A phase 1 dose-escalation study of the safety and pharmacokinetics (PK) of XL184, a VEGFR and MET kinase inhibitor, administered orally to patients (pts) with advanced malignancies

A152 Background: XL184 is an orally bioavailable small molecule inhibitor of MET and VEGFR2/KDR that also inhibits RET, KIT, FLT3, and Tie-2 both in vitro and in vivo in preclinical models. Significant tumor growth inhibition was observed following XL184 treatment in preclinical tumor models of human breast and lung cancer, and rat glioma. In addition, XL184 strongly inhibits cell proliferation in gastric or medullary thyroid cancer (MTC) cell lines harboring activated or overexpressed MET or activated RET. Preclinical single-dose pharmacodynamic studies with XL184 demonstrate substantial inhibition of RET phosphorylation in TT (MTC model) xenograft tumors. Methods: Pts with advanced malignancies were treated with XL184 orally daily for 5 days followed by a 9-day non-treatment period (intermittent “5 & 9” schedule; cohorts (C) 1-9), or with continuous daily dosing (C 10 and beyond). The initial dosing was based on body weight and then amended to flat dosing. Response is assessed after the first 2 cycles and every 8 wks thereafter by RECIST criteria. Pts with stable disease (SD) or better may continue to receive treatment. Plasma markers reflecting effects of anti-angiogenic therapy are being analyzed. Results: A total of 38 pts with advanced malignancies have been treated across 11 dose levels: 0.08 to 11.52 mg/kg on a 5 & 9 schedule (C1-9), and 175 (C10) and 265 mg (C11) PO QD. DLTs include grade 3 palmar/plantar erythema, and grade 3 elevations in AST, ALT and lipase, occurring at 11.52 mg/kg 5 & 9, and grade 2 mucositis in a pt dosed at 265 mg PO QD that resulted in dose reduction. Twenty-three of the 33 pts included in the most recent data transfer/analysis had no reported XL184-related toxicities of greater than grade 1. Preliminary PK analysis (0.08-11.52 mg/kg) suggests linear PK; the terminal half-life is 58-136 hrs. Pharmacodynamic analysis of plasma samples showed a trend towards increased VEGF-A and placenta growth factor as well as slightly reduced sVEGFR2 levels, demonstrating a pharmacological effect of XL184 on VEGF pathway biomarkers. Three patients have had partial responses (2 confirmed, MTC; 1 unconfirmed, neuroendocrine cancer originating in the thyroid). Of the 14 pts who have had SD ≥3 months, 9 pts have had SD ≥ 6 months including 1 pt with carcinoid (20% decrease in liver metastases) and 1 pt with cutaneous T-cell lymphoma (on treatment for >18 mos). One pt with papillary renal cell cancer, a disease in which a subset of cases harbor mutations in MET, has demonstrated 15% tumor reduction to date. Four of 5 pts with MTC (two of whom had a documented RET mutation) had substantial reductions in plasma calcitonin and CEA; 1 pt with MTC is too early to evaluate. Conclusions: XL184 appears generally well tolerated at doses tested to date. XL184 has a long terminal half-life and QD dose escalation continues to define the daily dosing MTD. Antitumor activity has been observed in pts with various cancers, including but not limited to those that may have genetic alterations in RET (medullary thyroid) or MET (papillary renal).