Abstract OT1-04-02: NRG oncology/RTOG 1119: Phase II randomized study of whole brain radiotherapy with concurrent lapatinib in patients with brain met from HER2-positive breast cancer — A collaborative study of RTOG & KROG (NCT01622868)
Authors: White JR , Moughan J , Kim IA , Peereboom DM , De Los Santos JF , Sperduto PW , Mehta MP 
Published: March 2017

Abstract
Background: The addition of trastuzumab to cytotoxic chemotherapy has improved outcomes for patients (pts) with HER2+ breast cancer. Increased survival coupled with limited blood-brain barrier (BBB) penetration of trastuzumab may contribute to the increased incidence of brain metastases (mets) in these pts. Half of these pts die of intracranial disease progression rather than extracranial systemic disease. Therefore, strategies to improve survival must include increased CNS disease control. Lapatinib crosses the BBB & demonstrates modest activity against intracranial mets. Based upon preclinical data & phase I study results, it's hypothesized that lapatinib plus whole brain radiotherapy (WBRT) can improve the intracranial disease control compared to WBRT alone.
Trial design: A randomized phase II trial that will evaluate if there is a sufficient enough signal in improved 12-week complete response (CR) rate following WBRT with the addition of lapatinib vs. WBRT alone in pts with mets from HER2+ breast cancer to warrant a future phase III trial. An amendment to allow protocol RT to be delivered as WBRT or stereotactic radiosurgery (SRS) is in process.
Eligibility Criteria: Eligibility includes HER2+ breast cancer with at least one measurable, unirradiated parenchymal brain met (≥10 mm if solitary, & &gt; 5 mm if multiple on enhanced MRI). The two populations targeted for accrual include pts with 1) newly diagnosed, multiple brain mets or 2) progressive brain mets after SRS or surgical resection of 1-3 mets. Pts are stratified by breast-specific graded prognostic assessment; use of non-CNS penetrating HER2 targeted therapy; & prior SRS or surgical resection. Non-CNS penetrating HER2 targeted therapy is permitted throughout the study, but ptsnot on trastuzumab, pertuzumab or any other breast cancer therapy at study entry are not permitted to begin this therapy while on protocol treatment, but may begin it 24 hours after its completion. Prior lapatinib is allowed, last dose &gt; 21 days prior to study entry.
Specific aims: Primary objective is to determine if there is an increase in CR rate in the brain at 12weeks post WBRT as determined by MRI scan of the brain, with the addition of lapatinib to WBRT vs. WBRT alone. Secondary objectives includes: CR rate at 4 weeks on MRI post WBRT, objective response rate on MRI at 4 & 12 weeks, evaluation of lesion specific MRI response rates; CNS progression-free survival rate, overall survival rate, & adverse event rates.
Statistical methods: The randomization of experimental & control arms is set as 1:1. With 114 eligible pts there will be 86% power to detect a 15% absolute increase in CR rate at a significance level of 0.10, using a 1-sided Z-test for 2 proportions. Targeted accrual is 143 accounting for up to a 5% ineligibility rate, 15% pts not evaluable for the primary endpoint due to death, pt withdrawal, or other reasons.
Activated:7/26/2012. Present accrual (5-1-2016): 85. Targeted accrual: 143.
Contact Information:
Protocol: CTSU member web site https://www.ctsu.org. Enrollment: OPEN at https://open.ctsu.org.
Supported by NCI U10 grants CA21661, CA180868, CA180822, CA37422 & UG1CA189867.
Citation Format: White JR, Moughan J, Kim IA, Peereboom DM, De Los Santos JF, Sperduto PW, Mehta MP. NRG oncology/RTOG 1119: Phase II randomized study of whole brain radiotherapy with concurrent lapatinib in patients with brain met from HER2-positive breast cancer — A collaborative study of RTOG & KROG (NCT01622868) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-04-02.