A Phase II, Randomized, Open-label Study of Lapatinib Plus Chemotherapy Versus Trastuzumab Plus Chemotherapy in HER2-positive and p95HER2-positive Metastatic Breast Cancer

Sponsor

GlaxoSmithKline (Industry)

Overall Status

Withdrawn

CT.gov ID

NCT01137994

Collaborator

(none)

Enrollment

Arms

Duration (Months)

Study Details

Study Description

Brief Summary

This is a Phase II, randomized, open-label, multi-center study evaluating the efficacy and safety of lapatinib in combination with chemotherapy versus trastuzumab in combination with chemotherapy in women with HER2-positive and p95HER2-positive metastatic breast cancer (MBC). Eligible subjects will have newly diagnosed metastatic breast cancer (Stage IV) either as a primary diagnosis or as a recurrence following treatment of curative intent; not have received systemic or local treatment for MBC and have breast cancer that is positive for HER2 and p95HER2. The primary objective is to compare progression-free survival (PFS) of lapatinib plus chemotherapy versus trastuzumab plus chemotherapy as first-line treatment in subjects with MBC exhibiting concurrent HER2 overexpression (and/or gene amplification) and expression of carboxy-terminal fragments of HER2 (p95HER2). The secondary objectives are to evaluate overall survival, overall response rate, clinical benefit response rate and the safety as well as tolerability of lapatinib plus chemotherapy and trastuzumab plus chemotherapy.

Condition or Disease	Intervention/Treatment	Phase
Neoplasms, Breast	Drug: Lapatinib Biological: Trastuzumab Drug: Docetaxel Drug: Paclitaxel Drug: Vinorelbine	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase II, Randomized, Open-label Study of Lapatinib Plus Chemotherapy Versus Trastuzumab Plus Chemotherapy as First-line Treatment for Women With HER2-positive and p95HER2-positive Metastatic Breast Cancer

Study Start Date :

Oct 1, 2011

Anticipated Primary Completion Date :

Dec 1, 2016

Anticipated Study Completion Date :

Mar 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lapatinib plus Chemotherapy Lapatinib (1250mg once daily) in combination with chemotherapy (docetaxel, paclitaxel or vinorelbine) selected at the discretion of the investigator	Drug: Lapatinib oral, reversible small molecule tyrosine kinase inhibitor of HER2 receptor Drug: Docetaxel Taxane chemotherapy Drug: Paclitaxel Taxane chemotherapy Drug: Vinorelbine Vinka alkaloid
Experimental: Trastuzumab plus Chemotherapy Trastuzumab (either 6mg/kg q3-weekly or 2mg/kg weekly) in combination with chemotherapy (docetaxel, paclitaxel or vinorelbine) selected at the discretion of the investigator	Biological: Trastuzumab monoclonal antibody directed to HER2 receptor Drug: Docetaxel Taxane chemotherapy Drug: Paclitaxel Taxane chemotherapy Drug: Vinorelbine Vinka alkaloid

Arm

Intervention/Treatment

Experimental: Lapatinib plus Chemotherapy

Lapatinib (1250mg once daily) in combination with chemotherapy (docetaxel, paclitaxel or vinorelbine) selected at the discretion of the investigator

Drug: Lapatinib

oral, reversible small molecule tyrosine kinase inhibitor of HER2 receptor

Drug: Docetaxel

Taxane chemotherapy

Drug: Paclitaxel

Taxane chemotherapy

Drug: Vinorelbine

Vinka alkaloid

Experimental: Trastuzumab plus Chemotherapy

Trastuzumab (either 6mg/kg q3-weekly or 2mg/kg weekly) in combination with chemotherapy (docetaxel, paclitaxel or vinorelbine) selected at the discretion of the investigator

Biological: Trastuzumab

monoclonal antibody directed to HER2 receptor

Drug: Docetaxel

Taxane chemotherapy

Drug: Paclitaxel

Taxane chemotherapy

Drug: Vinorelbine

Vinka alkaloid

Outcome Measures

Primary Outcome Measures

Progression-free survival [Time from randomization to disease progression]

