Estrogen Receptor-positive Breast Cancer, Progesterone Receptor-positive Breast Cancer, Recurrent Breast Cancer, Stage IV Breast Cancer
Conditions
Brief summary
This randomized phase II trial is studying how well giving gefitinib together with anastrozole works compared to giving gefitinib together with fulvestrant in treating postmenopausal women with recurrent or metastatic breast cancer. Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using anastrozole and fulvestrant may fight breast cancer by blocking the use of estrogen. Gefitinib (ZD1839) may stop the growth of cancer cells by blocking the enzymes necessary for their growth. It is not yet known whether gefitinib is more effective when combined with anastrozole or fulvestrant in treating breast cancer.
Detailed description
PRIMARY OBJECTIVES: I. Evaluate the antitumor activity of anastrozole given in combination with the EGFR tyrosine kinase inhibitor ZD1839, and of fulvestrant given in combination with the EGFR tyrosine kinase inhibitor ZD1839. II. Evaluate the safety of anastrozole given in combination with ZD1839 and fulvestrant given in combination with ZD1839. III. Evaluate the interaction of biological characteristics that predict for response of breast cancer to treatment with anastrozole and ZD1839 and with fulvestrant and ZD1839. OUTLINE: This is a randomized, open-label study. Patients are stratified according to prior hormonal therapy (yes vs. no) and dominant site of disease (soft tissue/lymph nodes vs. bone vs. visceral). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive oral anastrozole and oral gefitinib once daily on days 1-28. Arm II: Patients receive fulvestrant intramuscularly on day 1 and oral gefitinib once daily on days 1-28. Courses in both arms repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 2 years and then every 6 months for 1 year.
Interventions
DRUGanastrozole
Given orally
DRUGgefitinib
Given orally
DRUGfulvestrant
Given intramuscularly
OTHERlaboratory biomarker analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have estrogen and/or progesterone receptor positive histologically confirmed adenocarcinoma of the breast with measurable recurrent or metastatic carcinoma of the breast * Baseline measurements and evaluations of involved sites should be performed as close as possible to study entry, but must be within 4 weeks prior to randomization * Patients with available tissue blocks from either the primary or metastatic site must submit the tissue for EGFR analysis * All patients must be postmenopausal females defined by: * Prior bilateral oophorectomy or bilateral ovarian irradiation * No menstrual period for 12 months or longer. If age 55 years or less and on tamoxifen within the prior 6 months, must have an estradiol level in the postmenopausal range * Patients must not have had more than 2 prior chemotherapy regimens for metastatic disease and no chemotherapy within 3 weeks prior to randomization; no concurrent chemotherapy is allowed while on protocol therapy * Patients must not have prior hormonal therapy for metastatic disease; no prior therapy in the adjuvant setting with an estrogen receptor down-regulator (e.g. fulvestrant) or an aromatase inhibitor (e.g. anastrozole, letrozole, exemestane, aminoglutethamide); non-protocol concurrent hormonal therapy is not allowed * Patients must not have had prior therapy with agents that target EGFR * Previous, but not concomitant, therapy with trastuzumab (Herceptin) is allowed; patients must not receive trastuzumab (Herceptin) within 3 weeks prior to randomization * Patients must have ECOG performance status of 0, 1, or 2 * Neutrophils \>= 1500/mm\^3 * Platelets \>= 100,000/mm\^3 * Bilirubin =\< 1.25 x upper limit of normal * SGPT (ALT) and SGOT (AST) =\< 2.5 x upper limit of normal if no demonstrable liver metastases or =\< 5 times upper limit of normal in the presence of liver metastases * Calculated creatinine clearance \>= 30ml/min * INR, PT and PTT within normal range * Patients must not be receiving therapy with anticoagulants or have other contraindication to i.m. injections * Patients must not have a history of central nervous system metastasis * Patients may receive concurrent radiation therapy to painful sites of boney disease or areas of impending fracture as long as the radiation therapy is initiated prior to study entry and sites of measurable disease outside the radiation therapy port are available to follow; patient who have received prior radiation therapy must have recovered from toxicity of the prior radiation therapy * Patients must not take the following