRESSA®) in Previously Untreated Elderly Patients (≥70 Years Old) With Stage III-b (With Malignant Pleural Effusion [MPE+]) or Stage IV Non-Small Cell Lung Cancer (NSCLC)

ORR: Complete Response (CR) + Partial Response (PR). Response rate for Elderly (\> 70 years) previously untreated patients with Stage IIIb (With Malignant Pleural Effusion (MPE)) or IV non-small cell lung cancer (NSCLC) receiving Taxotere + ZD1839. Best clinical response to treatment with combination was determined using Response Evaluation Criteria in Solid Tumors (RECIST V1.0): \* Complete Response (CR)- Disappearance of all target lesions; \* Partial Response (PR)- At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD; \* Progressive Disease (PD)- At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; \* Stable Disease (SD)- Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.

PFS was calculated from the date of enrollment to the date of progression. All 44 treated were assessed for PFS, with a minimum follow-up of 19 months. Progression (PD): At least a 20% increase in the sum of LD of target lesions taking as references the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

OS was calculated from the date of enrollment to the date of death. All 44 treated were assessed for OS, with a minimum follow-up of 19 months.

AstraZeneca

H. Lee Moffitt Cancer Center and Research Institute

Patients will receive Taxotere at 75 mg/m2 given IV over 60 minutes on day 1 of a three week cycle.

ZD1839 will be administered orally at 250mg daily starting on day one, concurrently with the Taxotere.

ZD1839 : ZD1839 will be continued until progression, or until trial closure, whichever comes first.

docetaxel (Taxotere®) : Taxotere® will be administered to patients a maximum of 2 cycles, after a maximal response is achieved, and then discontinued.

Taxotere® (Docetaxel) + ZD1839 (IRESSA®)

Age, Customized

Sex: Female, Male

United States

Region of Enrollment

Alberto Chiappori, M.D.

Response was evaluable in 42 of the 44 patients.

Overall Response Rate (ORR)

All participants who initiated therapy between March 2003 and May 2005

Progression Free Survival (PFS) Rate

Overall Survival (OS) Rate

Eligible patients were treated with docetaxel 75 mg/m2 every three weeks and gefitinib 250 mg orally daily. Docetaxel and ZD1839 (gefitinib) were given for two cycles beyond maximal response. Gefitinib was continued until disease progression. Co-morbidities and activities of daily living were assessed (IADL).

Overall Study

Skin and Connective Tissue Diseases

Symptoms and General Pathology

Breast Neoplasms

Disease Progression

Breast Diseases

Skin Diseases

Capecitabine

Antimetabolites

1250 mg/m\^2 capecitabine (Xeloda®) orally twice a day on days 1 to 14 of each 3 week cycle, in combination with docetaxel (Taxotere®) 75 mg/m\^2 intravenous on day 1 of each 3 week cycle.

825 mg/m\^2 capecitabine orally twice a day on days 1 to 14 of each 3 week cycle, in combination with docetaxel 75 mg/m\^2 intravenous on day 1 of each 3 week cycle.

825 mg/m\^2 or 1250 mg/m2 orally twice a day on days 1 to 14 of each 3 week cycle.

capecitabine (Xeloda®)

75 mg/m\^2 intravenous on day 1 of each 3 week cycle

Clinical Trials

This 2 arm study compared the efficacy and safety of label dose of capecitabine (Xeloda®) to that of a lower dose of Xeloda® plus docetaxel (Taxotere®) in patients with locally advanced or metastatic breast cancer after failure of chemotherapy with an anthracycline. Patients were randomized to receive either 1250 mg/m\^2 or 825 mg/m\^2 orally twice a day (po bid) on days 1-14 of each 3 week cycle, in combination with Taxotere® 75 mg/m2 intravenous (iv) on day 1 of each 3 week cycle. The anticipated time on study treatment was until disease progression and the target sample size was 440 individuals.

A Study to Assess Capecitabine (Xeloda®) in Patients With Locally Advanced or Metastatic Breast Cancer

A Randomized, Open-label Study of the Effect of Different Dosing Regimens of Xeloda® in Combination With Taxotere® on Disease Progression in Patients With Locally Advanced and/or Metastatic Breast Cancer

Progression Free Survival was defined as the time from the date of randomization to the day of documented disease progression or death due to any cause.

According to Response Evaluation Criteria in Solid Tumors (RECIST) criteria: CR is defined as the disappearance of all target lesions and PR is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the nadir sum LD.

For patients with Best Overall Response being Complete Response (CR) or Partial Response (PR), time to response was measured as the time from randomization to the first time when the measurement criteria for CR or PR were met. The percentage of participants with overall response within the given time ranges in each of the categories: Weeks 1-6, 7-12, 13-18, 19-24, 25-30, 31-36, and 43-48 are reported.

Duration of overall response was measured from the time that measurement criteria were first met for Complete Response or Partial Response until the first date that progressive disease or death was documented.

The time to treatment failure was the time from the date of randomization to the first occurrence of any of the following events:

* adverse events
* insufficient therapeutic response (disease progression)
* death
* failure to return
* refusing treatment/being unwilling to cooperate
* withdrawing consent.

Overall Survival was measured as the time from the date of randomization to the date of death.

An adverse event was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study were reported as adverse events.

A serious adverse event is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is Life-Threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.

Additional information about Adverse Events can be found in the Adverse Event Section.

Hoffmann-La Roche

Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to the 1250 mg/m\^2 arm actual received an initial dose that ranged from 480 to 984 mg/m\^2 so were included in the 825 mg/m\^2 arm for safety.

1250 mg/m^2 Capecitabine + Docetaxel

825 mg/m^2 Capecitabine + Docetaxel

Total

Age Continuous

Medical Communications

Per protocol population included all participants who received at least one dose of study and who did not have any major protocol deviations.

Time to Progression of Disease or Death

Intent to treat population included all randomized participants.

Percentage of Participants With Best Overall Response Being Complete Response (CR) or Partial Response (PR)

Week 1-6

Week 7-12

Week 13-18

Week 19-24

Week 25-30

Week 31-36

Week 43-48

Time to Overall Response

Duration of Overall Response

Safety Population included all randomized participants who received study drug. Note: 14 patients randomized to 1250 mg/m\^2 actual received an initial dose that ranged from 480 to 984 mg/m\^2 so are included in the 825 mg/m\^2 arm for safety.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Target Dosing of Docetaxel Through Pharmacokinetic/Pharmacodynamic Optimisation of the First Chemotherapeutic Cycle	NCT00703378	Solid Tumors	Docetaxel (Taxo...	18 Years -	National University Hospital, Singapore
Phase II Study of Docetaxel + ZD1839 in Elderly Patients With Non-Small Cell Lung Cancer	NCT00231465	Non-Small Cell ...	docetaxel (Taxo... ZD1839	70 Years -	H. Lee Moffitt Cancer Center and Research Institute
A Study to Assess Capecitabine (Xeloda®) in Patients With Locally Advanced or Metastatic Breast Cancer	NCT00077857	Breast Cancer	capecitabine (X... docetaxel (Taxo...	18 Years -	Hoffmann-La Roche

Spots Global Cancer Trial Database for docetaxel (taxotere®)