Abstract OT1-1-13: A phase II study with lead-in safety cohort of cabazitaxel plus lapatinib as therapy for patients with HER2-positive metastatic breast cancer (MBC) and intracranial metastases
Authors: Yardley DA , Hainsworth JD , Hamilton E , Hart LL , Shastry M , Finney L , Burris HA 
Published: August 2014

Abstract
Background: HER2-targeted therapy has improved the progress of patients (pts) with HER2-positive breast cancer; however, CNS metastases remain a significant source of morbidity and mortality. It is hypothesized that the inability of drugs like trastuzumab to cross the intact blood-brain barrier (BBB) may render the CNS as a sanctuary site for metastases. Lapatinib is an oral small molecule tyrosine kinase EGFR1/HER2 inhibitor that crosses the BBB and has activity against CNS metastases. Cabazitaxel is a new taxoid that is active in docetaxel- or paclitaxel-resistant breast cancer, and differs from other taxanes in its ability to cross the BBB. The promising systemic activity shown by cabazitaxel in taxane-resistant MBC coupled with the CNS penetrance of both cabazitaxel and lapatinib make this an attractive combination to evaluate in HER2-positive MBC pts with CNS metastases.
Study Objectives: The primary objectives of the study are to determine the safety and CNS objective response rate (ORR = CR+PR) in HER2-positive MBC pts with CNS metastases when treated with cabazitaxel and lapatinib. The secondary objectives include evaluation of the clinical benefit rate (CBR), 3- and 6-month PFS rate for CNS metastases, and response rate and CBR for extra-cranial metastases.
Key eligibility: Pts &gt;18 yrs with HER2-positive (IHC 3+ or FISH/SISH-positive) MBC and unequivocal evidence of brain metastases are eligible. Additional eligibility criteria include: at least one measurable brain lesion &gt;1.0cm in longest dimension on MRI; pts with brain lesions previously treated with WBRT and/or SRS must have at least one intra-cranial lesion &gt;1.0cm not treated with SRS and must have evidence of intra-cranial progressive disease. Pts must have received at least 1 prior HER2-directed therapy in the adjuvant or metastatic setting; pts without prior chemotherapy for MBC are eligible if they progressed during or within 6 months of adjuvant therapy. Otherwise, there is no specific minimum or maximum number of previous chemotherapy regimens for MBC. ECOG performance status 0-2, adequate renal, bone marrow, and hepatic function are required; prior treatment with cabazitaxel or lapatinib (for MBC) not permitted.
Trial design: This is an open-label, non-randomized, phase II study with a lead-in safety cohort. During the lead-in phase, 6-15 pts will be treated in cohorts of 3 with increasing doses of cabazitaxel and lapatinib to determine the tolerability and optimal dose. Once the safety and dose is confirmed, subsequent pts will be treated at the optimal dose of the 2 agents. Each treatment cycle is 3 weeks and restaging will occur systemically and intra-cranially every 2 cycles for the first 8 cycles and every 3 cycles thereafter until progressive disease or unacceptable toxicity.
Statistical methods: We hypothesize that the addition of cabazitaxel will increase the CNS ORR from 6% (expected with single agent lapatinib) to ≥20% in this pt population. Treatment of 27 evaluable pts with the identified phase II doses will detect this difference with a power of 80% and alpha = 10% (one-sided test). Accounting for a 10% inevaluable rate and lead-in pts, a total of 45 pts will be enrolled on the study.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-1-13.