Letrozole, Herceptin in Her2neu +, Estrogen Receptor [ER] and/or Progesterone Receptor [PR] Positive, MBC
The purpose of the study is to investigate the effects (good and bad) that the combination of the drugs letrozole (also called Femara™) and trastuzumab (also called Herceptin®) has on breast cancer. The United States (US) Food and Drug Administration has approved both letrozole and Herceptin for the treatment of advanced breast cancer. Doctors hope that the combination will work better than either drug alone.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase II Trial of the Combination of Letrozole 2.5 mg Daily and Trastuzumab 2 mg/kg Weekly in ErbB2 Positive and Estrogen Receptor and/or Progesterone Receptor Positive Metastatic Breast Cancer|
- To determine the proportion of patients with ER and/or PR positive, ErbB2 positive tamoxifen resistant metastatic breast cancer who achieve complete remission (CR)
- or partial remission (PR)
- or no significant change in lesion size for greater than 24 weeks
- To determine duration of response and median time to progression with letrozole plus trastuzumab treatment
- To evaluate the clinical adverse experience during treatment with letrozole plus trastuzumab treatment
- To generate a tumor and serum bank from patients receiving combination trastuzumab and letrozole treatment
- To analyze ErbB2 expression on circulating malignant cells during treatment with letrozole and trastuzumab
|Study Start Date:||January 2000|
|Study Completion Date:||July 2005|
|Primary Completion Date:||January 2005 (Final data collection date for primary outcome measure)|
Experimental: Letrozole & Trastuzumab
Letrozole 2.5 mg tablets daily and Trastuzumab 2 mg/kg by IV weekly
Letrozole tablets 2.5 mg by mouth daily
Other Name: FemaraDrug: Trastuzumab
Weekly trastuzumab (4 mg/kg loading dose given by IV over 90 minutes folowed by 2 mg/kg given by IV weekly over 30 minutes, provided the previous dose was well tolerated.
Other Name: Herceptin
Since ER function is regulated by peptide growth factor signaling, the phenotype of ER positive tumors may be influenced by the expression of growth factors and growth factor receptors. A potential interaction between ErbB2 (HER2/neu) expression and the success of endocrine therapy has been examined. ErbB2 expression was shown to correlate with resistance to hormone therapy.
An inverse relationship between endocrine therapy responsiveness and ErbB2 expression has not been observed in all studies. This may be due to discordant ER status between the primary tumor and metastatic sites. ER status can be discordant in approximately 20% of cases, with a tendency for metastatic disease to become ER negative with time. Data concerning ErbB2 is more limited, but there may be similar lack of concordance between primary tumor and metastases.
Inhibition of ErbB2 signaling may slow the development of resistance to estrogen deprivation therapy by inhibiting a pathway that promotes estrogen independent growth. The ErbB2 signal transduction pathway bypasses the requirement for estrogen for breast epithelial cell growth. When ErbB2 is activated in ER positive breast cancer cells in vitro, ER becomes phosphorylated and capable of stimulating transcription without estrogen. Chronic activation with heregulin, a ligand for the ErbB family of receptors, leads to ER down-regulation and the acquisition of an ER negative phenotype.
Estrogen deprivation therapy with selective aromatase inhibitors (SAIs) has become the standard of care for postmenopausal women with tamoxifen-resistant advanced breast cancer. About 1/3 of patients benefit from this therapy. There is interest in treating endocrine therapy refractory breast cancer with the recombinant DNA-derived humanized monoclonal antibody trastuzumab. When given alone, trastuzumab has an endocrine therapy-like risk benefit ratio. Trastuzumab targets ErbB2 (HER2/neu). Some breast cancers may coexpress ER and ErbB2.
Letrozole (Femara™) is a highly selective oral non-steroidal aromatase inhibitor. According to in vitro data, letrozole is 170-fold more potent in inhibiting aromatase than aminoglutethimide (AG) and 19-fold more active than anastrozole. Letrozole effectively inhibits intratumoral aromatase according to in vitro and in vivo data. It is indicated for the treatment of advanced breast carcinoma in post-menopausal women who have failed prior anti-estrogen therapy. Final FDA approval was granted in 1997. In two randomized phase IIb/III studies in patients previously treated with an antiestrogen, 19.5% and 23.6% of patients achieved an objective response with letrozole 2.5 mg/day compared with 12.4% receiving AG and 16.4% of patients receiving megace. Median overall survival was increased in the letrozole 2.5 mg/day group by 8 months compared to AG and by 3 months compared to megace. The lower 0.5 mg/day dose of letrozole was associated with poorer response rates and overall survival in both studies.
Trastuzumab (Herceptin®) was approved in 1998. A trial of trastuzumab as a single agent for first line treatment of advanced disease has been reported. Response rate in the first 62 patients was 24%.
The primary objective of this trial is to determine the proportion of patients with ER and/or PR positive, ErbB2 positive tamoxifen resistant metastatic breast cancer who achieve complete remission or partial remission or no significant change in lesion size for > 24 weeks from a combination of letrozole and trastuzumab. The study will also determine duration of response and median time to progression, evaluate toxicity, generate a tumor and serum bank, and analyze ErbB2 expression on circulating malignant cells during treatment.
The study will enroll 35 patients
|United States, District of Columbia|
|Lombardi Cancer Institute, Georgetown University Medical Center|
|Washington, District of Columbia, United States, 20007|
|United States, Massachusetts|
|Dana Farber Cancer Institute|
|Boston, Massachusetts, United States, 02115|
|United States, Missouri|
|Siteman Cancer Center, Washington University|
|St. Louis, Missouri, United States, 63110|
|United States, North Carolina|
|Duke University Medical Center|
|Durham, North Carolina, United States, 27710|
|Principal Investigator:||Paul K Marcom, MD||Duke University|
|Study Director:||Matthew J Ellis, MB, PhD||Washington University|