Roy S. Herbst

Phase I Trial of the Oral Antiangiogenesis Agent AG-013736 in Patients With Advanced Solid Tumors: Pharmacokinetic and Clinical Results

PURPOSEnWe studied the safety, clinical activity, and pharmacokinetics (PK) of AG-013736, an oral receptor tyrosine kinase inhibitor of vascular endothelial cell growth factor, platelet-derived growth factor, and c-Kit, in patients with advanced cancer.nnnPATIENTS AND METHODSnPatients received fixed doses of AG-013736 orally in 28-day cycles. In the first cohort, patients initially received two single test doses of AG-013736 (10 and 30 mg); subsequent dosing was determined by individual PK parameters. Doses in subsequent cohorts were assigned by using a traditional dose-escalation/de-escalation rule based on observed toxicities in the current and previous cohorts. PK analysis included evaluation of the effect of food and antacid.nnnRESULTSnThirty-six patients received AG-013736 at doses ranging from 5 to 30 mg by mouth twice daily. The dose-limiting toxicities observed included hypertension, hemoptysis, and stomatitis and were seen primarily at the higher dose levels. The observed hypertension was manageable with medication. Stomatitis was generally tolerable and managed by dose reduction or drug holidays. AG-013736 was absorbed rapidly, with peak plasma concentrations observed within 2 to 6 hours after dosing. The maximum-tolerated dose and recommended phase II dose of AG-013736 is 5 mg, twice daily, administered in the fasted state. No significant drug interaction with antacid was seen. There were three confirmed partial responses and other evidence of clinical activity.nnnCONCLUSIONnIn this study, we have demonstrated clinical activity and safety of AG-013736 in patients with advanced solid tumors and identified the dose for phase II testing. The unique phase I study design allowed early identification of important absorption and metabolic issues critical to phase II testing of this agent.

Dynamic Contrast-Enhanced Magnetic Resonance Imaging As a Pharmacodynamic Measure of Response After Acute Dosing of AG-013736, an Oral Angiogenesis Inhibitor, in Patients With Advanced Solid Tumors: Results From a Phase I Study

PURPOSEnIdentifying suitable markers of biologic activity is important when assessing novel compounds such as angiogenesis inhibitors to optimize the dose and schedule of therapy. Here we present the pharmacodynamic response to acute dosing of AG-013736 measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).nnnPATIENTS AND METHODSnThirty-six patients with advanced solid tumors were treated with various doses of AG-013736. In addition to standard measures of objective disease response and pharmacokinetic analysis, DCE-MRI scans were acquired at baseline and repeated at cycle 1--day 2 after the scheduled morning dose of the AG-013736 in 26 patients. Indicators of a vascular response, such as the volume transfer constant (K(trans)) and initial area under the curve (IAUC), were calculated to assess the effect of treatment on tumor vascular function.nnnRESULTSnEvaluable vascular response data were obtained in 17 (65%) of 26 patients. A linear correlation was found in which the percentage change from baseline to day 2 in K(trans) and IAUC was inversely proportional to AG-013736 exposure. Using a conservative a priori assumption that a > or = 50% decrease in K(trans) was indicative of an objective vascular response, a 50% decrease in K(trans) was achieved and corresponded to a plasma AUC(0-24) of > 200 ng . h/mL.nnnCONCLUSIONnA sufficient decrease in tumor vascular parameters was observed at a dose chosen for additional phase II testing by conventional toxicity criteria. In addition, the day 2 vascular response measured using DCE-MRI seems to be a useful indicator of drug pharmacology, and additional research is needed to determine if it is a suitable marker for predicting clinical activity.

Clinical and dynamic imaging results of the first phase I study of AG–013736, an oral anti-angiogenesis agent, in patients (pts) with advanced solid tumors

2503 Background: AG-013736 is a potent and selective inhibitor of VEGF and PDGF receptor tyrosine kinases with broad preclinical activity in xenograft models of solid tumors.nnnMETHODSnThe primary objective was to determine maximum tolerated dose (MTD) and safety. Efficacy, pharmacokinetics (PK), and tumor vascular response were also evaluated. AG-013736 was administered orally once or twice daily in 28-day cycles in escalating doses to pts with solid tumors.nnnRESULTSn36 pts in 6 cohorts were treated. At least 2 cycles of data are available on the first 30. Tumor diagnoses: breast (11), thyroid (5), renal cell (5), lung (4), and other (5). The MTD was 5 mg twice daily (BID) fasted (no food or beverage within 2 hours of dose).nnnTOXICITYnDose-limiting toxicities (DLTs) at doses >MTD (16 pts) were hypertension (HTN) (6 pts); seizures associated with HTN (2); elevated liver function tests (2); mesenteric vein thrombosis and pancreatitis (1); and stomatitis (2). One pt with a cavitating lung lesion died of hemoptysis while on drug. At doses ≤MTD (14 pts), DLT was limited to grade 2 stomatitis in 1 pt; non-dose limiting HTN, managed by conventional antihypertensive meds, was observed in 6 pts.nnnRESPONSEnTwo durable partial responses (10+, 5 mo) by RECIST criteria were observed (in renal cell and adenoid cystic carcinomas); 7 pts had stable disease lasting ≥4 mo. PK: AG-013736 plasma concentrations were variable (39%-96% CV), linear within the dose range, with peaks at 2-4 h, and terminal half-life of 3-5 h. Plasma exposures were higher (∼ 49%) and intra-pt variability was reduced in the fasted vs fed state. Vascular response: Dynamic contrast enhanced MRI was performed at baseline, and after 2, 28, and 56 days of therapy. The % change in mean Ktrans and initial area under the contrast intensity X time curve (IAUC) was computed. 6 of 18 pts with evaluable serial scans had a tumor vascular response, defined as ≥50% decrease from baseline parameter values to day 2; correlation with PK and response will be reported.nnnCONCLUSIONSnThere is sufficient safety and activity of AG-013736 to warrant Phase II trials at a recommended dose of 5 mg BID fasted. [Table: see text].

Antiangiogenic Cancer Therapy

Antiangiogenic cancer therapy / , Antiangiogenic cancer therapy / , کتابخانه دیجیتال جندی شاپور اهواز