Abstract OT1-02-08: A phase II single arm trial to assess the efficacy of ASLAN001 plus capecitabine in previously irradiated, progressing central nervous system (CNS) metastases for HER2+ breast cancer patients
Authors: Lee GE 
Published: March 2017

Abstract
Brain metastasis in breast cancer (BMBC) has always been associated with very poor prognosis with no current standard of treatment. Treatment options generally involve local control. Subsequent to local treatment, systemic control can be re-initiated via systemic therapies or trial participation. ASLAN001 has been shown to be active in pre-clinical tumor models. It is a potent, specific, adenosine triphosphate competitive inhibitor of the tyrosine kinases of the cell surface receptors (HER)-1, HER-2, and HER-4. It also has a pre-clinical safety profile consistent with its known pharmacology. A Phase 1 study using ASLAN001 in combination with capecitabine showed a response rate of 38% in 20 HER2+ breast cancer patients.
This is a single arm phase II study. 29 patients with previously irradiated, progressing brain metastases in Her2 positive breast cancer will be enrolled to receive ASLAN001 (400mg bd daily) and capecitabine (1000mg/m2 bd per day for day 1-14 of 21 day cycle). Treatment will continue until disease progression or unacceptable toxicity. Baseline brain imaging using either Magnetic resonance imaging (MRI) will be performed, with follow-up scans repeated every 2 cycles until progression. Non-brain imaging will also be performed at the same settings.
Specific Aims:
Evaluate the efficacy of ASLAN001 in combination with capecitabine in terms of CNS response
Evaluate the activity (clinical benefit) of ASLAN001 in combination with capecitabine in systemic disease (outside CNS)
Evaluate the tolerability of ASLAN001 in combination with capecitabine
Eligibility:
HER2 positive breast cancer patients with previously irradiated, progressing brain metastases.
Previously irradiated CNS metastases (WBRT or SRS or both).
Adequate end organ function.
No prior exposure to either lapatinib or capecitabine
Statistical Design:
In order to minimize the expected number of patients treated in the event that the regimen proves to be very disappointing or very successful; a two-stage design will be used for patient accrual (Simon 1989).
Stage 1 of accrual: 10 response evaluable patients will be entered in the first stage. Using response hypothesis of H0&lt;5% and Ha&gt;20%, we would reject the drug combination at the end of the first stage of accrual if less than 1 response was observed.
Stage 2 of accrual: Additional 19 patients will be accrued. We would accept the drug combination as active if 4 or more objective responses are observed from a total of 29 patients accrued.
Significance level and power: To test the null hypothesis that the response rate is &lt;5% and rejects this in favour of the alternative hypothesis of response rate is &gt;20%. The significance level (i.e., the probability of rejecting H0 when it is true) is α=5% (1-tailed) and the power (i.e., 1-beta, the probability of deciding the regimen is active) is 80%. The expected sample size with this design is 29 using the optimal design criterion of Simon's two-stage method. At stage 1 (10 patients), at least 1 response needs to be seen in order to initiate stage two with the remainder of 19 patients. The trial will be positive if at the end 4 responses will be seen in the 29 patients.
Citation Format: Lee GE. A phase II single arm trial to assess the efficacy of ASLAN001 plus capecitabine in previously irradiated, progressing central nervous system (CNS) metastases for HER2+ breast cancer patients [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 OT1-02-08.