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Abraxane and Lapatinib in Treating Patients With Stage I, Stage II, or Stage III Breast Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00331630
Recruitment Status : Completed
First Posted : May 31, 2006
Results First Posted : March 6, 2020
Last Update Posted : March 6, 2020
Sponsor:
Collaborators:
GlaxoSmithKline
Celgene Corporation
Information provided by (Responsible Party):
Northwestern University

Brief Summary:

RATIONALE: Drugs used in chemotherapy, such as Abraxane, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Lapatinib may stop the growth of tumor cells by blocking some of the enzymes needed for their growth. Giving Abraxane together with lapatinib may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving Abraxane together with lapatinib works in treating patients with stage I, stage II, or stage III breast cancer.


Condition or disease Intervention/treatment Phase
Breast Cancer Drug: lapatinib ditosylate Drug: paclitaxel albumin-stabilized nanoparticle formulation Early Phase 1

Detailed Description:

OBJECTIVES:

Primary

  • Determine the clinical response rate, as measured by clinical exam and imaging studies, in patients with stage I-III breast cancer treated with neoadjuvant Abraxane in combination with lapatinib.

Secondary

  • Determine the pathologic complete response rate in patients treated with this regimen.
  • Correlate proliferation (Ki67), apoptosis (cleaved caspase-3), and angiogenesis (vW, CD34) markers, measured before and after treatment, with tumor response in these patients.
  • Conduct other correlative studies, including epidermal growth factor receptor (EGFR), HER2/neu, matrix metalloproteinases (MMPs), and transforming growth factor (TGF-β), before and after treatment with this regimen to assess tumor response in these patients.
  • Determine the toxicity of this regimen in these patients.

OUTLINE: This is a pilot study. Patients are assigned to 1 of 2 treatment groups.

  • Group 1: The first 10 patients receive Abraxane IV over 30 minutes on day 1 and oral lapatinib once daily on days 1-21. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
  • Group 2: The next 20 patients receive Abraxane and lapatinib (at a higher dose) as in group 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo blood collection and tumor biopsies periodically for correlative biomarker studies.

PROJECTED ACCRUAL: A total of 30 patients will be accrued to this study.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pilot Neoadjuvant Trial in Breast Cancer With Combination of ABI-007 (Abraxane) and GW572016 (Lapatinib)
Actual Study Start Date : May 4, 2006
Actual Primary Completion Date : November 10, 2006
Actual Study Completion Date : August 5, 2010

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Treatment arm
30 patients receive Abraxane IV over 30 minutes on day 1 and oral lapatinib once daily on days 1-21. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Drug: lapatinib ditosylate
Oral lapatinib is taken once daily on days 1-21 of each treatment cycle. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Other Names:
  • Tykerb
  • Tyverb

Drug: paclitaxel albumin-stabilized nanoparticle formulation
30 patients receive Abraxane IV over 30 minutes on day 1 each of each treatment cycle. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Other Names:
  • Abraxane
  • ABI-007




Primary Outcome Measures :
  1. Clinical Response Rate (cRR) [ Time Frame: At Baseline, then before each treatment cycle begins and after 4 cycles of study treatment (1 cycle = 21 days) ]

    cRR measured by RECIST for target lesions assessed by clinical exam+ mammogram+ ultrasound (US). cRR is defined as number of patients who's best response in any of the assessments (clinical exam/mammogram/US) is CR+PR. Response will be defined as one of the following in either clinical exam, mammogram or US: Complete Response (CR)-Disappearance of all target lesions. Partial Response (PR)>=30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum.

    Stable Disease-neither sufficient shrinkage to qualify for Partial disease nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum LD while on study.

    Progressive Disease <=20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.



Secondary Outcome Measures :
  1. Pathologic Complete Response (pCR) [ Time Frame: At baseline, then after 4 cycles of study treatment (1 cycle = 21 days ) and at surgery ]
    Pathologic Complete Response (pCR) will be assessed by breast biopsy at baseline and after 4 cycles of study treatment (1 cycle = 21 days) and at surgery. This will be defined as the number of patients that show a pCR after surgery. pCR is defined as the absence of histologic evidence of invasive tumor cells in the surgical breast specimen and axillary lymph nodes.

  2. Proliferation (Ki67) Measured at Baseline and After Completion of Study Treatment [ Time Frame: At baseline, then after 4 cycles of study treatment (1 cycle = 21 days ) ]
    Correlation of proliferation (Ki67) will be assessed by breast biopsy at baseline and after 4 cycles of study treatment (1 cycle = 21 days). Ki67 scoring was performed based on degree of staining (0= no staining, 1=weak nuclear staining, 2=moderate nuclear staining, 3=strong nuclear staining). Ki67 scores were counted on a maximum of 10 randomly selected x40 high-power fields with an eyepiece grid of 10x10 squares containing representative sections of tumor and calculated as percentage of positively stained cells to total tumor cells (Percent Score method) Ki67 labeling Index (LI) as assessed by counting a maximum of 1,000 malignant cells at x400 magnification.

