Phase I study combining MLN8237 with nab-paclitaxel in patients with advanced solid malignancies

2553 Background: MLN8237 is a potent Aurora A kinase inhibitor which synergizes with paclitaxel in preclinical studies for various solid malignancies. Methods: We conducted a two-part, phase 1 study combining MLN8237 with nab-paclitaxel in patient with advanced, refractory solid malignancies (NCT01677559). The part 1, dose-escalation phase utilizes a standard a 3+3 design for determination of maximum tolerated dose (MTD) and dose limiting toxicities (DLTs), starting from nab-Paclitaxel 100mg/m2/week 3 out of a 4-week cycle, and MLN8237 20mg BID D1-3/week (denoted nP/M 100/20). In the part 2, dose-expansion cohort, patients with advanced pancreatic ductal adenocarcinoma (PDAC) or high grade neuroendocrine tumor (pNET) who progressed on standard chemotherapy were enrolled. Results: Totally 33 patients (17 in part 1 and 16 in part 2) with a median age of 61 were enrolled. In part 1, the most frequent treatment-related toxicities (all Grade/Grade 3-4) were: nausea (65%/6%), neutropenia (61%/18%), fatigue (47%/6%), anorexia (47%/0%), oral mucositis (53%/6%) and anemia (35%/18%). Two of 3 patients experienced a DLT at dose nP/M 100/50 (Grade 4 neutropenia; febrile neutropenia). No treatment-related mortality occurred. MTD was set at nP/M 100/40 for part 2. At data cutoff, totally 20 patients from the entire study were evaluable for treatment response. One patient with small cell lung cancer achieved partial response and is in cycle 29. Nine other patients (9/20, 45%) with the following tumor histology achieved stable disease after two cycles: 1 small cell lung cancer, 1 lung neuroendocrine carcinoma, 1 lung squamous cell carcinoma, 1 PDAC and 5 high grade pNET (range: 3 and ongoing ~ 18 cycles). Conclusions: MLN8237 plus nab-paclitaxel has manageable side effect profile with very promising activity in tumors with high grade neuroendocrine features, warranting further testing. Exploratory studies on pharmacodynamic markers are ongoing. Clinical trial information: NCT01677559.