Doxorubicin and Cyclophosphamide Followed by Paclitaxel, Trastuzumab, and Lapatinib in Treating Patients With HER2/Neu-Overexpressed Breast Cancer - Full Text View

Purpose

RATIONALE: Drugs used in chemotherapy, such as doxorubicin, cyclophosphamide, and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. 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 combination chemotherapy together with trastuzumab and lapatinib may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving doxorubicin together with cyclophosphamide followed by paclitaxel, trastuzumab, and lapatinib works in treating patients with HER2/neu-overexpressed breast cancer.

Condition	Intervention	Phase
Breast Cancer	Biological: trastuzumab Drug: cyclophosphamide Drug: doxorubicin hydrochloride Drug: lapatinib ditosylate Drug: paclitaxel Other: laboratory biomarker analysis	Phase 2


Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Phase II Study of Dose-Dense Doxorubicin and Cyclophosphamide (AC) Followed by Weekly Paclitaxel With Trastuzumab and Lapatinib in HER2/NEU-Overexpressed/Amplified Breast Cancer: Feasibility

Resource links provided by NLM:

Genetics Home Reference related topics: breast cancer

MedlinePlus related topics: Breast Cancer Cancer

Drug Information available for: Cyclophosphamide Doxorubicin Doxorubicin hydrochloride Paclitaxel Trastuzumab Lapatinib Lapatinib Ditosylate

Genetic and Rare Diseases Information Center resources: Breast Cancer, Male

U.S. FDA Resources

Further study details as provided by Memorial Sloan Kettering Cancer Center.:

Primary Outcome Measures:

Feasibility [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Toxicity [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
Time to recurrence [ Time Frame: 2 years ] [ Designated as safety issue: No ]
Overall survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]


Enrollment:	95
Study Start Date:	March 2007
Study Completion Date:	July 2011
Primary Completion Date:	July 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: AC, PACLITAXEL , TRASTUZUMAB & LAPATINIB The regimen consists of AC (doxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2) q 14 days x 4 with pegfilgrastim, followed by weekly paclitaxel (80 mg/m2) x 12 + trastuzumab (H) + lapatinib (L). Pegfilgrastim 6mg is given subcutaneously (SQ) on day # 2 of each AC. Filgrastim may be used in lieu of pegfilgrastim at the physician's discretion. Trastuzumab will be administered weekly starting with paclitaxel treatment # 1. Near the completion of all chemotherapy, patients may receive trastuzumab on a q 3-weekly schedule, starting as early as with paclitaxel cycle # 12. The total duration of trastuzumab from beginning to end is 52 weeks. Lapatinib will be given orally at 1000 mg daily, starting with trastuzumab for a total duration of 52 weeks. Hormonal therapy such as tamoxifen or an aromatase inhibitor will be given to patients with hormone receptor positive disease at the physician's discretion. Radiation therapy to the breast or chest is recommended to patients as appropriate.	Biological: trastuzumab Drug: cyclophosphamide Drug: doxorubicin hydrochloride Drug: lapatinib ditosylate Drug: paclitaxel Other: laboratory biomarker analysis

Arms

Assigned Interventions

Experimental: AC, PACLITAXEL , TRASTUZUMAB & LAPATINIB

The regimen consists of AC (doxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2) q 14 days x 4 with pegfilgrastim, followed by weekly paclitaxel (80 mg/m2) x 12 + trastuzumab (H) + lapatinib (L). Pegfilgrastim 6mg is given subcutaneously (SQ) on day # 2 of each AC. Filgrastim may be used in lieu of pegfilgrastim at the physician's discretion. Trastuzumab will be administered weekly starting with paclitaxel treatment # 1. Near the completion of all chemotherapy, patients may receive trastuzumab on a q 3-weekly schedule, starting as early as with paclitaxel cycle # 12. The total duration of trastuzumab from beginning to end is 52 weeks. Lapatinib will be given orally at 1000 mg daily, starting with trastuzumab for a total duration of 52 weeks. Hormonal therapy such as tamoxifen or an aromatase inhibitor will be given to patients with hormone receptor positive disease at the physician's discretion. Radiation therapy to the breast or chest is recommended to patients as appropriate.

Biological: trastuzumab Drug: cyclophosphamide Drug: doxorubicin hydrochloride Drug: lapatinib ditosylate Drug: paclitaxel Other: laboratory biomarker analysis

Detailed Description:

OBJECTIVES:

Primary

Determine the feasibility of dose-dense doxorubicin hydrochloride and cyclophosphamide followed by paclitaxel, trastuzumab (Herceptin®), and lapatinib ditosylate in patients with HER2/neu-overexpressed/amplified breast cancer.

Secondary

Assess the toxicity of this regimen in these patients.
Determine the time to recurrence in patients treated with this regimen.
Determine the overall survival of patients treated with this regimen.
Explore the use of serial troponin I (cTnI) and C-reactive protein (CRP) as a predictor of cardiac toxicity of this regimen in these patients.

OUTLINE: This is a multicenter study. Patients may receive therapy as neoadjuvant or adjuvant administration. Chemotherapy must be completed before breast surgery in case of neoadjuvant therapy. Adjuvant therapy must begin within 84 days after breast surgery.

