Abstract P4-14-24: Optimization of intermittent high dose lapatinib administration with or without capecitabine: A rational approach to drug dosing and scheduling using Norton-Simon modeling
Authors: Morikawa A , De Stanchina E , Patil S , Chandarlapaty S , Li BT , Norton L , Seidman AD 
Published: May 2016

Abstract
Background: Systemic treatment of central nervous system (CNS) metastases remains a challenge partially due to poor drug penetration. Lapatinib and capecitabine are drugs with modest efficacy in treatment of brain metastases from HER2-positive (+) breast cancer (BC) and were shown to cross the blood-tumor barrier in clinical craniotomy specimens (Lin N et al., CCR 2009, Morikawa A et al., Neuro Oncol 2015). However, intratumoral drug concentrations observed were sub-optimal and heterogeneous. Administration of shorter-duration, high dose tyrosine kinase inhibitor is proposed as a way to improve efficacy and tolerability based on Norton-Simon modeling and drug exposure in the CNS (Traina T et al., JCO 2008, Grommes C et al., Neuro Oncol 2011, Chien AJ et al., J Clin Oncol 2014) . In this study, we examined optimization of high dose lapatinib administration with or without capecitabine to inform the design of a phase I trial for BC patients with HER2+ CNS metastases.
Methods: Mice bearing BT-474 BC xenograft tumors were treated with various lapatinib doses and schedules. A standard continuous daily dose (100mg/kg) was compared to various intermittent dosing schedules (at 100mg/kg, 400mg/kg, and 800mg/kg). In addition, high dose lapatinib (800mg/kg) was administered with capecitabine either concurrently or in tandem. Xenografts were treated when tumors reached 100mm3. Tumor volumes were evaluated for antitumor efficacy, and mice weights were measured for toxicity. Significance testing for between-group comparisons was conducted using a mixed effect model for repeated measures.
Results: Intermittent schedules of lapatinib at 100mg/kg given as 3 days on/11 days off (3/11), 5 days on/9 days off (5/9), and 7 days on/7days off (7/7) had a similar efficacy in tumor control: percent change in tumor volume of 225% (7/7), 222% (5/9), and 223% (3/11) (NS). Therefore, the 3 days on (with 4 days off or 11 days off ) schedule was subsequently chosen to evaluate for tolerability and antitumor efficacy of higher lapatinib dose. The 3 days on/4 days off (3/4) group at 800mg/kg demonstrated the highest tumor reduction (-69%) compared to the daily continuous dosing group (-18%) (p=0.04), but a trend toward higher toxicity was observed (p=0.12). Evaluation of concurrent vs. tandem administration of capecitabine with lapatinib at 800mg/kg given in 3 days on/11 days off was conducted. The concurrent treatment was discontinued early due to high toxicity. However, tandem administration of capecitabine with high dose lapatinib was tolerable without a significant difference in weight changes (p=0.62).
Conclusions: The intermittent schedule allows delivery of high dose lapatinib, which has better anti-tumor activity than standard continuous dosing. If given intermittently, high dose lapatinib is tolerable, even with capecitabine if given in tandem/sequence. Based on the result of these experiments, a phase I trial of high dose lapatinib using 3 days on/11 days off schedule in tandem with capecitabine is currently proposed for treatment of HER2-positive BC patient with CNS metastases.
Citation Format: Morikawa A, De Stanchina E, Patil S, Chandarlapaty S, Li BT, Norton L, Seidman AD. Optimization of intermittent high dose lapatinib administration with or without capecitabine: A rational approach to drug dosing and scheduling using Norton-Simon modeling. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-24.