medications that may alter ZD1839 pharmacokinetics while enrolled in this trial: phenytoin, carbamazapine, phenobarbitol, rifampicin, and St. John's Wort, oxcarbazepine, rifapentine, modafinil, and griseofulvin * Patients age =\< 55 years must not be receiving LHRH agonists or antagonists within 3 months prior to randomization * Patients who have an ocular inflammation or infection should be fully treated before entry into the trial; patients with a neuropathic keratopathy or diabetes or those with anterior basement membrane disease must be advised of the need for frequent opthalmalogic exams * Patients who continue to wear contact lenses must be advised that they have an increased risk of ocular events; the decision to wear contact lenses should be discussed with the patient's treating oncologist and ophthalmologist * Patients must not suffer from medical or psychiatric conditions that would interfere with protocol compliance, the ability to provide informed consent, or assessment of response or anticipated toxicities * Patients must be disease-free of prior invasive malignancies for \> 5 years with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Rate | assessed every 3 cycles while on treatment, assessed every 3 months when follow up <2 years, every 6 months between 2-3 years,no specific requirements after 3 years | Clinical benefit = complete response (CR), partial response (PR), or stable disease (SD) lasting for at least 6 months, assessed per Response Evaluation Criteria of Solid Tumor (RECIST).CR=disappearance of all target and non-target lesions. PR= disappearance of or at least 30% decrease in the sum of the longest diameters of target lesions, with non-progressive disease in non-target lesions. SD= sum of the longest diameters of target lesions decrease \<30% or increase \<20%, with non-progressive disease in non-target lesions. 141 eligible, treated patients were included. |
Countries
United States
Participant flow
Recruitment details
The study opened on September 16, 2003 and closed on May 29, 2007, with final accrual of 148 patients, 74 on each arm. Patients were accrued through ECOG group.
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Anastrozole and ZD1839) Patients receive oral anastrozole and oral gefitinib once daily on days 1-28. | 72 |
| Arm II (Fulvestrant and ZD1839) Patients receive fulvestrant intramuscularly on day 1 and oral gefitinib once daily on days 1-28. | 69 |
| Total | 141 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 7 | 9 |
| Overall Study | Death | 1 | 2 |
| Overall Study | Ineligible | 2 | 5 |
| Overall Study | insurance, symptomatic deterioration | 1 | 3 |
| Overall Study | Lack of Efficacy | 54 | 53 |
| Overall Study | still on treatment | 3 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 1 |
Baseline characteristics
| Characteristic | Arm II (Fulvestrant and ZD1839) | Total | Arm I (Anastrozole and ZD1839) |
|---|---|---|---|
| Age, Continuous | 63 years | 59 years | 58 years |
| Region of Enrollment Peru | 29 participants | 62 participants | 33 participants |
| Region of Enrollment South Africa | 1 participants | 1 participants | 0 participants |
| Region of Enrollment United States | 39 participants | 78 participants | 39 participants |
| Sex: Female, Male Female | 69 Participants | 141 Participants | 72 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 72 / 74 | 70 / 74 |
| serious Total, serious adverse events | 27 / 74 | 28 / 74 |
Outcome results
Primary
Clinical Benefit Rate
Clinical benefit = complete response (CR), partial response (PR), or stable disease (SD) lasting for at least 6 months, assessed per Response Evaluation Criteria of Solid Tumor (RECIST).CR=disappearance of all target and non-target lesions. PR= disappearance of or at least 30% decrease in the sum of the longest diameters of target lesions, with non-progressive disease in non-target lesions. SD= sum of the longest diameters of target lesions decrease \<30% or increase \<20%, with non-progressive disease in non-target lesions. 141 eligible, treated patients were included.
Time frame: assessed every 3 cycles while on treatment, assessed every 3 months when follow up <2 years, every 6 months between 2-3 years,no specific requirements after 3 years
Population: 141 eligible and treated patients, 72 on Arm I (Anastrozole and ZD1839) and 69 on Arm II (Fulvestrant and ZD1839)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anastrozole and ZD1839 | Clinical Benefit Rate | 44 percentage of participants |
| Fulvestrant and ZD1839 | Clinical Benefit Rate | 41 percentage of participants |