Lapatinib +/- Trastuzumab In Addition To Standard Neoadjuvant Breast Cancer Therapy.

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00524303
First received: August 31, 2007
Last updated: January 16, 2014
Last verified: October 2013
  Purpose

This study will examine safety and efficacy of Lapatinib in combination with a standard neoadjuvant chemotherapy including 5FU, Epirubicin, Cyclophosphamide and Paclitaxel. Tumor tissue will be obtained at 3 timepoints (optional 4th) to evaluate tumor response to treatment.


Condition Intervention Phase
Neoplasms, Breast
Drug: Trastuzumab
Drug: Paclitaxel
Drug: FEC75
Drug: Lapatinib
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Randomized Trial of Neoadjuvant Trastuzumab and/or Lapatinib Plus Chemotherapy (Sequential FEC75 and Paclitaxel) in Women With ErbB2- (HER2/Neu-) Overexpressing Invasive Breast Cancer

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Percentage of Participants With Overall Pathological Complete Response (pCR) After 26 Weeks of Therapy [ Time Frame: Week 26 ] [ Designated as safety issue: No ]
    A pCR in the breast was defined as no pathologic evidence of invasive disease (residual ductal carcinoma in situ [DCIS] or lobular carcinoma in situ [LCIS] was allowed). A pCR in the axillary lymph node(s) was defined as no evidence of breast cancer cells in the lymph node (including subcapsular sinus). Overall pCR was defined as the sum of pCR in the breast and pCR in the lymph nodes. 26 weeks of therapy comprised the 2-week run-in phase, 12 weeks of treatment with FEC, and 12 weeks of treatment with Paclitaxel.


Secondary Outcome Measures:
  • Percentage of Participants With Clinical Complete Response (cCR) at 26 Weeks or at End of Treatment (EOT) or Early Withdrawal [ Time Frame: Week 26 or EOT or Early withdrawal ] [ Designated as safety issue: No ]
    cCR was defined as the percentage of participants achieving either a Complete Response (CR) or a Partial Response (PR) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR was defined as the disappearance of all target lesions, and PR was defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD.

  • Disease-free Survival (DFS) up to 5 Years From First Dose or Until Disease Progression From Time of Surgery [ Time Frame: Up to 5 years or until disease progression ] [ Designated as safety issue: No ]
    DFS was defined as the date of definitive surgery until the date of disease recurrence.

  • Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal [ Time Frame: Baseline and EOT (up to Week 26) or Early withdrawal ] [ Designated as safety issue: No ]
    12-lead ECGs were performed, and participants were classified as having normal ECG, abnormal- not clinically significant (NCS) ECG, and abnormal-clinically significant (CS) ECG per investigator opinion and reported result.

  • Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline [ Time Frame: Weeks 3, 9, and 15; EOT or early withdrawal; and 3- and 6-month survival follow-up after last chemotherapy course ] [ Designated as safety issue: No ]
    LVEF is the measurement of how much blood is being pumped out of the left ventricle of the heart (the main pumping chamber) with each contraction and is used to determine cardiac function. LVEF was measured by performing echocardiogram (ECHO). If ECHO could not be performed or if the investigator believed that it was not conclusive to evaluate LVEF, then a multigated acquisition (MUGA) scan was performed.

  • Progression-free Survival (PFS) [ Time Frame: Up to 5 years or until disease progression ] [ Designated as safety issue: No ]
    PFS is defined as the time in weeks from the start of study treatment to the first documentation of objective tumor progression or death due to any cause. Although PFS was a registered protocol endpoint, analysis was not conducted. Data are reported as clinical response while on treatment (outcome measure: "Percentage of participants with clinical complete response (cCR) at 26 weeks or at end of treatment (EOT) or early withdrawal") or as disease-free progression (outcome measure: "Disease-free survival (DFS) up to 5 years from first dose or until disease progression from time of surgery").


Other Outcome Measures:
  • Biomarker Protein Expression as it Correlates to Response/Non-response to Treatment [ Time Frame: Tumor core biopsy taken at Baseline and Treatment Day 14 ] [ Designated as safety issue: No ]
    Because this outcome measure was planned to be exploratory and completed after all participants had been treated, data cannot be presented at this time. A biomarker indicates a change in expression or state of a protein that correlates with the risk or progression of a disease, or with the susceptibility of the disease to a given treatment. Biomarkers are characteristic biological properties that can be detected and measured in parts of the body like the blood or tissue.

  • Cancer Stem Cells and the Correlation to Response/Non-response to Treatment [ Time Frame: Tumor core biopsy taken at Baseline and Treatment Day 14 ] [ Designated as safety issue: No ]
    Because this outcome measure was planned to be exploratory and completed after all participants had been treated, data cannot be presented at this time. Increases or decreases in cancer stem cells and how the changes correlate with response/non-response to treatment will be assessed.

