Chemotherapy and Lapatinib or Trastuzumab in Treating Women With HER2/Neu-Positive Metastatic Breast Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
NCIC Clinical Trials Group
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00667251
First received: April 25, 2008
Last updated: July 3, 2014
Last verified: June 2014
  Purpose

RATIONALE: HER2/neu is a receptor (protein) which is found in unusually high amounts in approximately 1 in 5 cancer patients. Scientific evidence suggests that having high amounts of the HER2/neu receptor is important for breast cancer to grow and spread. Women with previously untreated metastatic breast cancer (breast cancer that has spread to other organs) and with high levels of the HER2/neu receptor receive as their usual treatment chemotherapy with one of the approved chemotherapy drugs paclitaxel or docetaxel (called "taxanes") together with another approved drug called "trastuzumab". Chemotherapy drugs, such as paclitaxel and docetaxel, work either by killing tumour cells or by stopping them from dividing. Trastuzumab is an antibody that is given through a vein in the arm and it works by specifically "targeting" the HER2/neu i.e. it attaches to it and "turns it off". Although some of the patients who receive this taxane plus trastuzumab treatment feel better for some months, the cancer usually starts to grow again. Lapatinib is a new drug. Like trastuzumab, it also works by specifically "targeting" the HER2/neu receptor, but it does so in a different way. Lapatinib is not an antibody. It is a pill that is taken daily by mouth. Because lapatinib works in a different way than trastuzumab, it may be worse, as good as or better than trastuzumab in keeping metastatic HER/neu positive cancer from growing. However, this is not known.

Purpose: This randomized Phase III trial is comparing chemotherapy (a taxane) given together with lapatinib with chemotherapy (a taxane) given together with trastuzumab in women with HER2/neu positive breast cancer.


Condition Intervention Phase
Breast Cancer
Biological: trastuzumab
Drug: docetaxel
Drug: lapatinib ditosylate
Drug: paclitaxel
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized, Open-Label, Phase III Study of Taxane Based Chemotherapy With Lapatinib or Trastuzumab as First-Line Therapy for Women With HER2/Neu Positive Metastatic Breast Cancer

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Progression-free Survival [ Time Frame: From randomization to RECIST V 1.0 progression or death assessed up to 39 months. ] [ Designated as safety issue: No ]
    Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions


Secondary Outcome Measures:
  • Overall Survival [ Time Frame: From randomization to death from any cause, assessed up to 44 months. ] [ Designated as safety issue: No ]
    OS median follow-up not achieved; estimated with quartile estimates

  • Time to CNS Metastases at the Time of First Progression [ Time Frame: From randomization to CNS metastases at time of first progression, assessed up to 39 months. ] [ Designated as safety issue: No ]
  • CNS Metastases at the Time of Progression (ITT) [ Time Frame: Incidence rate of CNS metastases at first progression assessed up to 39 months ] [ Designated as safety issue: No ]
  • CNS Metastases at the Time of Progression (HER2+) [ Time Frame: Incidence rate of CNS mestastes at first progression, assessed up to 39 months ] [ Designated as safety issue: No ]
  • Overall Objective Response Rate (Complete or Partial) ITT [ Time Frame: 4 years ] [ Designated as safety issue: No ]

    Patients included in this assessment must have had at least one measurable lesion at baseline, and had at least one RECIST re-evaluation after baseline while on protocol therapy, prior to, or on, date of progression.

    Best overall response was classified to be Complete Response (CR) or Partial Response (PR).


  • Overall Objective Response Rate (Complete or Partial) HER2/Neu+ [ Time Frame: Median follow-up of 21.5 months. ] [ Designated as safety issue: No ]
    Response determined by RECIST V 1.0

  • Clinical Benefit Response Rate (ITT) [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    Best overall response of CR, PR or stable disease at end of week 24.

  • Clinical Benefit Response Rate (HER2/Neu+)) [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    Best overall response of CR, PR, or stable disease at end of week 24.

  • Quality of Life as Measured by the EORTC QLQ-C30 Global Score From Baseline to 12 Weeks [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

    The EORTC QLQ-C30 is a questionnaire developed to assess the quality of life of cancer patients. The global score ranges from 0-100, with higher values representing a better quality of life.

