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Phase 2 Study of Neoadjuvant Docetaxel and Cyclophosphamide in Locally Advanced or Node Positive Primary Breast Cancer With Companion Pharmacokinetic and Pharmacogenomic Analyses

Phase 2
21 Years
Open (Enrolling)
Breast Cancer

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Trial Information

Phase 2 Study of Neoadjuvant Docetaxel and Cyclophosphamide in Locally Advanced or Node Positive Primary Breast Cancer With Companion Pharmacokinetic and Pharmacogenomic Analyses

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

Patient Sample

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

Patients with progressive disease at any time will discontinue study treatment and receive
salvage therapy.

Efficacy Measurements

Pathological response will be assessed by evaluation of resected surgical specimen after
completion of protocol treatment.

Safety Measurements

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%.

Data Analysis

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


Inclusion Criteria:

- Patients must have histologically confirmed invasive breast cancer.

- Patients must have either locally advanced (cT3-T4, N0-3 or cTx, T0-4, N2-N3) or
lymph node positive breast cancer

- Age >21 years. Because no dosing or adverse event data are currently available on
the use of docetaxel in patients <21 years of age, children are excluded from this
study but will be eligible for future pediatric phase 2 combination trials.

- Life expectancy of greater than 10 years.

- ECOG performance status <2 (Karnofsky >60%; see Appendix A).

- Patients must have normal organ and marrow function as defined below:

- leukocytes >3,000/mL

- absolute neutrophil count >1,500/mL

- platelets >100,000/mL

- total bilirubin within normal institutional limits

- AST(SGOT)/ALT(SGPT) <2.5 X institutional upper limit of normal

- creatinine within normal institutional limits OR

- creatinine clearance >40 mL/min for patients if creatinine levels above
institutional normal

- The effects of docetaxel on the developing human fetus at the recommended therapeutic
dose are unknown. For this reason, women of child-bearing potential must agree to
use adequate contraception (hormonal or barrier method of birth control; abstinence)
prior to study entry and for the duration of study participation. 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

Exclusion Criteria:

- HER2 positive breast cancer

- Metastatic breast cancer

- Patients who have had any chemotherapy or radiotherapy prior to entering the study.

- Patients receiving any other investigational agents.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to docetaxel, cyclophosphamide, lenograstim or filgrastim.

- History of pre-existing peripheral neuropathy

- 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 chemotherapy in general including
docetaxel and cyclophosphamide used in this study are pregnancy class D agents with
the potential for teratogenic or abortifacient effects. Because there is an unknown
but potential risk for adverse events in nursing infants secondary to treatment of
the mother with chemotherapy, breastfeeding should be discontinued if the mother is
treated with chemotherapy. These potential risks may also apply to other agents used
in this study.

- Because patients with immune deficiency are at increased risk of lethal infections
when treated with marrow-suppressive therapy, HIV-positive patients receiving
combination anti-retroviral therapy are excluded from the study because of possible
pharmacokinetic interactions with chemotherapy or other agents administered during
the study. Appropriate studies will be undertaken in patients receiving combination
anti-retroviral therapy when indicated.

- Patients with prior malignancies are excluded except for basal cell carcinoma of the
skin and carcinoma in-situ of the cervix who have received curative treatment.

- Inclusion of Women and Minorities

- Both men and women of all races and ethnic groups are eligible for this trial.

- Protocol precautions and restrictions

- Patients who are pregnant or actively breast feeding are not eligible to participate
in this study as stated in 3.2.8. Female patients of child bearing potential will be
required to use reliable methods of contraception for the duration of the study and
until 4 weeks after the last dose of study treatment.

Type of Study:


Study Design:

Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To evaluate tumour pathological complete response rate after 6 cycles of neoadjuvant docetaxel and cyclophosphamide in Asian population

Outcome Description:

To evaluate tumour pathological complete response rate after 6 cycles of neoadjuvant docetaxel and cyclophosphamide in Asian population

Outcome Time Frame:

2 years

Safety Issue:



Singapore: NCCS Clinical Trials Compliance Unit

Study ID:




Start Date:

August 2010

Completion Date:

August 2012

Related Keywords:

  • Breast Cancer
  • Locally Advanced or Node Positive Primary Breast Cancer
  • Breast Neoplasms