  3. Apoptosis (Cleaved Caspase-3) Measured at Baseline and After Completion of Study Treatment [ Time Frame: At baseline, then after 4 cycles of study treatment (1 cycle = 21 days ) ]
    Apoptosis/cleaved caspase-3 (CC3) will be assessed by breast biopsy at baseline and after 4 cycles of study treatment (1 cycle = 21 days). Scoring was based on the degree of staining (0=more than 90% of tumor cells with no staining, 1= more than 90% of tumor cells have weak staining, 2= more than 90% of tumor cells have moderate staining, 3= more than 90% of tumor cells have strong staining). CC3 scores were counted on a maximum of 10 randomly selected x40 high-power fields with an eyepiece grid of 10x10 squares containing representative sections of tumor and calculated as percentage of positively stained cells to total tumor cells (Percent Score method) CC3 labeling Index (LI) as assessed by counting a maximum of 1,000 malignant cells at x400 magnification.

  4. Angiogenesis (vW, CD34) Markers as Measured at Baseline and After Completion of Study Treatment [ Time Frame: At baseline, then after 4 cycles of study treatment (1 cycle = 21 days ) ]

    Angiogenesis (vW, CD34) markers will be assessed by breast biopsy at baseline and after 4 cycles of study treatment (1 cycle = 21 days). Expressions were analyzed by light microscopy in invasive breast cancer regions.

    Tumor cells were assigned a score:

    0 = no staining

    1. weak staining less than 1% of tumor cells
    2. = medium staining in 1-10% of tumor cells/weak staining in less than 1% of tumor cells
    3. = medium or strong staining in more than 10% of the tumor cells. Capillary density was assessed in breast sections stained for CD34 at a x200 magnification by counting the number of capillaries per field with five fields per slide and results expressed as the average number of capillaries per field.

  5. Epidermal Growth Factor Receptor (EGFR), and Matrix Metalloproteinases (MMPs), Measured at Baseline and After Completion of Study Treatment [ Time Frame: At baseline, then after 4 cycles of study treatment (1 cycle = 21 days ) ]

    Epidermal growth factor receptor (EGFR), HER2/neu, matrix metalloproteinases (MMPs), and transforming growth factor (TGF-β) will be assessed by breast biopsy at baseline and after 4 cycles of study treatment (1 cycle = 21 days) with expressions analyzed by light microscopy in invasive breast cancer regions.

    MMP2 cytoplasmic staining intensity was assigned a score:

    0=no reactivity,

    1. =1-10% of tumor cells reactive,
    2. =11-25% of tumor cells reactive,
    3. = 26-50% of cells reactive,
    4. = more than 50% of cells reactive

    Greater than or equal to 2+ score was considered positive for expression.

    EGFR membrane staining was assigned a score:

    0 = no staining or faint staining in less than 10% of cells

    1. = faint incomplete membrane staining in more than 10% of cells
    2. = weak to moderate complete membrane staining of more than 10% of cells
    3. = strong complete membrane staining in more than 10% of tumor cells

  6. Side Effects From the Combination of Abraxane and Lapatinib [ Time Frame: At baseline, then before the start of each study treatment cycle (1 cycle = 21 days) begins ]

    Side effects from the combination of Abraxane and Lapatinib will be assessed using CTCAE 3.0. Side effects that were related to study treatment and grade 3 or higher were collected where:

    Grade 1= Mild Grade 2 = Moderate Grade 3 = Severe Grade 4 = Life-threatening Grade 5 = Death



Other Outcome Measures:
  1. Circulating Tumor Cell Measurement [ Time Frame: At baseline, then before each study treatment cycle begins (1 cycle = 21 days) ]
    Circulating tumor cell measurement will be assessed by lab tests done at baseline, then before each study treatment cycle begins (1 cycle = 21 days)



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Histologically confirmed breast cancer

    • Clinical stage I-III disease
  • Measurable disease defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm with spiral CT scan
  • HER2/neu 3+ by immunohistochemistry or positive by fluorescent in situ hybridization
  • No known brain metastases
  • Hormone receptor status unspecified

PATIENT CHARACTERISTICS:

