Female patients aged ³18 years, pre/post menopausal with ER and/or PR positive metastatic adenocarcinoma of the breast determined by each laboratory in each centre. Patients will be stratified into 2 categories based on prior hormonal therapy: ·newly diagnosed metastatic disease or that completed adjuvant therapy with tamoxifen at least 1 year prior to starting this protocol ·recurrent disease during, or after adjuvant AI or failing first line treatment with AI for metastatic disease.
Conditions
Sponsors
AstraZeneca AB
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Age ³ 18 years 2.Histologically confirmed metastatic adenocarcinoma of the breast (seeTNM staging Appendix I) that is ER and/or PR positive as determined in local laboratories at each investigator site (central verification of ER status will be performed after the patient starts treatment: results will be dealt with as per section 3.3.5.1) 3.Patients with either non-measurable or measurable disease as per RECIST criteria are eligible for the study Patients with measurable disease must have measurable lesion(s) outside a previously irradiated site 4.Prior hormonal therapy for breast cancer is allowed as follows: ·Patients who have developed metastatic disease after adjuvant hormonal therapy with tamoxifen/Nolvadex if the treatment was completed at least one year prior to recurrence and randomisation in this study (Strata 1), OR ·Pre and post menopausal patients with metastatic breast cancer who are candidates for hormonal treatment and have not received any prior hormonal treatment for metastatic disease (Strata 1), OR ·Patients who progressed/recurred during or after adjuvant hormonal therapy with an aromatase inhibitor (Strata 2), or failed first line treatment with AI for metastatic disease regardless of any adjuvant hormonal treatment (Strata 2) 5.Patients who have a history of receiving adjuvant chemotherapy are eligible 6.WHO performance status of 0,1 or 2 7.Patients with reproductive potential must use an accepted and effective non-hormonal method of contraception 8.Patients must not be pregnant or breast-feeding. A negative pregnancy test is required within 7 days prior to randomisation if pre- or peri-menopausal. Postmenopausal patients are defined as: -natural menopause with last menses > 1 year ago, -radiation induced oophorectomy with last menses > 1 year ago, -chemotherapy induced menopause with 1 year interval since last menses, or -serum FSH and LH and plasma estradiol levels in the postmenopausal range for the institution. -bilateral oophorectomy 9.All patients must give signed written informed consent Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1.Patients for which the paraffin block from the original primary tumour or a metastatic site is unavailable, and/or can not be submitted for central review to perform repeated testing for ER/PR status, HER2, AIB1 and other markers (see sections 4.6.6 and 4.11) 2.Previously irradiated tumour constitutes the only site of disease 3.Prior chemotherapy for metastatic disease 4.Prior hormonal therapy ·progression of breast cancer while on adjuvant tamoxifen or recurrence within a year of adjuvant treatment with tamoxifen 5.Treatment with LH-RH analog 6.Patients on Hormone replacement therapy (HRT) 7.Acute or chronic medical or psychiatric condition or a laboratory abnormality that may increase the risks associated with the study participation or may interfere with the interpretation or compliance with the study 8.Rapidly progressive visceral metastasis, CNS metastasis, and liver metastatic disease with greater than one-third involvement of the liver, or significant symptomatic pulmonary metastasis or lymphangitis. 9.Treatment with an investigational drug within 30 days of treatment initiation 10.Prior treatment with a Tyrosine Kinase inhibitor regardless of the targeted receptor 11.Known hypersensitivity to tamoxifen or any of its excipients 12.Known severe hypersensitivity to ZD1839 or any of the excipients of this product 13.Any evidence of clinically active interstitial lung disease (patients with chronic stable radiographic changes who are asymptomatic need not necessarily be excluded) 14.Other malignancies diagnosed within the last 5 years with the exception of basal cell carcinoma or cervical cancer in situ 15.Any unresolved chronic toxicity greater than CTC grade 2 from previous anticancer therapy 16.Laboratory values as follow ·Bilirubin >1.5 times upper limit of normal ULN, alanine amino transferase (ALT) or aspartate amino transferase (AST) >2.5 times the ULN if no demonstrable liver metastases, or >5 times the ULN in the presence of liver metastases ·Bone marrow function: WBC <1500 mm3 17.Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the subject to participate in the trial 18.Pregnancy or breast feeding 19.Concomitant use of phenytoin, carbamazepine, rifampicin, barbiturates, or St John’s Wort
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Strata 1 To compare the time to progression between 2 treatment arms (ZD1839/Nolvadex vs placebo/Nolvadex ) Strata 2 To compare the clinical benefit rate between 2 treatment arms (ZD1839/Nolvadex vs placebo/Nolvadex) ;Secondary Objective: To compare 2 treatment arms (ZD1839/Nolvadex vs placebo/Nolvadex): 1. clinical benefit rate in Strata 1 and overall 2. time to progression in Strata 2 and overall 3. objective response rate in each strata and overall 4. estimate duration of response in each strata and overall 5. overall survival in each strata and overall 6. To assess whether patients with high tumour levels of HER-2 and /or AIB1 demonstrate de novo resistance to Nolvadex therapy or have shorter TTP or response duration when compared with Nolvadex/ZD1839 treatment 7. To compare the objective response rate between the ZD1839/Nolvadex and placebo/Nolvadex treatment arms in the subset of all patients with ER+ tumours staining 2+/3+ for Her2neu by IHC 8. To compare the safety and tolerability of ZD1839/Nolvadex to placebo/Nolvadex Plus additional secondary objectives for Pharmacokinetics and Quality of Life. ;Primary end point(s): | — |
Countries
Denmark
Outcome results
None listed