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

Neoplasms, Breast Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00524303
• Other study ID #: LPT109096
• Status: Active, not recruiting
• Phase: Phase 2
• First received: August 31, 2007
• Last updated: January 16, 2014
• Start date: August 2007
• Est. completion date: October 2015

Study information

• Verified date: October 2013
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 100
• Est. completion date: October 2015
• Est. primary completion date: October 2010
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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).

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Neoplasms
• Neoplasms, Breast

Intervention

Drug:
• Trastuzumab
4mg/kg IV loading dose followed by 2mg/kg IV weekly
• Paclitaxel
80mg/m2 IV weekly for 4 (21 day) cycles
• FEC75
5FU 500mg/m2 + Epirubicin 75 mg/m2 + cyclophosphamide 500 mg/m2 IV on day 1 of 4 (21 day) cycles
• 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

Locations

Country	Name	City	State
United States	GSK Investigational Site	Austin	Texas
United States	GSK Investigational Site	Beaumont	Texas
United States	GSK Investigational Site	Bedford	Texas
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Denver	Colorado
United States	GSK Investigational Site	El Paso	Texas
United States	GSK Investigational Site	Fountain Valley	California
United States	GSK Investigational Site	Henderson	Nevada
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Hudson	Florida
United States	GSK Investigational Site	Indianapolis	Indiana
United States	GSK Investigational Site	Lewisville	Texas
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Miami	Florida
United States	GSK Investigational Site	Norfolk	Virginia
United States	GSK Investigational Site	Pembroke Pines	Florida
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	Seattle	Washington
United States	GSK Investigational Site	Sugar Land	Texas
United States	GSK Investigational Site	Tyler	Texas
United States	GSK Investigational Site	Yakima	Washington

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Biomarker Protein Expression as it Correlates to Response/Non-response to Treatment	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.	Tumor core biopsy taken at Baseline and Treatment Day 14	No
Other	Cancer Stem Cells and the Correlation to Response/Non-response to Treatment	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.	Tumor core biopsy taken at Baseline and Treatment Day 14	No
Other	Transcriptional Profiling of Total RNA and the Correlation to Response/Non-response to Treatment	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.	Tumor core biopsy taken at Baseline and Treatment Day 14	No
Primary	Percentage of Participants With Overall Pathological Complete Response (pCR) After 26 Weeks of Therapy	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.	Week 26	No
Secondary	Percentage of Participants With Clinical Complete Response (cCR) at 26 Weeks or at End of Treatment (EOT) or Early Withdrawal	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.	Week 26 or EOT or Early withdrawal	No
Secondary	Disease-free Survival (DFS) up to 5 Years From First Dose or Until Disease Progression From Time of Surgery	DFS was defined as the date of definitive surgery until the date of disease recurrence.	Up to 5 years or until disease progression	No
Secondary	Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal	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.	Baseline and EOT (up to Week 26) or Early withdrawal	No
Secondary	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	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.	Weeks 3, 9, and 15; EOT or early withdrawal; and 3- and 6-month survival follow-up after last chemotherapy course	No
Secondary	Progression-free Survival (PFS)	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").	Up to 5 years or until disease progression	No