    At 12 weeks: Group mean difference between arms


  • Effects of Changes in Biomarkers on Clinical Outcomes [ Time Frame: Not available at this time ] [ Designated as safety issue: No ]
  • Economic Evaluation, Including Health Utilities, as Measured by the EQ-5D Questionnaire, and Healthcare Utilization [ Time Frame: Not available at this time ] [ Designated as safety issue: No ]

Enrollment: 652
Study Start Date: October 2008
Estimated Study Completion Date: July 2014
Primary Completion Date: August 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Lapatinib
Plus taxane based chemotherapy
Drug: docetaxel
75mg/m2 IV q 3 weekly, day 1 of a 3 week cycle for 8 cycles plus G-CSF (when given together with lapatinib).
Drug: lapatinib ditosylate
1250 mg po daily (while given with taxane). 1500mg PO daily (when given alone after taxane completion).
Drug: paclitaxel
80mg/m2 IV q weekly days 1, 8 and 15 of a 4-week cycle for 6 cycles.
Active Comparator: Trastuzumab
Plus taxane based chemotherapy.
Biological: trastuzumab
IV q weekly (loading dose 4mg/kg; subsequent doses 2mg/kg) or IV q 3 weekly (loading dose 8mg/kg, subsequent doses 6mg/kg).
Drug: docetaxel
75mg/m2 IV q 3 weekly, day 1 of a 3 week cycle for 8 cycles plus G-CSF (when given together with lapatinib).
Drug: paclitaxel
80mg/m2 IV q weekly days 1, 8 and 15 of a 4-week cycle for 6 cycles.

Detailed Description:

OBJECTIVES:

Primary

  • To compare the progression-free survival of women with HER2/neu-positive metastatic breast cancer treated with taxane-based chemotherapy in combination with lapatinib ditosylate or trastuzumab (Herceptin®).

Secondary

  • To compare the overall survival.
  • To compare the time to CNS metastases at the time of first progression.
  • To compare the incidence rates of CNS metastases at the time of progression.
  • To compare the overall objective response rate (complete or partial response), time to response, and duration of response in patients with measurable disease at baseline.
  • To compare the clinical benefit response rate.
  • To compare the adverse event profile.
  • To compare the quality of life.
  • To compare clinical outcomes using biomarker changes in biological samples.
  • To compare health economics, including healthcare utilization and health utilities.

OUTLINE: This is a multicenter study. Patients are stratified according to prior neoadjuvant/adjuvant anti-HER2/neu-targeted therapy (yes vs no), prior neoadjuvant/adjuvant taxane chemotherapy (yes vs no), planned taxane therapy (paclitaxel vs docetaxel), and liver metastasis (yes vs no). Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive either paclitaxel IV on days 1, 8, and 15; treatment with paclitaxel repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. Alternatively, patients may receive docetaxel IV on day 1; treatment with docetaxel repeats every 3 weeks for 8 courses in the absence of disease progression or unacceptable toxicity. Patients on docetaxel also receive filgrastim (G-CSF) according to institutional standard. All patients receive oral lapatinib ditosylate once daily during taxane treatment and continue after completion of taxane treatment, in the absence of disease progression or unacceptable toxicity.
  • Arm II: Patients receive paclitaxel IV on days 1, 8, and 15 and trastuzumab (Herceptin®) IV on days 1, 8, 15, and 22. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. Alternatively, patients may receive docetaxel IV and trastuzumab IV on day 1. Treatment repeats every 3 weeks for 8 courses in the absence of disease progression or unacceptable toxicity. After completion of taxane chemotherapy and trastuzumab, all patients receive trastuzumab alone IV once every 3 weeks in the absence of disease progression or unacceptable toxicity.

Formalin-fixed paraffin-embedded tissue samples are analyzed for ER, PgR, EGFR, CK5/6, Ki67, and other molecular biomarkers by tissue microarray and immunohistochemistry.

Patients complete quality of life questionnaires (EORTC QLQ-C30 and a Trial Specific Checklist) at baseline, every 12 weeks for 96 weeks, and then every 24 weeks until disease progression.

After completion of study treatment, patients are followed at 4 weeks post treatment, and then every 12 weeks thereafter (counting from the beginning of study therapy).

  Eligibility

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

DISEASE CHARACTERISTICS:

  • Histologically confirmed adenocarcinoma of the breast
  • Metastatic (stage IV) disease at primary diagnosis or at relapse after curative intent therapy
  • Local or central laboratory confirmedHER2/neu* overexpressing and/or amplified disease in the invasive component of the primary or metastatic lesion as defined by the following:

    • 3+ overexpression (in > 30% of invasive tumor cells) by immunohistochemistry (IHC)
    • 2+ or 3+ overexpression (in ≤ 30% of invasive tumor cells) by IHC AND demonstrates HER2/neu gene amplification by fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization (CISH)
    • HER2/neu gene amplification by FISH/CISH (> 6 HER2/neu gene copies per nucleus, or a FISH/CISH ratio [HER2 gene copies to chromosome 17 signals] of ≥ 2.2) NOTE: *Patients with a negative or equivocal overall result (FISH/CISH ratio of < 2.2, ≤ 6.0 HER2/neu gene copies per nucleus, or staining scores of 0, 1+, 2+, or 3+ [in ≤ 30% of neoplastic cells] by IHC) are not eligible
  • Formalin-fixed paraffin-embedded tumor specimen available
  • No CNS metastases (including leptomeningeal involvement)
  • Hormone receptor status not specified

