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Safety, Pharmacokinetics, and Efficacy of AMG 706, an Oral Multikinase Inhibitor, in Patients With Advanced Solid Tumors

Lee S. Rosen, Razelle Kurzrock, Marilyn Mulay, Andy Van Vugt, Michelle Purdom, Chaan Ng, Jeffrey Silverman, Antonis Koutsoukos, Yu-Nien Sun, Michael B. Bass, Ren Y. Xu, Anthony Polverino, Jeffrey S. Wiezorek, David D. Chang, Robert Benjamin, Roy S. Herbst

From the Premiere Oncology, Santa Monica; Landmark Imaging, Los Angeles; Amgen Inc, Thousand Oaks, CA; and the Division of Cancer Medicine Phase 1 Program, Department of Radiology, Department of Sarcoma, and Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX

Address reprint requests to Roy S. Herbst, MD, PhD, The University of Texas M.D. Anderson Cancer Center, Thoracic/Head and Neck Medical Oncology, 1515 Holcombe Blvd, Unit 432, Houston, TX 77030; e-mail: rherbst{at}mdanderson.org

Purpose AMG 706 is an investigational, orally bioavailable inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptor, and stem-cell factor receptor. This phase I, dose-finding study evaluated the safety, pharmacokinetics, and pharmacodynamics of AMG 706 in patients with refractory advanced solid tumors.

Patients and Methods AMG 706 was administered at escalating doses of 50 to 175 mg once daily or 25 mg bid for the first 21 days of a 28-day cycle. The 125-mg once-daily dose was also administered continuously. The maximum-tolerated dose (MTD), safety, pharmacokinetics, tumor response, and serum levels of proangiogenic markers were determined.

Results Seventy-one patients received AMG 706. The MTD was 125 mg once daily administered continuously. The most frequent adverse events were fatigue (55%), diarrhea (51%), nausea (44%), and hypertension (42%). Plasma AMG 706 concentrations increased in a dose-proportional manner with no accumulation after multiple doses. Five patients (7%) had a partial response, 35 patients (49%) had stable disease (at least through day 50), and 31 patients (44%) had progressive disease. Changes in tumor size correlated significantly with an increase in placental growth factor (P = .003) and a decrease in soluble kinase domain receptor (P = .001).

Conclusion In this study of patients with advanced refractory solid tumors, AMG 706 was well tolerated and displayed favorable pharmacokinetics and evidence of antitumor activity. Additional studies of AMG 706 as monotherapy and in combination with various agents are ongoing.

Supported by Amgen Inc and the Cancer Center Support Core Grant No. 5P30 CA016672-30 (R.S.H.).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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