Trastuzumab and Letrozole in Treating Postmenopausal Women With Progressive Advanced Breast Cancer

Trastuzumab Monotherapy Followed By the Combination of Trastuzumab and Letrozole in Post-Menopausal Women With ER-Positive, HER-2 Positive Advanced Breast Cancer Resistant to a Nonsteroidal Aromatase Inhibitor: A Multicenter Two-Step Phase II Trial

RATIONALE: Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Estrogen can cause the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by lowering the amount of estrogen the body makes. Giving trastuzumab together with letrozole after disease progression may be an effective treatment for breast cancer.

PURPOSE: This phase II trial is studying how well giving trastuzumab together with letrozole works in treating postmenopausal women with progressive advanced breast cancer.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Trastuzumab + Letrozole

Detailed Description

OBJECTIVES:

Primary

• Determine the efficacy of trastuzumab (Herceptin®) monotherapy followed by trastuzumab and letrozole in women with progressive advanced breast cancer that is resistant to prior treatment with a nonsteroidal aromatase inhibitor.

Secondary

• Determine the safety profile of this regimen in these patients.
• Correlate HER-2-extracellular domain (ECD) levels with response to treatment in these patients.
• Determine the efficacy of this regimen in these patients.
• Correlate response and time to tumor progression with changes in serum HER-2-ECD levels in patients treated with this regimen.

OUTLINE: This is a multicenter study.

Patients receive trastuzumab (Herceptin®) IV over 30-90 minutes once in weeks 1-3 OR once in week 1. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression after 9 weeks receive trastuzumab as before and oral letrozole once daily in the absence of further disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 12 weeks until disease progression and then at 6 months.

PROJECTED ACCRUAL: A total of 30-40 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 2

Contacts and Locations

Study Locations

• Switzerland
  • Aarau, Switzerland, CH-5001
    • Kantonspital Aarau
  • Baden, Switzerland, CH-5404
    • Kantonsspital Baden
  • Basel, Switzerland, CH-4016
    • Saint Claraspital AG
  • Basel, Switzerland, CH-4031
    • Universitaetsspital-Basel
  • Bern, Switzerland, CH-3010
    • Inselspital Bern
  • Bruderholz, Switzerland, CH-4101
    • Kantonsspital Bruderholz
  • Chur, Switzerland, CH-7000
    • Kantonsspital Graubuenden
  • Lausanne, Switzerland, CH-1011
    • Centre Hospitalier Universitaire Vaudois
  • Liestal, Switzerland, CH-4410
    • Kantonsspital Liestal
  • Mendrisio, Switzerland, CH-6850
    • Ospedale Beata Vergine
  • Rheinfelden, Switzerland, CH-4310
    • Praxis Dr. Beretta
  • St. Gallen, Switzerland, CH-9007
    • Kantonsspital - St. Gallen
  • Zurich, Switzerland, CH-8063
    • City Hospital Triemli
  • Zurich, Switzerland, CH-8091
    • Universitaetsspital Zuerich

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed breast cancer

  • Advanced disease

• Measurable disease, defined as ≥ 1 unidimensionally measurable lesion outside previously irradiated areas that is ≥ 20 mm OR ≥ 10 mm if the slice thickness of the CT scan or MRI is ≤ 5 mm

  • No nonmeasurable lesions as the only site of measurable disease, including any of the following:

    • Osteoblastic bone metastases
    • Ascites
    • Pleural or pericardial effusions
    • Carcinomatous lymphangitis of the lung
• Progressive disease after prior treatment with a nonsteroidal aromatase inhibitor (e.g., letrozole or anastrozole) in an adjuvant or advanced disease setting
• HER-2 amplification ≥ 2 by fluorescence in situ hybridization
• No clinical symptoms or history of CNS or leptomeningeal metastases (no imaging is required)
• No visceral involvement with risk for organ dysfunction

• Hormone receptor status:

  • Estrogen receptor- and/or progesterone receptor-positive tumor

PATIENT CHARACTERISTICS:

Age

• 18 and over

Sex

• Female

Menopausal status

• Postmenopausal, defined by 1 of the following:

