Paclitaxel and Trastuzumab With or Without Lapatinib in Treating Patients With Stage II or Stage III Breast Cancer That Can Be Removed by Surgery

Phase 3

Active, not recruiting

• Conditions: Male Breast Carcinoma; Stage IIA Breast Cancer AJCC v6 and v7; Stage IIIC Breast Cancer AJCC v7; Stage IIB Breast Cancer AJCC v6 and v7; Stage IIIA Breast Cancer AJCC v7; Stage IIIB Breast Cancer AJCC v7
• Interventions: Other: Laboratory Biomarker Analysis; Drug: Lapatinib Ditosylate; Drug: Paclitaxel; Biological: Trastuzumab

• Registration Number: NCT00770809
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

This randomized phase III trial studies paclitaxel and trastuzumab with or without lapatinib to see how well they work in treating patients with stage II or stage III breast cancer that can be removed by surgery. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. 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. Lapatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving paclitaxel with trastuzumab and/or lapatinib before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. It is not yet known which regimen is more effective in treating patients with breast cancer.

Detailed Description

PRIMARY OBJECTIVE:

I. To determine if the pathologic complete response (pCR) in the breast to neoadjuvant weekly paclitaxel with trastuzumab plus lapatinib (THL) is 20% greater than the pCR to weekly paclitaxel with trastuzumab alone (TH).

SECONDARY OBJECTIVES:

I. To determine the pathologic complete response in the breast and axilla, using American Joint Committee on Cancer (AJCC) Tumor, Lymph Nodes and Metastasis (TMN) criteria (version 6), to neoadjuvant weekly paclitaxel plus human epidermal growth factor 2 (HER2)- targeted therapy in patients with HER2-positive operable breast cancer.

II. To evaluate residual cancer burden (RCB) as a predictor of long term relapse free survival (RFS) and overall survival (OS).

III. To document the toxicity of all chemotherapeutic regimens (THL, TH). IV. To determine the correlation between clinical, radiographic and pathologic response.

V. To compare overall survival (OS), relapse free survival (RFS) and time to first failure (TFF) among the treatment groups.

VI. To obtain blood, fresh frozen and fixed tumor tissue to test specific hypotheses for which biomarker data exist and to evaluate biomarkers in blood, serum and tissue that are likely to influence response to and toxicity of trastuzumab alone or trastuzumab plus lapatinib, when given with paclitaxel.

VII. To determine the surgical practice patterns for breast conservation and sentinel lymphadenectomy in patients undergoing neoadjuvant chemotherapy.

VIII. To determine the radiotherapy practice patterns for post-mastectomy and regional nodal irradiation in patients undergoing neoadjuvant chemotherapy.

IX. To evaluate pharmacogenomic determinants of toxicity.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM I: Patients receive trastuzumab IV over 30-90 minutes and paclitaxel IV over 1 hour once weekly and lapatinib ditosylate orally (PO) once daily for 16 weeks in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive trastuzumab and paclitaxel as in arm I.

ARM III: Patients receive paclitaxel and lapatinib ditosylate as in arm I. (Discontinued as of 6-15-11) Within 42 days after completion of neoadjuvant therapy, patients in both arms undergo definitive surgery (breast conservation or total mastectomy).

After completion of study treatment, patients are followed every 6 months for 2 years and then annually for up to 10 years.

Study Timeline

• Study First Submitted: 2008-10-09
• Study First Submitted QC: 2008-10-09
• Study First Posted: 2008-10-10
• Study Start: 2008-12-01
• Primary Completion: 2014-01-31
• Results First Submitted: 2015-05-07
• Results First Submitted QC: 2015-05-07
• Results First Posted: 2015-05-27
• Status Verified: 2025-01
• Last Update Submitted: 2025-06-21
• Last Update Posted: 2025-06-24
• Study Completion: 2025-07-10

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 305

Inclusion Criteria

• Pathologic confirmation of invasive breast cancer; patients with inflammatory breast cancer are not eligible

• Clinical stage II-III operable invasive breast cancer with intent to perform surgical resection after neoadjuvant therapy

  • Patients with multicentric or bilateral disease are eligible as long as the target lesion meets the eligibility criteria for this study
  • Staging to rule out metastatic disease is recommended for clinical stage III patients

• Tumors must be HER2 positive defined as HER2 3+ by immunohistochemical (IHC) assays or gene amplification by fluorescence in situ hybridization (FISH) with a ratio of >= 2 on invasive tumor

• Estrogen receptor (ER) and progesterone receptor (PgR) status must be known

• The target lesion in the breast must be >= 1 cm on physical examination or by radiographic measurement; palpable axillary adenopathy will be documented but not serve as measurable disease for the primary endpoint; patients with axillary disease only are not eligible to participate

• Patient agrees to provide pretreatment biopsies

• No prior chemotherapy, hormone therapy, biologic, or radiation therapy with therapeutic intent for this cancer

• Cardiac ejection fraction must be >= 50% by echocardiogram or multiple gated acquisition (MUGA) scan

• Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance status 0-1

• Patients must not be pregnant or nursing

• Absolute neutrophil count (ANC) >= 1,000/ul

• Platelet count >= 100,000/ul

• Bilirubin =< 1.5 times upper limit of normal

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 times upper limit of normal (ULN)

• Serum beta-human chorionic gonadotropin (HCG) negative (in female patients unless status-post (s/p) hysterectomy or menopausal or no menses for 24 consecutive months); assay must have a sensitivity of at least 50 mIU/mL

