A Phase I Study of Ombrabulin (O) Combined with Bevacizumab (B) in Patients with Advanced Solid Tumors
Journal of clinical oncology(2013)
摘要
2535 Background: O, a vascular-disrupting agent derived from combretastatin A4-phosphate, induces rapid tumor vascular shutdown via endothelial cell damage. Resistance to O may occur by surges in circulating endothelial progenitors (CEP) that repopulate the tumor vasculature. Experimental models suggest prolonged and synergistic antitumor activity when O is combined with VEGF-blockade, with reduction in CEP surge. This phase I study was performed to determine the maximum tolerated dose, safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of O combined with B. Methods: Patients (pts) with advanced treatment-refractory solid tumors, ECOG PS ≤1, and adequate organ function were eligible. O (mg/m²) was administered intravenously (IV) on day (d)1 with B (mg/kg) IV on d2 in 21d cycles (C). A Bayesian model informed dose escalation steps. PK sampling, dynamic contrast-enhanced ultrasound (DCE-US) for tumor perfusion, and CEP samples were collected. Results: 39 pts (M:F 10:29; median age 51 years [range 25-75]) were treated at 12 dose levels combining O [8 to 50mg/m2] with B [5, 10, or 15mg/kg]. Ovary (16/39, 41%) and colon (4/39, 10%) were the most common primary sites. No C1 dose-limiting toxicities occurred in 37 evaluable pts. Drug-related grade 3-4 treatment emergent adverse events (AE) were hypertension (6/39, 15%), intestinal perforation (2/39, 5%), headache (1/39, 3%), myocardial infarction (1/39, 3%), and pulmonary embolism (1/39, 3%). 36 pts (14 ovarian) were evaluable for response by RECIST 1.1. Antitumor activity was observed at O 20mg/m2+ B 10mg/kg and above, with confirmed partial responses in 2/14 pts with ovarian primary (14%), CA125 responses in 2 further ovary/endometrial cancers lasting ≥ 6 months, and stable disease in 15/36 pts (42%) lasting ≥ 6 months in 3 pts. PK indicated no interactions of O+B. Analyses of CEP levels post O and paired DCE-US data are ongoing. Conclusions: The maximum administered dose (MAD) was O 50mg/m2 with B 15mg/kg, with no dose-limiting toxicities and vascular toxicity that was manageable. Promising antitumor activity was observed at doses below the MAD and warrants further evaluation. Clinical trial information: NCT01193595.
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