  • Menopausal status not specified
  • Male or female
  • Life expectancy > 12 weeks
  • ECOG performance status (PS) 0-1 OR Karnofsky PS 80-100%
  • WBC ≥ 3,000/mm^3
  • Absolute neutrophil count ≥ 1,500 mm^3
  • Platelet count ≥ 100,000/mm^3
  • Total bilirubin normal
  • AST and ALT ≤ 2.5 times upper limit of normal
  • Creatinine normal OR creatinine clearance ≥ 60 mL/min
  • LVEF ≥ 50% as measured by echocardiogram or MUGA scan
  • No other malignancy within the past year
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • Able to swallow and retain oral medication
  • No history of allergic reactions attributed to compounds of similar chemical or biologic composition to lapatinib
  • No ongoing or active infection
  • No symptomatic congestive heart failure
  • No unstable angina pectoris
  • No cardiac arrhythmia
  • No psychiatric illness or social situation that would preclude study compliance
  • No other uncontrolled illness
  • No gastrointestinal (GI) tract disease that would preclude ability to take oral medication
  • No malabsorption syndrome
  • No requirement for IV alimentation
  • No uncontrolled inflammatory GI disease (e.g., Crohn's disease or ulcerative colitis)

PRIOR CONCURRENT THERAPY:

  • No prior chemotherapy, immunotherapy, radiotherapy, or hormonal therapy for breast cancer
  • No prior treatment with epidermal growth factor receptor targeting therapies
  • No prior surgical procedures affecting absorption
  • No prior surgery for breast cancer
  • At least 14 days since prior and no concurrent CYP3A4 inducers, including any of the following:

    • Dexamethasone or dexamethasone equivalent dose ≥ 1.5 mg/day, including any of the following:

      • Cortisone (≥ 50 mg/day)
      • Hydrocortisone (≥ 40 mg/day)
      • Prednisone (≥ 10 mg/day)
      • Methylprednisolone (≥ 8 mg/day)
    • Phenytoin
    • Carbamazepine
    • Phenobarbital
    • Efavirenz
    • Nevirapine
    • Rifampin
    • Rifabutin
    • Rifapentine
    • Hypericum perforatum (St. John's wort)
    • Modafinil
  • At least 7 days since prior and no concurrent CYP3A4 inhibitors, including any of the following:

    • Clarithromycin
    • Erythromycin
    • Troleandomycin
    • Delavirdine
    • Ritonavir
    • Indinavir
    • Saquinavir
    • Nelfinavir
    • Amprenavir
    • Lopinavir
    • Itraconazole
    • Ketoconazole
    • Voriconazole
    • Fluconazole (doses up to 150 mg/day are permitted)
    • Nefazodone
    • Fluvoxamine
    • Verapamil
    • Diltiazem
    • Cimetidine
    • Aprepitant
    • Grapefruit or its juice
  • At least 6 months since prior and no concurrent amiodarone
  • At least 2 days since prior and no concurrent gastric pH modifiers*, including any of the following:

    • Cimetidine
    • Ranitidine
    • Nizatidine
    • Famotidine
    • Omeprazole
    • Esomeprazole
    • Rabeprazole
    • Pantoprazole
    • Lansoprazole
  • NOTE: *Antacids are allowed within 1 hour before and after administration of study drug
  • No other concurrent investigational agents
  • No other concurrent anticancer therapy, including chemotherapy, radiotherapy, immunotherapy, or antitumor hormonal therapy
  • No concurrent herbal (alternative) medicines
  • No concurrent combination antiretroviral therapy for HIV-positive patients
  • Concurrent bisphosphonates allowed

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): NCT00331630


Locations
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United States, Illinois
Northwestern University, Northwestern Medical Faculty Foundation
Chicago, Illinois, United States, 60611-3013
Hematology-Oncology Associates of Illinois
Chicago, Illinois, United States, 60611
Midwest Center for Hematology/Oncology
Joliet, Illinois, United States, 60432
Saint James Hospital and Health Centers Comprehensive Cancer Institute - Olympia Fields
Olympia Fields, Illinois, United States, 60461
United States, Texas
Joe Arrington Cancer Research and Treatment Center
Lubbock, Texas, United States, 79410-1894
Sponsors and Collaborators
Northwestern University
GlaxoSmithKline
Celgene Corporation
Investigators
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Principal Investigator: Virginia G. Kaklamani, MD Northwestern University
Publications of Results:
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Responsible Party: Northwestern University
ClinicalTrials.gov Identifier: NCT00331630    
Other Study ID Numbers: NU 05B2
NU 05B2 ( Other Identifier: Northwestern University )
STU00007257 ( Other Identifier: Northwestern University IRB )
First Posted: May 31, 2006    Key Record Dates
Results First Posted: March 6, 2020
Last Update Posted: March 6, 2020
Last Verified: January 2020
Keywords provided by Northwestern University:
stage I breast cancer
stage II breast cancer
stage IIIA breast cancer
stage IIIB breast cancer
stage IIIC breast cancer
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Albumin-Bound Paclitaxel
Lapatinib
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Protein Kinase Inhibitors
Enzyme Inhibitors