  • At least 55 years of age
  • Less than 55 years of age with spontaneous cessation of menses for ≥ 1 year
  • Less than 55 years of age with spontaneous cessation of menses within the past year, but amenorrheic with biochemical evidence of postmenopausal status
  • Underwent prior bilateral oophorectomy
  • Radiation or chemically induced menopause (treatment with luteinizing hormone-releasing hormone antagonists must continue during study treatment)

Performance status

• WHO 0-1

Life expectancy

• Not specified

Hematopoietic

• WBC ≥ 3,000/mm^3
• Platelet count ≥ 100,000/mm^3

Hepatic

• AST and ALT ≤ 2 times upper limit of normal

Renal

• Creatinine clearance > 30 mL/min

Cardiovascular

• No uncontrolled cardiac disease, including any of the following:

  • Unstable angina
  • Arrhythmia
  • Hypertension
• No history of congestive heart failure
• No myocardial infarction within the past 6 months
• LVEF > 50% by echocardiogram

Pulmonary

• No severe dyspnea at rest

Other

• No other malignancy within the past 5 years except adequately treated carcinoma in situ of the cervix or localized nonmelanoma skin cancer
• No psychiatric disability that would preclude study participation or giving informed consent
• No active autoimmune disease
• No uncontrolled diabetes
• No other serious underlying medical condition that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior trastuzumab (Herceptin®)

Chemotherapy

• Prior neoadjuvant or adjuvant chemotherapy allowed
• No prior palliative chemotherapy

Endocrine therapy

• See Disease Characteristics

Radiotherapy

• See Disease Characteristics

Surgery

• Not specified

Other

• More than 1 month since prior experimental drugs on another clinical trial
• No concurrent drugs that contraindicate study treatment
• No other concurrent anticancer drugs
• No other concurrent investigational drugs

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Arm A; Patients receive trastuzumab (Herceptin®) IV over 30-90 minutes once in weeks 1-3 OR once in week 1. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression after 9 weeks receive trastuzumab as before and oral letrozole once daily in the absence of further disease progression or unacceptable toxicity.

Drug: Trastuzumab + Letrozole; Patients receive trastuzumab (Herceptin®) IV over 30-90 minutes once in weeks 1-3 OR once in week 1. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression after 9 weeks receive trastuzumab as before and oral letrozole once daily in the absence of further disease progression or unacceptable toxicity.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Objective response rate as assessed by CT scan or MRI every 3 months	3 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Time to tumor progression (TTP) every 3 months	3 months
Overall survival every 3 months	3 months
Toxicity every 3 months	3 months

Collaborators and Investigators

• Sponsor: Swiss Group for Clinical Cancer Research

Publications and helpful links

General Publications

• Koeberle D, Ruhstaller T, Jost L, Pagani O, Zaman K, von Moos R, Oehlschlegel C, Crowe S, Pilop C, Thuerlimann B; Swiss Group for Clinical Cancer Research (SAKK). Combination of trastuzumab and letrozole after resistance to sequential trastuzumab and aromatase inhibitor monotherapies in patients with estrogen receptor-positive, HER-2-positive advanced breast cancer: a proof-of-concept trial (SAKK 23/03). Endocr Relat Cancer. 2011 Mar 9;18(2):257-64. doi: 10.1530/ERC-10-0317. Print 2011 Apr.

Study record dates

Study Major Dates

• Study Start: May 1, 2005
• Primary Completion (Actual): January 1, 2010
• Study Completion (Actual): April 1, 2011

Study Registration Dates

• First Submitted: October 12, 2005
• First Submitted That Met QC Criteria: October 12, 2005
• First Posted (Estimate): October 13, 2005

Study Record Updates

• Last Update Posted (Actual): May 15, 2019
• Last Update Submitted That Met QC Criteria: May 13, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: stage IV breast cancer; stage IIIA breast cancer; recurrent breast cancer; stage IIIB breast cancer; stage IIIC breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Immunological; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Trastuzumab; Letrozole
• Other Study ID Numbers: SAKK 23/03; EU-20527