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Phase 2 Neoadjuvant Doxorubicin and Cyclophosphamide -> Docetaxel With Lapatinib in Stage II/III Her2Neu+ Breast Cancer

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ClinicalTrials.gov Identifier: NCT00404066
Recruitment Status : Completed
First Posted : November 27, 2006
Results First Posted : December 22, 2017
Last Update Posted : December 22, 2017
Sponsor:
Collaborators:
GlaxoSmithKline
Sanofi
Information provided by (Responsible Party):
George Albert Fisher, Stanford University

Brief Summary:
This trial combines dose dense chemotherapy with doxorubicin and cyclophosphamide (AC) followed by standard, every 3 week docetaxel and GW572016 (lapatinib) for neoadjuvant treatment of Her2neu positive stage II/III breast cancer. The purpose of the study was to determine whether lapatinib combined with chemotherapy was safe and resulted in an increase in pathologic complete response rates.

Condition or disease Intervention/treatment Phase
Breast Cancer Metastatic Breast Cancer Drug: Lapatinib Drug: Doxorubicin Drug: Cyclophosphamide Drug: Docetaxel Drug: Pegfilgrastim Drug: Filgrastim Drug: Dexamethasone Drug: Trastuzumab Phase 2

Detailed Description:

Lapatinib acts as a dual inhibitor of both epidermal growth factor receptor (EGFR) and ErbB-2 (Her2/neu) tyrosine kinase activity. EGFR and ErbB2 receptors are frequently over-expressed or altered in human cancers including breast cancer. This study plans to determine the antitumor activity of this regimen and its effectiveness preventing tumor growth and spread.

Neoadjuvant chemotherapy which achieves pathologic complete responses (pCR) has been shown to predict improved long-term survival and serves as a surrogate for clinical outcome. By using this primary endpoint we can obtain statistical data with smaller patient numbers and at a lower overall cost. Additionally, we hope to correlate clinical and radiologic outcomes with gene expression data.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 21 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Neoadjuvant Chemotherapy Trial in Clinical Stage II/III Her2Neu Positive Breast Cancer With Sequential AC -> Docetaxel With Concurrent Dual EGFR Kinase Blockade by GW572016 (Lapatinib) Followed by 1 Year Adjuvant Trastuzumab
Study Start Date : October 2006
Actual Primary Completion Date : December 2010
Actual Study Completion Date : March 2011

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Neoadjuvant Chemotherapy
Doxorubicin (Adriamycin) + cyclophosphamide (Cytoxan) with pegfilgrastim or filgrastim growth factor support every 2 weeks for 4 cycles, followed by docetaxel + lapatinib for four 21-day cycles, followed by surgery. Dexamethasone was administered twice-a-day for 3 days, starting 24 hours before the docetaxel infusions. After surgery +/- radiation, participants may receive trastuzumab (Herceptin) for a year.
Drug: Lapatinib
1250 mg, tablets, oral daily during treatment with docetaxel (3-week cycles x 4 cycles)
Other Name: GW572016

Drug: Doxorubicin
60 mg/m2, intravenously every 2 weeks for 4 cycles. Given as first treatment with cyclophosphamide.
Other Names:
  • Adriamycin
  • Adriablastin

Drug: Cyclophosphamide
600 mg/m2, intravenously every 2 weeks for 4 cycles. Given as first treatment with doxorubicin.
Other Names:
  • Cytoxan
  • ASTA

Drug: Docetaxel
100 mg/m2, intravenously every 3 weeks for 4 cycles (after treatment cycles of doxorubicin and cyclophosphamide
Other Name: Taxotere

Drug: Pegfilgrastim
6 mg, subcutaneously on day 2 of all cytotoxic chemotherapy treatments.
Other Name: Neulasta

Drug: Filgrastim
300 or 480 mcg, subcutaneously on days 3 to 10 after cytotoxic chemotherapies.
Other Names:
  • Neupogen
  • Granulocyte Colony-Stimulating Factor (G-CSF)

Drug: Dexamethasone
8 mg, oral taken twice a day for 3 days starting 24 hours before docetaxel
Other Name: Adexone

Drug: Trastuzumab
Loading dose 8 mg/kg, then 6 mg/kg, intravenously every 3 weeks for 1 year
Other Name: Herceptin




Primary Outcome Measures :
  1. Percentage of Participants With Pathologic Complete Response (pCR) [ Time Frame: 12 weeks ]
    Pathologic Complete Response (pCR) rate, assessed as no evidence of invasive disease in excised surgical specimens of breast and/or axilla, in participants who received at least 1 cycle of docetaxel and lapatinib and at least one follow-up evaluation.


