Clin Cancer Res
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This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of the investigational oral drug MLN8237 (alisertib), a small-molecule Aurora A kinase (AAK) inhibitor, in 87 adult patients with advanced solid tumors. ⋯ This first-in-human trial of MLN8237 showed tolerability and favorable pharmacokinetics in this patient population. The recommended phase II dose of MLN8237 is 50 mg twice daily orally for 7 days in 21-day cycles, which is being evaluated further in the treatment of various solid tumors and hematologic malignancies.
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Oncogenic gene fusions involving the 3' region of ROS1 kinase have been identified in various human cancers. In this study, we sought to characterize ROS1 fusion genes in non-small cell lung cancer (NSCLC) and establish the fusion proteins as drug targets. ⋯ ROS1 inhibition may be an effective treatment strategy for the subset of patients with NSCLC whose tumors express ROS1 fusion genes.
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This phase I study assessed the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetics, pharmacodynamics, and clinical activity of the first-in-class dual MEK/RAF inhibitor, RO5126766. ⋯ This first-in-human study shows that oral RO5126766 has manageable toxicity, a favorable pharmacokinetic/pharmacodynamic profile, and encouraging preliminary antitumor activity in this population of heavily pretreated patients, achieving tumor shrinkage in around 40% of patients across all dose levels and all tumor types.
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Carfilzomib is a next-generation, selective, proteasome inhibitor with clinical activity in relapsed and/or refractory multiple myeloma. The objectives of this phase I study were to establish the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of escalating doses of carfilzomib in patients with relapsed or refractory hematologic malignancies. ⋯ Escalated dosing of carfilzomib on a schedule of 2 consecutive days for 3 weeks of a 4-week cycle was tolerable and showed promising activity. This dose regimen has been selected for ongoing and future clinical studies, including PX-171-003A1 and the pivotal trial ASPIRE.
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This phase I study of the mitogen-activated protein/extracellular signal-regulated kinase inhibitor RO4987655 (CH4987655) assessed its maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetic/pharmacodynamic profile, and antitumor activity in patients with advanced solid tumors. ⋯ In this population of heavily pretreated patients, oral RO4987655 showed manageable toxicity, a favorable pharmacokinetics/pharmacodynamics profile, and promising preliminary antitumor activity, which has been further investigated in specific populations of patients with RAS and/or RAF mutation driven tumors.