  • Transcriptional Profiling of Total RNA and the Correlation to Response/Non-response to Treatment [ Time Frame: Tumor core biopsy taken at Baseline and Treatment Day 14 ] [ Designated as safety issue: No ]
    Because this outcome measure was planned to be exploratory and completed after all participants had been treated, data cannot be presented at this time. Gene pathways that correlate with response/non-response to treatment will be evaluated.


Enrollment: 100
Study Start Date: August 2007
Estimated Study Completion Date: October 2015
Primary Completion Date: October 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm 1
Trastuzumab alone for 2 weeks then in combination with FEC75 for 4 (21 Day) cycles and Paclitaxel for 4 (21 day) cycles then continued trastuzumab until time of definitive surgery
Drug: Trastuzumab
4mg/kg IV loading dose followed by 2mg/kg IV weekly
Drug: Paclitaxel
80mg/m2 IV weekly for 4 (21 day) cycles
Drug: FEC75
5FU 500mg/m2 + Epirubicin 75 mg/m2 + cyclophosphamide 500 mg/m2 IV on day 1 of 4 (21 day) cycles
Experimental: Arm 2
Lapatinib alone for 2 weeks then in combination with FEC75 for 4 (21 Day) cycles followed by Paclitaxel for 4 (21 day) cycles then continued lapatinib until time of definitive surgery
Drug: Paclitaxel
80mg/m2 IV weekly for 4 (21 day) cycles
Drug: FEC75
5FU 500mg/m2 + Epirubicin 75 mg/m2 + cyclophosphamide 500 mg/m2 IV on day 1 of 4 (21 day) cycles
Drug: Lapatinib
1250 mg oral daily dose in arm 2, 750 mg oral daily dose for FEC cycles and then 1000 mg oral daily dose during the Paclitaxel cycles in arm 3
Experimental: Arm 3
Trastuzumab + Lapatinib for 2 weeks then added FEC75 for 4 (21 Day) cycles followed by Paclitaxel for 4 (21 day) cycles then continued trastuzumab + lapatinib until time of definitive surgery
Drug: Trastuzumab
4mg/kg IV loading dose followed by 2mg/kg IV weekly
Drug: Paclitaxel
80mg/m2 IV weekly for 4 (21 day) cycles
Drug: FEC75
5FU 500mg/m2 + Epirubicin 75 mg/m2 + cyclophosphamide 500 mg/m2 IV on day 1 of 4 (21 day) cycles
Drug: Lapatinib
1250 mg oral daily dose in arm 2, 750 mg oral daily dose for FEC cycles and then 1000 mg oral daily dose during the Paclitaxel cycles in arm 3

  Eligibility

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

Inclusion Criteria:

  • Have signed an informed consent form (ICF) and a Patient Authorization Form (HIPAA).
  • Have histologically or cytologically confirmed ErbB2- (HER2/neu-) overexpressing invasive breast cancer (T2-4, N0-2).
  • ErbB2 overexpressing breast cancer, defined as one of the following definitions:
  • 3+ staining by immunohistochemistry (IHC),
  • a fluorescent in situ hybridization (FISH) result of more than six HER2 gene copies per nucleus
  • a FISH ratio of more than 2.2.
  • Have either measurable or evaluable disease.
  • Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 (Refer to Section 11.4).
  • Have LVEF within the institutional range of normal as measured by either echocardiogram (ECHO) or MUGA scans. The same modality must be used consistently throughout the study.
  • Be deemed able to tolerate 8 cycles of preoperative chemotherapy, including 4 cycles with an anthracycline (epirubicin).
  • Must be willing to undergo 2 mandatory core biopsies (4 passes each) after diagnosis to obtain tissue for biologic expression profiling. Any subject with clinically palpable residual disease may undergo an optional third biopsy to allow identification of presumed pathways of resistance to therapy. This information might be useful in providing the subject with options for other targeted therapies if definitive surgery confirms residual disease. Definitive local therapy with surgery and radiation therapy as indicated will be performed after completion of 12 weeks of paclitaxel-based chemotherapy.
  • Are able to swallow and retain oral medication (intact pill).
  • Are able to complete all screening assessments as outlined in the protocol.
  • Have adequate organ function as defined in Table 4:

Table 1 Baseline Laboratory Values

Hematologic:

ANC (absolute neutrophil count) >1.5 x 109/L hemoglobin >9 g/dL platelets >75 x 109/L

Hepatic:

albumin >2.5 g/dL serum bilirubin <1.25 x ULN AST / ALT <3 x ULN if no documented liver metastases AST / ALT <3 x ULN with documented liver metastases

Renal:

serum creatinine <2.0 mg/dL

  • OR - calculated creatinine clearance >40 mL/min
  • Are subjects aged >18 years with any menopausal status:

Non-child-bearing potential (i.e., women with functioning ovaries who have a current documented tubal ligation or hysterectomy, or women who are postmenopausal)