Secondary Outcome Measures :
  1. Disease-free Survival (DFS) [ Time Frame: 42 months (median follow-up) ]
    Disease-free survival (DFS) is expressed as the percentage of participants who were disease-free and alive at the time of analysis.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

INCLUSION CRITERIA

  • Female
  • Histologically-confirmed Her2neu positive breast cancer, by either Immunohistochemistry (IHC) 3+ or Fluorescence In Situ Hybridization (FISH)+
  • Stage II/III breast cancer including any large primary tumor (> 2 cm), tumors of any size associated with skin or chest wall involvement, tumors of any size with axillary lymph node involvement, (T2-T4, N0-N2) and those with ipsilateral subclavicular or supraclavicular lymph nodes).
  • At least one bi-dimensional, measurable indicator lesion.
  • Between 18 and 70 years of age
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 / Karnofsky ≥ 60% at screening and on the first day of treatment.
  • Informed consent must be obtained prior to registration.
  • Cardiac ejection fraction within the institutional range of normal as measured by multigated acquisition (MUGA) or echocardiography (ECHO) scan.
  • Absolute neutrophil count > 1,500/mm³
  • Hemoglobin > 8.0 g/dL
  • Platelet count > 100,000/mm³
  • Creatinine within normal institutional limits
  • Total Bilirubin equal to or less than institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST); alanine aminotransferase (ALT); and alkaline phosphatase must be within the range allowing for eligibility. In determining eligibility the more abnormal of the two values (AST or ALT) should be used.
  • Eligibility of patients receiving medications or substances known to affect, or with the potential to affect the activity or pharmacokinetics of GW572016 will be determined following review of their use by the Principal Investigator

    • Antacid use is prohibited 1 hour before and 1 hour after GW572016 dosing.
    • All herbal (alternative) medicines are prohibited.
    • Medications prohibited during the administration of lapatinib .
  • Women of child-bearing potential must have negative pregnancy test and must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for the duration of study participation.
  • Peripheral neuropathy: must be < grade 1
  • Able to swallow and retain oral medication

EXCLUSION CRITERIA

  • Evidence of disease outside the breast or chest wall, except for ipsilateral axillary , supraclavicular, or infraclavicular lymph nodes.
  • Prior chemotherapy, immunotherapy, or hormonal therapy for breast cancer.
  • More than 3 months between histologic diagnosis and registration on this study.
  • History of other malignancy within the last 5years, except curatively treated basal cell carcinoma of the skin or carcinoma in situ of the cervix.
  • Psychological, familial, sociological or geographical conditions which do not permit weekly medical follow-up and compliance with the study protocol. Those who are medically-unstable, including but not limited to active infection, acute hepatitis, deep vein thrombosis requiring anticoagulant therapy, gastrointestinal bleeding, uncontrolled hypercalcemia, uncontrolled diabetes, dementia, seizures, superior vena cava syndrome, and those whose circumstances do not permit completion of the study or the required follow-up.
  • Congestive heart failure, abnormal left ventricular ejection fraction (LVEF), angina pectoris, uncontrolled cardiac arrhythmias, or other significant heart disease, or who have had a myocardial infarction within the past year.
  • Pregnant or lactating
  • Of childbearing potential and not employing adequate contraception
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to GW572016.
  • HIV-positive and receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with lapatinib. Appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated.
  • GI tract disease resulting in an inability to take oral medication, malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's, ulcerative colitis).
  • History of severe hypersensitivity reaction to taxotere or other drugs formulated with polysorbate 80.
  • Current active hepatic or biliary disease (with exception of patients with Gilberts syndrome, asymptomatic gallstones, or stable chronic liver disease per investigator assessment ).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00404066


Locations
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United States, California
Santa Clara Valley Medical Center
San Jose, California, United States, 95128
Stanford University School of Medicine
Stanford, California, United States, 94305
Sponsors and Collaborators
George Albert Fisher
GlaxoSmithKline
Sanofi
Investigators
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Principal Investigator: George A Fisher, MD, PhD Stanford University

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Responsible Party: George Albert Fisher, Associate Professor of Medicine, Stanford University
ClinicalTrials.gov Identifier: NCT00404066     History of Changes
Other Study ID Numbers: IRB-03518
BRSADJ0002 ( Other Identifier: OnCore )
First Posted: November 27, 2006    Key Record Dates
Results First Posted: December 22, 2017
Last Update Posted: December 22, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Dexamethasone
Dexamethasone acetate
Cyclophosphamide
Docetaxel
Doxorubicin
Liposomal doxorubicin
Trastuzumab
Lapatinib
BB 1101
Lenograstim
Sargramostim
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action