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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

Phase 2
18 Years
Not Enrolling
Metastatic Breast Cancer

Thank you

Trial Information

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

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

Inclusion Criteria:

- Postmenopausal.

- If premenopausal at diagnosis, eligible if undergoes treatment with luteinising
hormone-releasing hormone (LHRH) agonist or surgical ovarian ablation before
initiating treatment (tx).

- Tumor cell expression of ER and/or PR and ErbB2. Expression can be ascertained on
either primary or metastatic site.

- Patient may have received adjuvant and/or neoadjuvant chemotherapy.

- Patient who received adjuvant/neoadjuvant chemotherapy, tx. must have been
discontinued for 4 weeks and patient must have recovered from all acute toxicities,
except alopecia.

- Prior radiotherapy is permitted as long as it was planned before start of study
medication and is completed within 3 weeks of starting trial medication.

- Prior megestrol acetate or raloxifene therapy is permitted, but must be stopped prior
to trial entry.

- Prior tamoxifen therapy.

- At least one bidimensionally measurable lesion.

- ECOG performance status 0-2.

- Patient should have life expectancy of 6 months.

- Patient must have adequate hematologic function: absolute neutrophil count (ANC)
1000/mm3; platelets 75,000/mm3.

- Patient must have adequate renal and liver function, defined as: serum creatinine
less than or equal to 1.5 times the upper limit of normal; serum bilirubin less than
or equal to 1.5 times the upper limit of normal (three times the upper limit of
normal for patients with hereditary benign hyperbilirubinaemia); transaminases (ALT,
AST) less than or equal to 2.5 times the upper limit of normal in patients without
liver metastasis, or less than or equal to 5 times the upper limit of normal in
patients with liver metastasis.

- Ejection fractions by multiple-gated acquisition (MUGA) scan or echocardiogram
greater than 50%

- Patient must give written informed consent prior to initiation of any invasive
study-related procedures that would otherwise not be performed, and must be able to
comply with scheduled visits and evaluations.

- Treatment with bisphosphonates during the trial is permitted.

Exclusion Criteria:

- Prior exposure to any aromatase inhibitor (aminoglutethimide, formestane anastrozole,
letrozole or exemestane) for more than 28 days. Patients that have already started on
aromatase inhibitors (AIs) will be eligible for the protocol if they meet all other
eligibility requirements and receive loading dose of trastuzumab not more than 28
days after starting AI therapy. Patients who initially received anastrozole or
exemestane will be switched to letrozole.

- Prior treatment with trastuzumab

- Prior anthracycline exposure in adjuvant setting > 360 mg/m2.

- Patients with central nervous system (CNS) involvement with metastatic breast cancer
or life threatening lymphangitic or large volume lung or liver disease.

- Patient's only qualifying lesions have been previously irradiated or are scheduled
for irradiation following study entry.

- Severe or uncontrolled concomitant disease from other causes.

- More than 1 prior course of chemotherapy for metastatic disease. If patient has
received one course of palliative chemotherapy, acute toxicities must have resolved
and patient must be experiencing progressive disease at time of enrollment.

- ECOG performance status 3 or 4.

- Patient has previous malignancies other than breast cancer except:

- adequately treated in situ carcinoma of cervix;

- localized basal or squamous cell carcinoma of skin; or

- any previous malignancy treated with curative intent with recurrence risk of
less than 30%.

- Patient is unable to understand informed consent or is unlikely to be compliant with

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To determine the proportion of patients with ER and/or PR positive, ErbB2 positive tamoxifen resistant metastatic breast cancer who achieve complete remission (CR)

Principal Investigator

Paul K Marcom, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Duke University


United States: Institutional Review Board

Study ID:




Start Date:

January 2000

Completion Date:

July 2005

Related Keywords:

  • Metastatic Breast Cancer
  • estrogen receptor positive
  • progesterone receptor positive
  • ErbB2 positive
  • metastatic breast cancer
  • Breast Neoplasms



Duke University Medical Center Durham, North Carolina  27710
Dana Farber Cancer Institute Boston, Massachusetts  02115
Lombardi Cancer Institute, Georgetown University Medical Center Washington, District of Columbia  20007
Siteman Cancer Center, Washington University St. Louis, Missouri  63110