Abstract
TGF-&bgr; signaling plays an important role in tumorigenesis and contributes to the hallmarks of cancer, including tumor proliferation, invasion and metastasis, inflammation, angiogenesis, and escape of immune surveillance. Galunisertib (LY2157299 monohydrate) is an oral small molecule inhibitor of the TGF-&bgr; receptor I kinase that specifically down-regulates the phosphorylation of SMAD2, abrogating activation of the canonical pathway. Programmed Cell Death-1 (PD-1) is expressed on activated T cells and can act to dampen the immune response. Tumor cells overexpress PD-1 ligand (PD-L1) and inhibit the local immune response. Nivolumab blocks the binding of PD-L1 to its PD-1 receptor, allowing the activated T cells to identify and attack cancer cells. Thus, blockade of both TGF-&bgr; and PD-1 could be expected to reverse the immune escape and to potentially provide immune restoration to improve immune response and induce tumor regression. Trial design: This study (NCT02423343) is a phase 1b/2 open-label study that will be conducted in 2 parts. The phase 1b is an open-label, dose-escalation assessment of the safety and tolerability of galunisertib administered in escalating doses over 4 cohorts ending with 150 mg BID in combination with nivolumab 3 mg/kg IV every 2 weeks in patients with advanced refractory solid tumors. The phase 2 will be disease restricted and includes 3 expansion cohorts of patients with non-small cell lung cancer (n = 25), hepatocellular carcinoma (n = 25), or glioblastoma (n = 25). Patients in the 3 cohorts will be assigned to treatment concurrently, and enrollment will be complete when all cohorts have reached the prespecified enrollment target. Enrollment of patients in phase 1b began on 09 October 2015; as of 27April2016, seven patients entered the study; one withdrew for a non-DLT reason, and one patient remains on treatment every 2 weeks. Clinical trial identification: NCT02423343 Legal entity responsible for the study: Eli Lilly and Company
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