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (THL)	Lapatinib Ditosylate	Patients receive trastuzumab 2 mg/kg IV over 30-90 minutes and paclitaxel 80 mg/m\^2 IV over 1 hour once weekly and lapatinib ditosylate 750 mg PO once daily for 16 weeks in the absence of disease progression or unacceptable toxicity.
Arm III (TL)	Lapatinib Ditosylate	Patients receive paclitaxel 80 mg/m\^2 IV over 1 hour once weekly and lapatinib ditosylate 15000 mg PO once daily for 16 weeks in the absence of disease progression or unacceptable toxicity. (Discontinued as of 6-15-11)
Arm I (THL)	Laboratory Biomarker Analysis	Patients receive trastuzumab 2 mg/kg IV over 30-90 minutes and paclitaxel 80 mg/m\^2 IV over 1 hour once weekly and lapatinib ditosylate 750 mg PO once daily for 16 weeks in the absence of disease progression or unacceptable toxicity.
Arm I (THL)	Paclitaxel	Patients receive trastuzumab 2 mg/kg IV over 30-90 minutes and paclitaxel 80 mg/m\^2 IV over 1 hour once weekly and lapatinib ditosylate 750 mg PO once daily for 16 weeks in the absence of disease progression or unacceptable toxicity.
Arm I (THL)	Trastuzumab	Patients receive trastuzumab 2 mg/kg IV over 30-90 minutes and paclitaxel 80 mg/m\^2 IV over 1 hour once weekly and lapatinib ditosylate 750 mg PO once daily for 16 weeks in the absence of disease progression or unacceptable toxicity.
Arm II (TH)	Laboratory Biomarker Analysis	Patients receive trastuzumab 2 mg/kg IV over 30-90 minutes and paclitaxel 80 mg/m\^2 IV over 1 hour once weekly for 16 weeks in the absence of disease progression or unacceptable toxicity.
Arm II (TH)	Paclitaxel	Patients receive trastuzumab 2 mg/kg IV over 30-90 minutes and paclitaxel 80 mg/m\^2 IV over 1 hour once weekly for 16 weeks in the absence of disease progression or unacceptable toxicity.
Arm II (TH)	Trastuzumab	Patients receive trastuzumab 2 mg/kg IV over 30-90 minutes and paclitaxel 80 mg/m\^2 IV over 1 hour once weekly for 16 weeks in the absence of disease progression or unacceptable toxicity.
Arm III (TL)	Paclitaxel	Patients receive paclitaxel 80 mg/m\^2 IV over 1 hour once weekly and lapatinib ditosylate 15000 mg PO once daily for 16 weeks in the absence of disease progression or unacceptable toxicity. (Discontinued as of 6-15-11)

Primary Outcome Measures

Name	Time	Method
pCR Rate	At time of surgery	Complete pathological response is defined as the absence of residual invasive carcinoma in the breast at the time of definitive surgical removal. Pathologic complete response in the lymph nodes is defined as no detectable invasive tumor by H\&E. Analysis will use a chi-square test for the difference in proportions of patients on the THL arm versus the TH arm who achieve a pCR. Exact binomial methods will be used to construct 95% confidence intervals around the pCR incidence for each arm.

Secondary Outcome Measures

Name	Time	Method
Radiographic Response Rate (at Completion of Neoadjuvant Therapy)	Week 16	Response was defined by the Response Evaluation Criteria in Solid Tumors (RECIST). A responding participant had either a complete response (disappearance of all target lesions) or partial response (30% decrease in sum of longest diameter of target lesions).
Time to First Failure	Time from study entry to any recurrence ( up to 10 years)	Time to first failure is defined as the interval from study entry to ipsilateral invasive breast tumor recurrence, regional invasive breast cancer recurrence, distant recurrence or death from any cause. Patients who have not experienced any of these events will be censored at the date of last clinical assessment. Distribution was estimated using the Kaplan Meier product-limit method.
Overall Survival	Time from randomization to death or last follow-up (up to 10 years)	Overall survival was measured as the interval from study entry until death, from any cause, or last contact. Distribution was estimated using the Kaplan Meier product-limit method
Pathologic Stage in the Breast and Axilla	At time of surgery	Stage will be determined by the American Joint Committee on Cancer (AJCC) TNM (tumor, lymph nodes, metastasis) staging system.
Incidence of Adverse Events as Graded by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 3	Up to 30 days post-treatment	The type and grade of treatment-related toxicity will be tabulated by treatment arm.
Relapse-free Survival (RFS)	Time from surgery to any recurrence (up to 10 years)	Relapse free survival is defined as the interval from definitive surgery to ipsilateral invasive breast tumor recurrence, regional invasive breast cancer recurrence, distant recurrence, or death from any cause, whichever occurs first. Patients who have not experienced any of these events will be censored at the date of last clinical assessment. Patients who do not undergo definitive surgery will not be assessable for RFS. Distribution was estimated using the Kaplan Meier product-limit method.

Trial Locations

Locations (316)

Dana-Farber Cancer Institute at Boston Medical Center - Brighton; 🇺🇸 Brighton, Massachusetts, United States

Banner University Medical Center - Tucson; 🇺🇸 Tucson, Arizona, United States

Sparks Regional Medical Center; 🇺🇸 Fort Smith, Arkansas, United States

Providence Saint Joseph Medical Center/Disney Family Cancer Center; 🇺🇸 Burbank, California, United States

East Bay Radiation Oncology Center; 🇺🇸 Castro Valley, California, United States

Eden Hospital Medical Center; 🇺🇸 Castro Valley, California, United States

Valley Medical Oncology Consultants-Castro Valley; 🇺🇸 Castro Valley, California, United States

Bay Area Breast Surgeons Inc; 🇺🇸 Emeryville, California, United States

Valley Medical Oncology Consultants-Fremont; 🇺🇸 Fremont, California, United States

Contra Costa Regional Medical Center; 🇺🇸 Martinez, California, United States

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