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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

Tracking Information
First Submitted Date  ICMJE November 22, 2006
First Posted Date  ICMJE November 27, 2006
Results First Submitted Date  ICMJE February 3, 2017
Results First Posted Date  ICMJE December 22, 2017
Last Update Posted Date December 22, 2017
Study Start Date  ICMJE October 2006
Actual Primary Completion Date December 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 28, 2017)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: November 22, 2006)
Pathologic complete response
Change History Complete list of historical versions of study NCT00404066 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 28, 2017)
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.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 22, 2006)
  • Radiological complete response
  • Rate of breast conserving surgery
  • To determine the side effects and toxicity profile of Docetaxel and GW572016(Lapatinib)
  • Disease free survival
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase 2 Neoadjuvant Doxorubicin and Cyclophosphamide -> Docetaxel With Lapatinib in Stage II/III Her2Neu+ Breast Cancer
Official Title  ICMJE 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
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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Breast Cancer
  • Metastatic Breast Cancer
Intervention  ICMJE
  • 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
Study Arms  ICMJE 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.
Interventions:
  • Drug: Lapatinib
  • Drug: Doxorubicin
  • Drug: Cyclophosphamide
  • Drug: Docetaxel
  • Drug: Pegfilgrastim
  • Drug: Filgrastim
  • Drug: Dexamethasone
  • Drug: Trastuzumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 8, 2011)
21
Original Enrollment  ICMJE
 (submitted: November 22, 2006)
71
Actual Study Completion Date  ICMJE March 2011
Actual Primary Completion Date December 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 ).
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00404066
Other Study ID Numbers  ICMJE IRB-03518
BRSADJ0002 ( Other Identifier: OnCore )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party George Albert Fisher, Stanford University
Study Sponsor  ICMJE George Albert Fisher
Collaborators  ICMJE
  • GlaxoSmithKline
  • Sanofi
Investigators  ICMJE
Principal Investigator: George A Fisher, MD, PhD Stanford University
PRS Account Stanford University
Verification Date November 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP