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A Phase II Neo-Adjuvant Study of Letrozole in Combination With Lapatinib in Post -Menopausal Patients With HER2-Positive and Hormone Receptor-Positive Operable Breast Cancer

Phase 2
18 Years
Not Enrolling
Breast Cancer

Thank you

Trial Information

A Phase II Neo-Adjuvant Study of Letrozole in Combination With Lapatinib in Post -Menopausal Patients With HER2-Positive and Hormone Receptor-Positive Operable Breast Cancer



- To determine the pathological complete response in patients with HER2-positive and
hormone receptor-positive operable stage I-III breast cancer.


- To determine tumor cell apoptosis in situ as measured by TUNEL analysis of tumor
sections from fresh frozen or paraffin-embedded core biopsies. (Parts 1 and 2)

- To determine whether EGFR, P-EGFR, P-HER2, Ser118 P-ERα, P-Akt, and P-MAPK (by IHC
using fresh frozen or paraffin-embedded core biopsies) predict the inhibition of
proliferation in situ (Ki67) and/or induction of cell death (TUNEL). (Parts 1 and 2)

- To determine the safety profile of neoadjuvant letrozole and lapatinib. (Part 2)

- To evaluate tumor response to treatment as measured by ultrasound. (Part 2)

- To evaluate the rate of breast conservation surgery. (Part 2)

- To determine the inhibition in cell proliferation in situ in response to letrozole and
lapatinib as measured by the change in percentage of Ki67-positive tumor cells
(determined by IHC using tumor sections from fresh frozen or paraffin-embedded surgical
material). (Part 2)

OUTLINE: This is a randomized, double-blind, placebo-controlled, two-part study.

- Part 1: Patients are randomized to treatment arm.

- Patients receive lapatinib and letrozole once daily for 2 weeks.

- Patients receive letrozole and placebo once daily for 2 weeks. Patients then
proceed to part 2.

- Part 2: All patients receive lapatinib and letrozole once daily for 14 weeks. Patients
then undergo surgical resection of disease.

Patients undergo tissue sample collection at baseline, at 2 weeks, and then at the time of
surgery for biomarker and laboratory studies. Samples are analyzed by IHC and TUNEL.


Inclusion Criteria:

- Clinical stage I, II, or III operable invasive mammary carcinoma, confirmed by
histological analysis

- Measurable residual tumor at the primary site

- Measurable disease is defined as any mass that can be reproducibly measured
by physical examination, mammogram, and/or ultrasound and can be accurately
measured in at least one dimension (longest diameter to be recorded) as 10
mm (1 cm)

- Available core biopsies from the time of diagnosis

- May include sections of paraffin-embedded material

- Scheduled to undergo surgical treatment with either segmental resection or total

- Prior history of contralateral breast cancer allowed if patient has no evidence of
recurrence of their initial primary breast cancer within the last 5 years

- HER2-positive by Herceptest (3+) or FISH

- ER-positive and/or PR-positive by IHC

Exclusion Criteria:

- Locally recurrent breast cancer

- Evidence of distant metastatic disease (i.e., lung, liver, bone, or brain metastases)


Inclusion Criteria:

- Female

- Postmenopausal, as defined by any of the following:

- At least 55 years of age

- Under 55 years of age and amenorrheic for at least 12 months OR
follicle-stimulating hormone (FSH) values ≥ 40 IU/L and estradiol levels ≤ 20

- Prior bilateral oophorectomy or prior radiation castration with amenorrhea for
at least 6 months

- ECOG performance status 0-1

- ANC ≥ 1,000/mm³

- Platelet count ≥ 100,000/mm³

- Creatinine ≤ 1.5 times upper limit of normal (ULN)

- Bilirubin ≤ 1.5 times ULN

- AST and ALT ≤ 1.5 times ULN

- Able to swallow and retain oral medication

- Cardiac ejection fraction normal by echocardiogram (or MUGA scan if an echocardiogram
cannot be performed or is inconclusive)

Exclusion Criteria:

- Premenopausal breast cancer, pregnant, or lactating

- Serious medical illness, that in the judgment of the treating physician, places the
patient at high risk of operative mortality

- Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
resection of the stomach or small bowel

- Ulcerative colitis

- History of other malignancy

- Patients who have been disease-free for 5 years, or patients with a history of
completely resected non-melanoma skin cancer or successfully treated in situ
carcinomas are eligible

- Active or uncontrolled infection

- Dementia, altered mental status, or any psychiatric condition that would prohibit the
understanding or rendering of informed consent

- Known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart


Exclusion Criteria:

- Prior chemotherapy for primary breast cancer

- Tamoxifen or raloxifene as a preventive agent within the past 21 days

- Hormone replacement therapy (e.g., conjugated estrogens tablets [Premarin]) within
the past month

- Prior therapy with anthracyclines

- Investigational drug within the past 30 days or 5 half-lives, whichever is longer

- Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery,
immunotherapy, hormonal therapy, or any other biologic therapy) other than letrozole

- Concurrent treatment with an investigational agent

Type of Study:


Study Design:

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Outcome Measure:

Number of Participants With a Pathological Complete Response

Outcome Description:

Progressive disease (PD): >=20% increase in sum of longest diameter (LD) of target lesion(s), taking as reference smallest sum LD recorded since treatment started. Complete response (CR): disappearance of all target lesions. Partial response (PR): >=30% decrease in sum of LD of target lesion(s), taking as reference baseline sum LD. Stable disease (SD): neither sufficient shrinkage to qualify as PR nor sufficient increase to qualify as PD.

Outcome Time Frame:

at 14 weeks

Safety Issue:


Principal Investigator

Ingrid Mayer, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Vanderbilt-Ingram Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

July 2007

Completion Date:

December 2010

Related Keywords:

  • Breast Cancer
  • stage I breast cancer
  • stage II breast cancer
  • stage IIIA breast cancer
  • stage IIIB breast cancer
  • Breast Neoplasms



Vanderbilt-Ingram Cancer Center Nashville, Tennessee  37232-6838
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute Boston, Massachusetts  02115
Vanderbilt-Ingram Cancer Center - Cool Springs Nashville, Tennessee  37064
Vanderbilt-Ingram Cancer Center at Franklin Nashville, Tennessee  37064