Secondary Outcome Measures

Overall Survival [end of study]
Overall response rate (ORR: complete response [CR] or partial response [PR]) [end of study]
Clinical benefit response rate (CBR: CR or PR at any time, or stable disease [SD] >=24 weeks [end of study]
Safety and tolerability of lapatinib plus chemotherapy and trastuzumab plus chemotherapy [end of study]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Female ≥ 18 years of age
Histologically or cytologically confirmed invasive breast cancer with distant metastasis(ses) (designated as Stage IV or metastatic breast cancer)
Diagnosis with Stage IV or metastatic disease at either primary diagnosis or recurrence
Not received prior systemic or local treatment (e.g., chemotherapy, endocrine or radiotherapy) for Stage IV/metastatic breast cancer
Prior adjuvant and/or neo-adjuvant therapy is permitted
Documentation of HER2 overexpression or gene amplification, in the invasive component of either a metastatic disease site or primary tumor, defined as: 3+ by IHC and/or HER2/neu gene amplification by fluorescence, chromogenic or silver in situ hybridization [FISH, CISH or SISH; >6 HER2/neu gene copies per nucleus or a FISH, CISH or SISH test ratio (HER2 gene copies to chromosome 17 signals) of ≥2.0]
Documentation by the central laboratory of positive p95HER2 expression in the invasive component of either a metastatic disease site (preferred) or primary tumor
No history of CNS metastases (including leptomeningeal involvement) or stable CNS metastases (defined as asymptomatic and off steroids for ≥ 3 months)
Baseline Left Ventricular Ejection Fraction (LVEF) ≥50% measured by echocardiography (ECHO) or multi-gated acquisition scan (MUGA)
Recovered or stabilized from all adverse events associated with prior anti-cancer therapies, including radiotherapy, at the time of screening
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
Have adequate marrow and organ function as defined as:

SYSTEM LABORATORY VALUES Hematologic ANC ≥1.5 x 109/L Hemoglobin ≥9 g/dL (after transfusion if needed) Platelets ≥100 x 109/L Hepatic Albumin ≥ 2.5 g/dL Serum bilirubin ≤1.5 x ULN unless due to Gilbert's syndrome AST and ALT ≤3 x ULN Renal Calculated creatinine clearance ≥ 40 mL/min Serum Creatinine ≤1.5 mg/dL or 132.6µmol/L (Abbreviations: ANC, absolute neutrophil count; ULN, upper limit of normal; AST, aspartate aminotransferase; ALT, alanine aminotransferase)

Women of childbearing potential, including women whose last menstrual period was <12 months ago (unless surgically sterile) must have a negative serum pregnancy test and agree to use effective contraception, as defined in protocol
Signed Informed Consent Form

Exclusion Criteria:

History of other malignancy. Exception: Subjects who have been disease-free for 5 years or subjects with a history of completely resected non-melanoma skin cancer (basal or squamous) are eligible
Concurrent anti-cancer treatment or concurrent treatment with an investigational drug
Administration of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment
Prior treatment with anti-HER2 therapy, except trastuzumab or lapatinib (time from last dose of trastuzumab or lapatinib to randomization must be ≥3 months)
Serious cardiac illness or medical condition including but not confined to:
Uncontrolled arrhythmias
Uncontrolled or symptomatic angina
History of congestive heart failure (CHF)
Documented myocardial infarction <6 months from study entry
Current active hepatic or biliary disease (with exception of Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
Concurrent disease or condition, or any pre-existing medical disorder that in the opinion of the investigator may interfere with the subject's safety, obtaining informed consent or compliance to the study procedures
Pregnant or lactating female
Any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels (consult with GSK Medical Monitor if uncertain about eligibility)
Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to any of the study drugs or their excipients that, in the opinion of the investigator contra-indicates participation