Defining the HER2 Positive (+) Breast Cancer Kinome Response to Trastuzumab, Pertuzumab, Combination Trastuzumab +Pertuzumab, or Combination Trastuzumab + Lapatinib

Breast Neoplasms Clinical Trial

Official title: Defining the HER2 Positive (+) Breast Cancer Kinome Response to Trastuzumab, Pertuzumab, Combination Trastuzumab +Pertuzumab, or Combination Trastuzumab + Lapatinib

Status Completed

Clinical Trial Summary

Kinases are a group of proteins that are important in how cancer cells grow. HER2 is a kind of kinase. This study looks at a new approach to identifying kinases, which may help target therapy more precisely.

LCCC1214 is a randomized, multiarm, multicenter, open-label window trial designed to explore the kinome response in Stage I-IV HER2 positive (HER2+) breast cancer patients scheduled to undergo definitive surgery (either lumpectomy, mastectomy or surgical resection of oligometastatic disease). Patients will initiate dosing with either a single HER2-directed agent or a combination of two HER2-directed agents, one week prior to surgery. Forty patients will be randomized to one of four study groups:

A) single dose trastuzumab; B) single dose pertuzumab; C) combination single dose trastuzumab plus single dose pertuzumab; or D) combination single dose trastuzumab plus lapatinib daily for 7 days.

Pre- and post- dosing tissue will be analyzed for kinome response and resistant signatures. The initiation of study drug will be defined by the surgical schedule; there will be no delays in standard treatment for the purposes of this study.

Clinical Trial Description

Until recently, our understanding of the kinome has been limited to just 5-10% of the genome-encoded kinases. This limited knowledge prevents a thorough understanding of resistance mechanisms, and precludes individualizing HER2-targeted therapy in HER2+ disease. Fortunately, we have now developed a chemical proteomics approach to define comprehensive kinome activity in cells and tumors (MIB/MS).[1]

We hypothesize that our proteomics approach can be used to characterize the heterogeneity of the kinome activation profiles in HER2+ breast cancer and permit us to identify if adaptive response to HER2 inhibition differs depending on the anti-HER2 drug mechanism of action. This will allow rational prediction of new combinatorial therapies in future clinical trials.

To explore kinome activation in this population, we propose a window trial in stage I-IV HER2+ patients scheduled to undergo definitive surgery (either lumpectomy, mastectomy or surgical resection of oligometastatic disease). Enrolled patients will be randomized to one of four treatment arms; A) single dose trastuzumab; B) single dose pertuzumab; C) combination trastuzumab + pertuzumab for one dose each; or D) combination single dose trastuzumab plus lapatinib daily for one week.

Dosing in each arm will be initiated 7 days prior to surgery, with pre- and post-dosing tissue samples analyzed for kinome response and resistant signatures. To ensure adequate levels of trastuzumab and pertuzumab at the time of surgery, a loading dose of each agent (8 mg/kg IV for trastuzumab, and 840 mg IV fixed dose for pertuzumab) were chosen. The dose of lapatinib was based on prior studies of lapatinib administered in combination with trastuzumab. Given the varied pharmacokinetic profiles of the three agents and limited dosing, we expect exposure levels of the agents to be different relative to respective steady state levels. Therefore qualitative rather than quantitative measures will be key. ;

Related Conditions & MeSH terms

• Breast Neoplasms

• NCT number: NCT01875666
• Study type: Interventional
• Source: UNC Lineberger Comprehensive Cancer Center
• Status: Completed
• Phase: Early Phase 1
• Start date: August 5, 2013
• Completion date: December 19, 2016