Phase I/IB multicenter study of afatinib in combination with capecitabine in patients (pts) with refractory solid tumors and pancreatico-biliary cancers.

TPS515 Background: The epidermal growth factor receptor (EGFR)/HER2 pathway is overactive in several solid tumors, including gastroesophageal, hepatic, colorectal, and pancreatico-biliary cancers. Afatinib is an irreversible inhibitor of the Erb family approved for metastatic non-small cell lung cancer with EGFR mutations. Afatinib downregulates thymidine synthase (TS) the intracellular target of fluoropyrimidine chemotherapy such as capecitabine. Treatment of colorectal cancer cell lines with cytotoxic drugs can up-regulate EGFR expression, and increase sensitivity to EGFR inhibition. Based on this preclinical rationale, and given that capecitabine is commonly used in refractory gastrointestinal cancers, we have developed a phase I/Ib trial to evaluate the safety and maximum tolerated dose (MTD) of afatinib with capecitabine in advanced solid tumors, and assess preliminary antitumor activity in pts with refractory pancreatico-biliary cancers at MTD. Methods: Eligible pts have metastatic solid tumors (phase I) or pancreatico-biliary cancers (phase Ib), ECOG PS 0-2 (PS 0-1 phase Ib), any number of prior therapies (phase I), or ≤ 2 prior therapies (phase Ib), no prior erlotinib (phase Ib), and have archived paraffin embedded tumor tissue, or ability to undergo tumor biopsy at baseline. Tumor tissue is analyzed with UW-OncoPlex, a multiplexed gene sequencing panel of 200+ cancer-related genes, to identify predictive biomarkers of benefit. The study design is standard “3+3”. Afatinib is administered orally (PO) daily (QD) in escalating doses of 20, 30 and 40 mg, with capecitabine at 1000 mg/m 2 PO BID Days 1-14, in 21-day cycles (C). Dose limiting toxicity (DLT) is assessed in C1. Once the MTD is identified, the phase Ib expansion cohorts will enroll 15 pts each with refractory pancreatic and biliary cancers, with afatinib dosed at MTD and standard dose capecitabine. The study was activated in November 2015, and to date 4 pts were enrolled in cohort 1, 3 pts in cohort 2, and 2 pts in cohort 3. The phase I is ongoing and the phase Ib is expected to start enrollment in December 2016. Clinical trial information: NCT02451553.