Lapatinib and Temozolomide for the Treatment of Progressive Brain Disease in HER-2 Positive Breast Cancer (LAPTEM)

Phase 1 Study of the Combination of Lapatinib and Temozolomide for the Treatment of Progressive Brain Disease in HER-2 Positive Breast Cancer

Objectives:

Primary - Determine the maximum tolerated dose (MTD) and evaluate the dose limiting toxicities (DLT) of combining lapatinib and temozolomideSecondary - Obtain preliminary information on the clinical anti-tumor activity of lapatinib plus temozolomide on brain metastases secondary to HER-2 positive breast cancer including Objective Response Rate (ORR), Clinical Benefit (CB) and Duration of Response (DR)

Methodology:

Phase I, single-centre, open-label, dose-escalation study of combining lapatinib and temozolomide in HER-2 positive breast cancer patients with progressive brain metastases after surgery or radiotherapy or radiosurgery

Treatment:

Temozolomide will be given orally for 5 days of every 28 days, at doses of either 100mg/m2/day or 150mg/m2/day or 200mg/m2/day AND Lapatinib will be given orally every day at either 1000mg/day or 1250mg/day or 1500mg/day.Sequential cohorts will be escalated in increments according to the dose escalation scheme, and determined by dose limiting toxicities.

Study Overview

• Status: Completed
• Conditions: Metastatic Breast Cancer; Brain Metastases; HER2 Positive
• Intervention / Treatment: Drug: lapatinib and temozolomide

Detailed Description

Patients selection criteria:

• age 18 - 70 years
• Women with cytologically or histologically proven metastatic breast cancer with recurrent / progressive brain metastases evaluable by MRI, after standard treatment with surgery (at least 3 weeks prior) or WBRT (at least 3 weeks prior) or stereotactic RT (at least 1 week prior); or otherwise deemed as unsuitable for standard treatment in the first instance
• Known HER-2 positive status (immunohistochemistry (IHC) 3+ Fluorescence In Situ Hybridization (FISH) positive )
• Previous chemotherapy (adjuvant and metastatic regimens) allowed
• Previous treatment with trastuzumab allowed (Trastuzumab to be discontinued prior to study entry)
• At least one measurable lesion in the brain, defined as any lesion >5mm in longest dimension on T1-weighted, gadolinium-enhanced MRI
• Expected life-expectancy of more than 3 months
• ECOG performance status of 0, 1 or 2
• Adequate bone marrow, renal and hepatic functionsLVEF
• LVEF 50% measured by echocardiography or MUGA scan
• Concomitant corticosteroids and anti-convulsants for symptomatic brain metastases are allowed

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1000
    • Jules Bordet Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• 18 - 70 years
• Women with cytologically or histologically proven metastatic breast cancer with recurrent / progressive brain metastases evaluable by MRI, after standard treatment with surgery (at least 3 weeks prior) or WBRT (at least 3 weeks prior) or stereotactic RT (at least 1 week prior); or otherwise deemed as unsuitable for standard treatment in the first instance
• Known HER-2 positive status (immunohistochemistry (IHC) 3+ Fluorescence In Situ Hybridization (FISH) positive )
• Previous chemotherapy (adjuvant and metastatic regimens) allowed
• Previous treatment with trastuzumab allowed (Trastuzumab to be discontinued prior to study entry)
• At least one measurable lesion in the brain, defined as any lesion >5mm in longest dimension on T1-weighted, gadolinium-enhanced MRI
• Expected life-expectancy of more than 3 months
• ECOG performance status of 0, 1 or 2
• Adequate bone marrow, renal and hepatic functionsLVEF
• LVEF >50% measured by echocardiography or MUGA scan
• Concomitant corticosteroids and anti-convulsants for symptomatic brain metastases are allowed

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: I; Lapatinib plus temozolomide	Drug: lapatinib and temozolomide; Temozolomide will be given orally for 5 days of every 28 days, at doses of either 100mg/m2/day or 150mg/m2/day or 200mg/m2/day AND Lapatinib will be given orally every day at either 1000mg/day or 1250mg/day or 1500mg/day.; Other Names: Tykerb

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Primary - Determine the maximum tolerated dose (MTD) and evaluate the dose limiting toxicities (DLT) of combining lapatinib and temozolomide	18 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Obtain preliminary information on the clinical anti-tumor activity of lapatinib plus temozolomide on brain metastases secondary to HER-2 positive breast cancer including Objective Response Rate, Clinical Benefit and Duration of Response	18 months

Collaborators and Investigators

• Sponsor: Jules Bordet Institute
• Collaborators: GlaxoSmithKline; Schering-Plough

Study record dates

Study Major Dates

• Study Start: January 1, 2008
• Primary Completion (Actual): June 1, 2011
• Study Completion (Actual): June 1, 2011

Study Registration Dates

• First Submitted: February 1, 2008
• First Submitted That Met QC Criteria: February 13, 2008
• First Posted (Estimate): February 14, 2008

Study Record Updates

• Last Update Posted (Estimate): September 19, 2012
• Last Update Submitted That Met QC Criteria: September 18, 2012
• Last Verified: June 1, 2011

More Information

Terms related to this study

• Keywords: HER-2 positive; brain metastases
• Additional Relevant MeSH Terms: Pathologic Processes; Central Nervous System Diseases; Nervous System Diseases; Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Neoplastic Processes; Central Nervous System Neoplasms; Nervous System Neoplasms; Breast Neoplasms; Neoplasm Metastasis; Brain Neoplasms; Brain Diseases; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Protein Kinase Inhibitors; Temozolomide; Lapatinib
• Other Study ID Numbers: LAP111172; EuDRACT 2007-005132-83