Trial of Ibrutinib Plus Trastuzumab in HER2-amplified Metastatic Breast Cancer

Ado-trastuzumab emtansine (T-DM1) is approved by the FDA for patients with HER2-positive metastatic breast cancer (MBC) previously treated with a taxane and trastuzumab, and is currently listed as the preferred second-line therapy in the NCCN guidelines (NCCN 2014). While the benefit of continued HER2 inhibition has been conclusively established for disease that has progressed on a trastuzumab-containing regimen, there are currently no data regarding the efficacy of HER2- targeted therapies following progression on T-DM1. With the population of T-DM1-treated patients steadily growing, clinical trials are needed to investigate novel therapies in this setting,to meet the medical need for effective, evidence-based therapies for these patients. The oral small-molecule Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib has also demonstrated the ability to inhibit erythroblastosis virus oncogene B (ErbB)/HER receptor family kinases in preclinical studies at clinically relevant concentrations, with an equivalent or greater potency than other HER2-directed tyrosine kinase inhibitors (TKIs) with demonstrated activity in HER2-positive MBC, including lapatinib, neratinib, and afatinib. Of note, in preclinical HER2-positive cell model systems the growth inhibitory ability of ibrutinib was substantially greater in HER2-amplified breast cancer cells versus those that simply overexpressed the HER2 protein. Ibrutinib is currently approved for use in patients with Chronic lymphocytic leukemia (CLL) or Mantle cell lymphoma (MCL), and has an established safety record from clinical trials in these patient populations. Thus there is a reasonable rationale to investigate ibrutinib in patients with HER2- amplified MBC, in the setting of T-DM1-pretreated disease. Previous studies have demonstrated that combined targeting of HER2 with multiple HER2-directed agents is more effective that single agent therapy and therefore this study will explore the safety and efficacy of ibrutinib in combination with trastuzumab. This is a Phase I/II, open-label, unblinded, nonrandomized, standard 3+3 dose-escalation study designed to evaluate the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of ibrutinib (560 or 840 or 420 mg QD) given orally in combination with trastuzumab (8 mg/kg loading dose followed by 6 mg/kg q3w) administered intravenously (IV) in patients with HER2-amplified MBC that has progressed on prior therapy with ado-trastuzumab emtansine. Once the recommended phase II dose of ibrutinib plus trastuzumab has been determined (no more than 1 of 6 patients with dose-limiting toxicity) in the required 6 to 18 patients over the 3 possible dose levels, additional patients will be enrolled on the phase II part of the study at the recommended phase II dose of ibrutinib plus trastuzumab, for a maximum of 51 patients total.