Child-bearing potential (i.e., women with functioning ovaries and no documented impairment of oviductal or uterine function that would cause sterility.) This category includes women with oligomenorrhea (severe), women who are perimenopausal, and young women who have begun to menstruate. These subjects must have a negative serum pregnancy test at screening and agree to one of the following:

Complete abstinence from intercourse from 2 weeks prior to administration of the first dose of study medication until 28 days after the final dose of study medication; or Consistent and correct use of one of the following acceptable methods of birth control: male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female subject; any intrauterine device (IUD) with a documented failure rate of less than 1% per year; oral contraceptives (either combined or progestogen only) where not contraindicated for this subject population or per local practice.; or barrier methods, including diaphragm or condom with a spermicide.

Please note that breast cancer subjects on this trial cannot receive injectable levonorgestrel or injectable progestogen due to the potential for an adverse effect of anti-hormonal therapies on chemotherapy administered for breast cancer [Albain, 2002]. Progestogen may also affect the proliferative rate of endocrine-responsive tumors.

Exclusion Criteria:

  • Have received any prior chemotherapy.
  • Had prior therapy with an ErbB1 and/or ErbB2 inhibitor.
  • Are receiving concurrent anti-cancer therapy (chemotherapy, immunotherapy, and biologic therapy) while taking study medication.
  • Have malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Women with ulcerative colitis are also excluded.
  • Have a concurrent disease or condition that would make the woman inappropriate for study participation, or any serious medical disorder that would interfere with the woman's safety.
  • Have an active or uncontrolled infection.
  • Have dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent.
  • Have active cardiac disease, defined as one or more of the following:

History of uncontrolled or symptomatic angina History of arrhythmias requiring medications, or clinically significant Myocardial infarction <6 months from study entry Uncontrolled or symptomatic congestive heart failure Ejection fraction below the institutional normal limit Any other cardiac condition, which in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient

  • Are pregnant or breastfeeding.
  • Have received concurrent treatment with an investigational agent or participate in another clinical trial.
  • Have received concurrent treatment with prohibited medications (refer to Section 5.8.2 for details on prohibited medications).
  • Have used an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study medication.
  • Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to any of the agents used in this study or their excipients.
  • Are receiving therapeutic anti-coagulation therapy (i.e. warfarin, heparin).
  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: NCT00524303

Locations
United States, California
GSK Investigational Site
Fountain Valley, California, United States, 92708
GSK Investigational Site
Los Angeles, California, United States, 90057
United States, Colorado
GSK Investigational Site
Denver, Colorado, United States, 80220
United States, Florida
GSK Investigational Site
Hudson, Florida, United States, 34667
GSK Investigational Site
Miami, Florida, United States, 33176
GSK Investigational Site
Pembroke Pines, Florida, United States, 33028
United States, Indiana
GSK Investigational Site
Indianapolis, Indiana, United States, 46219
United States, Nevada
GSK Investigational Site
Henderson, Nevada, United States, 89052
United States, Pennsylvania
GSK Investigational Site
Philadelphia, Pennsylvania, United States, 19107
United States, Texas
GSK Investigational Site
Austin, Texas, United States, 78731
GSK Investigational Site
Beaumont, Texas, United States, 77702-1449
GSK Investigational Site
Bedford, Texas, United States, 76022
GSK Investigational Site
Dallas, Texas, United States, 75246
GSK Investigational Site
Dallas, Texas, United States, 75320-2510
GSK Investigational Site
Dallas, Texas, United States, 75231
GSK Investigational Site
El Paso, Texas, United States, 79915
GSK Investigational Site
Houston, Texas, United States, 77024
GSK Investigational Site
Lewisville, Texas, United States, 75067
GSK Investigational Site
Sugar Land, Texas, United States, 77479
GSK Investigational Site
Tyler, Texas, United States, 75702
United States, Virginia
GSK Investigational Site
Norfolk, Virginia, United States, 23502
United States, Washington
GSK Investigational Site
Seattle, Washington, United States, 98117
GSK Investigational Site
Yakima, Washington, United States, 98902
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided by GlaxoSmithKline

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00524303     History of Changes
Other Study ID Numbers: LPT109096
Study First Received: August 31, 2007
Results First Received: July 14, 2011
Last Updated: January 16, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
ErbB2 Overexpressing
ErbB2 Positive
Lapatinib
Invasive Breast Cancer

Additional relevant MeSH terms:
Breast Neoplasms
Breast Diseases
Neoplasms
Neoplasms by Site
Skin Diseases
Lapatinib
Paclitaxel
Trastuzumab
Antimitotic Agents
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Enzyme Inhibitors
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protein Kinase Inhibitors
Therapeutic Uses
Tubulin Modulators

ClinicalTrials.gov processed this record on October 20, 2014