Study of Neoadjuvant Docetaxel and Cyclophosphamide in Locally Advanced or Node Positive Primary Breast Cancer With Companion Pharmacokinetic and Pharmacogenomic Analyses
The purpose of this study is to evaluate tumour pathological complete response rate after six cycles of neoadjuvant docetaxel and cyclophosphamide in an Asian population.
- Pharmacokinetics (PK) and pharmacogenomics (PG) of docetaxel cyclophosphamide in Asian patients,
- Safety and toxicity of docetaxel cyclophosphamide in Asian patients, and
- To determine efficacy of short course (3 days) filgrastim in primary and secondary prophylaxis against febrile neutropenia in patients receiving docetaxel and cyclophosphamide.
|Study Design:||Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase 2 Study of Neoadjuvant Docetaxel and Cyclophosphamide in Locally Advanced or Node Positive Primary Breast Cancer With Companion Pharmacokinetic and Pharmacogenomic Analyses|
- To evaluate tumour pathological complete response rate after 6 cycles of neoadjuvant docetaxel and cyclophosphamide in Asian population [ Time Frame: 2 years ] [ Designated as safety issue: No ]To evaluate tumour pathological complete response rate after 6 cycles of neoadjuvant docetaxel and cyclophosphamide in Asian population
|Study Start Date:||August 2010|
|Estimated Study Completion Date:||August 2018|
|Estimated Primary Completion Date:||August 2018 (Final data collection date for primary outcome measure)|
|Experimental: Docetaxel + cyclophosphamide||
Drug: Neoadjuvant Docetaxel and Cyclophosphamide
5.1.1 Docetaxel Docetaxel at a dose of 75 mg/m2 will be administered by intravenous infusion over 90 minutes (AFTER completion of cyclosphosphamide 600 mg/m2) on D1 every 21 days for 6 cycles using nonpolyvinylchloride tubing.
Standard premedication with oral dexamethasone 8 mg bd on D-1, D1 and D2 will be administered. Alternatively, intravenous dexamethasone 8 mg before docetaxel followed by oral dexamethasone 8 mg bd on D1 and D2 can be given.
Routine prevention of chemotherapy induced emesis will be administered (see 5.2.2)
Cyclophosphamide 600 mg/m2 by slow intravenous infusion over 10 minutes (BEFORE docetaxel) will be administered every 21 days for 6 cycles.
No premedications are required except for routine prevention of chemotherapy induced emesis (see 5.2.2)
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Study Design and Duration
Simon Optimal two-stage Phase II design will be used for this trial. With a null hypothesis of p0=5% and an alternative hypothesis of p1=20%, significance level, α=5% and power, (1-β)=90%, a total of 41 patients will be required, with 21 patients to be recruited for the first stage.
Hence, 21 to 41 patients will be recruited at National Cancer Centre Singapore over 36 months
Patients with newly diagnosed, histological confirmed HER-2 negative clinically node positive or locally advanced (cT3-T4, N0-3 or cTx, T0-4, N2-N3) primary breast cancer without evidence of metastatic disease.
Dosage/ Dosage Form, Route and Dose Regimen
Node Positive or Locally Advanced HER2 Negative Breast Cancer proceed to Docetaxel 75 mg/m2 + Cyclophosphamide 600 mg/m2 q21 days x 6 proceed to surgery
NOTE: cyclophosphamide is administered by intravenous infusion over 10 minutes followed by docetaxel over 90 minutes Patients will receive further chemotherapy, radiotherapy, endocrine therapy and targeted therapy as per institutional guidelines after surgery.
Patients with clinical non-response after 4 cycles of docetaxel and cyclophosphamide are most unlikely to have a pathological complete response. Hence, discontinuation of study and cross over to an anthracycline based chemotherapy is allowed at that point at the discretion of the treating oncologist. These patients will be classified as pathological non complete response.
Patients with progressive disease at any time will discontinue study treatment and receive salvage therapy.
Pathological response will be assessed by evaluation of resected surgical specimen after completion of protocol treatment.
Vital signs, Eastern Cooperative Oncology Group (ECOG) performance status, adverse events (AEs), serial laboratory safety tests. Proportion of patients with febrile neutropenia despite primary prophylactic G-CSF will be reviewed when 6,12 ,18, 24 and 30 patients have been accrued. Increase in number of doses of primary prophylactic G-CSF will be implemented if the lower limit of the 95% confidence interval of proportion exceeds 20%.
All patients who have received at least 1 dose of study treatment will be included in the safety and efficacy analyses.
Pharmacokinetic (PK), Pharmacogenetic (PG) and Correlative Studies
Consent will be obtained for future analysis of any stored preoperative tumour biopsy specimens for possible gene expression profiles predictive of docetaxel and cyclophosphamide. Patients will undergo blood sampling for docetaxel and cyclophosphamide PK studies on cycle 1 day 1 (see page 22 for detailed timing). Whole blood will be collected at baseline for genotyping for CYP3A4, CYP3A5, CYP2B6, CYP2C19, ALDH, GST, ABCB1, SLCO1B3, PXR, CAR, HNF4α genes
ALL PATIENTS WITH SERIOUS ADVERSE EVENTS MUST BE FOLLOWED UP FOR OUTCOME.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01540110
|National Cancer Centre Singapore|
|Singapore, Singapore, 169610|