PATIENT CHARACTERISTICS:

  • Menopausal status not specified
  • ECOG performance status 0-2
  • Life expectancy > 6 months
  • Absolute granulocyte count > 1,500/mm³
  • Platelet count > 75,000/mm³
  • Hemoglobin > 10 g/dL
  • Serum creatinine ≤ 2.0 times upper limit of normal (ULN)
  • Total bilirubin ≤ 1.5 times ULN (< 3 times ULN for patients with Gilbert's disease)
  • AST and/or ALT ≤ 2.5 times ULN (< 5 times ULN for patients planning to receive paclitaxel-based therapy)
  • LVEF ≥ 50% by MUGA or ECHO
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • Must be accessible for study treatment and follow-up
  • No history of other malignancies, except adequately treated ductal carcinoma in situ or lobular carcinoma in situ, adequately treated nonmelanoma skin cancer, curatively treated carcinoma in situ of the cervix, or other curatively treated solid tumor (non-breast) with no evidence of disease for ≥ 5 years
  • No serious cardiac illness or condition including, but not limited to, any of the following:

    • History of documented congestive heart failure
    • Systolic dysfunction (LVEF < 50%)
    • High-risk uncontrolled arrhythmias (i.e., ventricular tachycardia, high-grade atrioventricular block, or supraventricular arrhythmias that are not adequately rate-controlled)
    • Unstable angina pectoris requiring anti-anginal medication
    • Clinically significant valvular heart disease
    • Evidence of transmural infarction on ECG
    • Inadequately controlled hypertension (i.e., systolic blood pressure [BP] > 180 mm Hg or diastolic BP > 100 mm Hg)
    • New York Heart Association class III-IV functional status
  • No serious illness or medical condition that would not allow the patient to be managed according to the protocol including, but not limited to, any of the following:

    • History of significant neurologic or psychiatric disorder that would impair the ability to obtain informed consent or limit compliance with study requirements
    • Active uncontrolled infection
    • Serious or nonhealing wound, ulcer, or bone fracture
  • No peripheral neuropathy ≥ grade 2
  • No gastrointestinal (GI) tract disease resulting in an inability to take oral medication including, but not limited to, any of the following:

    • Malabsorption syndrome
    • Requirement for IV alimentation
    • Uncontrolled inflammatory GI disease (e.g., Crohn's disease or ulcerative colitis)
  • No history of allergic or hypersensitivity reactions to any study drug or their excipients or to compounds with similar chemical composition to any of the study drugs

    • Prior allergic reactions to taxanes are allowed provided they were adequately treated and, according to the treating physician, would not prohibit further treatment with taxanes

PRIOR CONCURRENT THERAPY:

  • Recovered from all prior therapy
  • No prior chemotherapy, immunotherapy, biological therapy, or anti-HER2/neu-targeted therapy for recurrent or metastatic breast cancer
  • At least 12 months since prior chemotherapeutic agents, including taxanes, in the neoadjuvant or adjuvant setting
  • At least 12 months since prior anti-HER2/neu-targeted therapy in the neoadjuvant or adjuvant setting
  • Prior treatment with endocrine therapy in the neoadjuvant, adjuvant, or metastatic setting allowed
  • At least 2 weeks since prior radiotherapy in the adjuvant or metastatic setting

    • Prior radiotherapy to a solitary metastatic lesion allowed provided there is documented disease progression after completion of radiotherapy
  • More than 30 days (or 5 half-lives) since prior investigational drugs
  • At least 7 days since prior and no concurrent CYP3A4 inhibitors (6 months for amiodarone)
  • At least 14 days since prior and no concurrent CYP3A4 inducers
  • No prior surgical procedures affecting absorption (e.g., resection of stomach or small bowel)
  • No concurrent palliative radiotherapy
  • No other concurrent anticancer treatment
  • No other concurrent investigational drugs for breast cancer
  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: NCT00667251

  Show 252 Study Locations
Sponsors and Collaborators
GlaxoSmithKline
NCIC Clinical Trials Group
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Additional Information:
No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00667251     History of Changes
Other Study ID Numbers: 108919, EGF108919, CAN-NCIC-MA31, 2007-004568-27, CDR0000594764
Study First Received: April 25, 2008
Results First Received: September 24, 2013
Last Updated: July 3, 2014
Health Authority: United States: Food and Drug Administration
Canada: Health Canada

Keywords provided by GlaxoSmithKline:
HER2-positive breast cancer
stage IV breast cancer
recurrent breast cancer

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

ClinicalTrials.gov processed this record on September 29, 2014