Chemotherapy: Patients receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1. Treatment repeats every 2 weeks for 4 courses. Patients then receive paclitaxel IV once weekly for 12 weeks.
Trastuzumab (Herceptin®) and lapatinib ditosylate: Beginning concurrently with paclitaxel, patients receive trastuzumab IV over 30-90 minutes once weekly for 12 weeks and then once every 3 weeks, beginning at least 1 week after completion of paclitaxel, for a total of 52 weeks. Patients also receive oral lapatinib ditosylate once daily, beginning concurrently with paclitaxel, for a total of 52 weeks.

Treatment continues in the absence of disease progression or unacceptable toxicity.

Blood samples are collected at baseline, every 2 weeks during chemotherapy, and at 6, 9, and 18 months. Samples are examined for serial troponin and C-reactive protein.

After completion of study treatment, patients are followed every 3-6 months for 3 years, every 6 months for 2 years, and then annually thereafter.

Eligibility


Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Histologically confirmed adenocarcinoma of the breast
- Bilateral synchronous breast tumors allowed
- Any nodal status or tumor size allowed
  - No stage IV disease
HER2/neu-positive disease
- 3+ by IHC OR FISH-amplified
Hormone receptor status not specified

PATIENT CHARACTERISTICS:

Male or female
Menopausal status not specified
ECOG performance status 0-1
Absolute neutrophil count ≥ 1,000/mm³
Platelet count ≥ 100,000/mm³
Bilirubin ≤ 1.1 mg/dL
SGOT or SGPT ≤ 2.5 times upper limit of normal (ULN)
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective barrier contraception during and after completion of study therapy
LVEF ≥ 50% by MUGA scan
No peripheral neuropathy > grade 1
No active second malignancy within the past 5 years except for adequately treated nonmelanoma skin cancer or in situ carcinoma of the cervix
No known allergy or hypersensitivity to doxorubicin hydrochloride, cyclophosphamide, paclitaxel, or other drugs formulated in Cremophor EL
No psychiatric illness or concurrent medical conditions that would preclude study treatment
No other conditions, including any of the following:
- Unstable angina
- Congestive heart failure
- Myocardial infarction within the past 12 months
- High-risk uncontrolled arrhythmias (e.g., ventricular tachycardia, high-grade AV block, or supraventricular arrhythmias that are not adequately controlled)
No QT prolongation (> 500 ms)
No active unresolved infections
No sensitivity to E. coli derived proteins

PRIOR CONCURRENT THERAPY:

Prior hormonal therapy for chemoprevention allowed
No prior trastuzumab (Herceptin®)
No prior anthracyclines
No concurrent hormonal therapy, including hormonal contraception (e.g., birth control pills or ovarian hormonal or replacement therapy)
No other concurrent chemotherapy, radiotherapy, immunotherapy, or biotherapy for breast cancer
No concurrent drugs that may prolong the QT

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00482391

Locations


United States, Massachusetts
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, New York
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10021

Sponsors and Collaborators

Memorial Sloan Kettering Cancer Center.

National Cancer Institute (NCI)

Dana-Farber Cancer Institute

GlaxoSmithKline

Investigators


Principal Investigator:	Chau T. Dang, MD	Memorial Sloan Kettering Cancer Center.
Principal Investigator:	Clifford A. Hudis, MD	Memorial Sloan Kettering Cancer Center.

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Publications:

Dang C, Lin N, Moy B, Come S, Sugarman S, Morris P, Abbruzzi A, Chen C, Steingart R, Patil S, Norton L, Winer E, Hudis C. Dose-dense doxorubicin and cyclophosphamide followed by weekly paclitaxel with trastuzumab and lapatinib in HER2/neu-overexpressed/amplified breast cancer is not feasible because of excessive diarrhea. J Clin Oncol. 2010 Jun 20;28(18):2982-8. doi: 10.1200/JCO.2009.26.5900. Epub 2010 May 17. Erratum in: J Clin Oncol. 2010 Aug 1;28(22):3670.


Responsible Party:	Memorial Sloan Kettering Cancer Center.
ClinicalTrials.gov Identifier:	NCT00482391 History of Changes
Other Study ID Numbers:	07-013, MSKCC-07013
Study First Received:	June 4, 2007
Last Updated:	March 6, 2013
Health Authority:	United States: Institutional Review Board

Keywords provided by Memorial Sloan Kettering Cancer Center.:


recurrent breast cancer stage I breast cancer stage II breast cancer stage IIIA breast cancer	stage IIIB breast cancer stage IIIC breast cancer male breast cancer

Additional relevant MeSH terms:


Breast Neoplasms Breast Diseases Neoplasms Neoplasms by Site Skin Diseases Cyclophosphamide Doxorubicin Lapatinib Liposomal doxorubicin Paclitaxel Trastuzumab Alkylating Agents Antibiotics, Antineoplastic Antimitotic Agents Antineoplastic Agents	Antineoplastic Agents, Alkylating Antineoplastic Agents, Phytogenic Antirheumatic Agents Enzyme Inhibitors Immunologic Factors Immunosuppressive Agents Mitosis Modulators Molecular Mechanisms of Pharmacological Action Myeloablative Agonists Pharmacologic Actions Physiological Effects of Drugs Protein Kinase Inhibitors Therapeutic Uses Topoisomerase II Inhibitors Topoisomerase Inhibitors

ClinicalTrials.gov processed this record on March 01, 2015