Gefitinib, Trastuzumab, and Docetaxel in Treating Patients With Metastatic Breast Cancer

City of Hope

Status and phase

Completed

Phase 2

Phase 1

Conditions

Breast Cancer

Treatments

Biological: trastuzumab

Drug: docetaxel

Drug: gefitinib

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00086957

CDR0000371908 (Registry Identifier)

03049

ZENECA-1839US/0274

CHNMC-03049

P30CA033572 (U.S. NIH Grant/Contract)

ZENECA-IRUSIRES0012

Details and patient eligibility

About

RATIONALE: Gefitinib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining gefitinib and trastuzumab with docetaxel may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the best dose of docetaxel when given together with gefitinib and trastuzumab in treating patients with metastatic breast cancer.

Full description

OBJECTIVES:

Primary

Determine the safety and efficacy of gefitinib, trastuzumab (Herceptin®), and docetaxel, in terms of time to disease progression, in patients with HER2/neu-overexpressing metastatic adenocarcinoma of the breast.

Secondary

Determine the objective tumor response rate in patients treated with this regimen.
Correlate expression and/or degree of phosphorylation of epidermal growth factor receptor, HER2/neu, c-fos, Akt, ERK½, P13K, p53, p21, and p27 with outcome in patients treated with this regimen.

OUTLINE: This is a phase I, multicenter, dose-escalation study of docetaxel followed by a phase II study. Patients are stratified according to trastuzumab (Herceptin®)-naive vs trastuzumab-failure.

Phase I: Patients receive oral gefitinib once daily on days 2-14. Patients also receive trastuzumab* IV over 30-90 minutes and docetaxel IV over 1 hour on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

NOTE: *Trastuzumab is given at a higher dose (loading dose) in course 1 and then at a lower dose in subsequent courses.

Cohorts of 3-6 patients receive docetaxel at dose level 1. If no dose-limiting toxicity (DLT) is observed in the first cohort of 3 patients, the dose of docetaxel remains the same. If 1 DLT is observed in the first cohort of 3 patients, 3 additional patients are added (for a total of 6 patients) to dose level 1. If no further DLTs are observed at dose level 1, the dose of docetaxel remains the same. If 2 of 3 or 2 of 6 patients experience DLT at dose level 1, the dose of docetaxel is considered above the maximum tolerated dose (MTD) and is subsequently reduced. If 2 of 3 or 2 of 6 patients experience DLT at the reduced dose of docetaxel, the study is stopped.

Phase II: Patients receive docetaxel at the MTD and gefitinib and trastuzumab as in phase I.

Patients are followed for survival.

PROJECTED ACCRUAL: A total of 3-76 patients will be accrued for this study within 26 months.

Enrollment

31 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

Histologically confirmed adenocarcinoma of the breast
- Metastatic disease
HER-2/neu overexpression (3+ by immunohistochemistry OR 2+ by fluorescence in situ hybridization)
Measurable or evaluable disease
Hormone receptor status:
- Not specified

PATIENT CHARACTERISTICS:

Age

18 and over

Sex

Male or female

Menopausal status

Not specified

Performance status

ECOG 0-2

Life expectancy

Not specified

Hematopoietic

Absolute granulocyte count ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3

Hepatic

AST and ALT < 2.5 times upper limit of normal (ULN) (5.0 times ULN in the presence of liver metastases)
Bilirubin < 1.5 times ULN
No unstable or uncompensated hepatic disease

Renal

Creatinine < 1.6 mg/dL
No unstable or uncompensated renal disease

Cardiovascular

LVEF > 45% by echocardiogram or MUGA
No prior New York Heart Association class I-IV heart disease
No prolonged PR interval or atrioventricular block on ECG
No unstable or uncompensated cardiac disease

Pulmonary

No unstable or uncompensated respiratory disease
No clinically active interstitial lung disease
- Patients who are asymptomatic and have chronic stable radiographic changes are allowed

Immunologic

No autoimmune disorders
No conditions of immunosuppression
No severe hypersensitivity to taxane or gefitinib or any of its excipients

Other

Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No other prior or concurrent malignancy within the past 5 years except basal cell carcinoma or carcinoma in situ of the cervix
No other severe or uncontrolled systemic disease
No other acute or chronic medical condition that would preclude study participation
No other significant clinical disorder or laboratory finding that would preclude study participation
No psychiatric illness that would preclude study compliance

PRIOR CONCURRENT THERAPY:

Biologic therapy

Prior adjuvant trastuzumab (Herceptin®) allowed if > 6 months elapsed before disease recurrence
No prior trastuzumab for metastatic breast cancer
No prior monoclonal antibodies directed at the epidermal growth factor receptor (EGFR)

Chemotherapy

Prior adjuvant chemotherapy (or as first-line therapy for metastatic breast cancer) allowed
Prior adjuvant taxane allowed if completed > 6 months before diagnosis of metastatic breast cancer
No prior docetaxel for metastatic breast cancer

Endocrine therapy

Prior adjuvant hormonal therapy (or as first-line therapy for metastatic breast cancer) allowed
No concurrent hormonal therapy
- Concurrent steroids allowed provided dose is stable

Radiotherapy

Not specified

Surgery

Fully recovered from prior oncologic or other major surgery
No concurrent surgery within 7 days of gefitinib administration

Other

Recovered from prior anticancer therapy (alopecia allowed)
More than 30 days since prior non-approved drug or investigational agent
No other prior EGFR-directed therapy (i.e., tyrosine kinase inhibitors)
No concurrent use of any of the following medications:
- Phenytoin
- Carbamazepine
- Barbiturates
- Rifampin
- Hypericum perforatum (St. John's wort)
No other concurrent anticancer therapy
No concurrent cardioprotective drugs
No concurrent oral retinoids
Concurrent participation in the City of Hope indium-labeled trastuzumab imaging study allowed