Clinical trial NCT00086957: Gefitinib, Trastuzumab, and Docetaxel in Treating Patients With Metastatic Breast Cancer
Official title: Phase I/II Trial of ZD1839 (Iressa®), Trastuzumab (Herceptin®), and Docetaxel (Taxotere®) in Patients With erbB-2 (HER-2) Overexpressing, Stage IV Breast Carcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Breast Cancer
Keywords: stage IV breast cancer
male breast cancer
recurrent breast cancer
Lead sponsor: City of Hope Medical Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2004-07-12
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

Eligibility 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

Primary outcomes:
measure: Number of Participants With at Least One Dose Limiting Toxicity in Phase I
timeFrame: 4 weeks from start of treatment, up to 2 years
measure: Recommended Phase II Dose
timeFrame: 4 weeks from start of treatment, up to 2 years
Secondary outcomes:
measure: Progression-free Survival
timeFrame: Until disease progression, up to 5 years.
measure: Objective Response Rate
timeFrame: After 3 cycles of treatment, up to 2 years.
measure: Overall Survival
timeFrame: Until death from any cause, up to 5 years.
Other outcomes:
Locations:
city: Beverly Hills
country: United States
facility: Tower Cancer Research Foundation
state: California
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Hemet
country: United States
facility: Hematology Oncology Consultants-Hemet
state: California
city: Long Beach
country: United States
facility: Breastlink Medical Group, Incorporated at Long Beach Memorial Medical Center
state: California
city: Los Angeles
country: United States
facility: USC/Norris Comprehensive Cancer Center and Hospital
state: California
city: Pasadena
country: United States
facility: City of Hope Medical Group
state: California
Study officials:
affiliation: City of Hope Medical Center
name: George Somlo, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Somlo G, Koczywas M, Luu T, et al.: A phase I-II study of trastuzumab, gefitinib, and docetaxel as first line chemotherapy in patients with HER-2 overexpressing stage IV breast carcinoma. [Abstract] Breast Cancer Research and Treatment 94 (Suppl 1): A-2035, 2005.