A phase I, open-label, multicenter study of cediranib and AZD0530 in patients with advanced solid tumors
Authors: T. Trarbach, J. Drevs, D. Strumberg, T. C. Gauler, V. Schneider, W. E. Eberhardt, M. Marotti, T. A. Puchalski, A. J. Swaisland
Journal: Journal of Clinical Oncology (2008)

3592 Background: Combining targeted agents with different mechanisms of action is an attractive approach to developing improved treatments for cancer. Cediranib (AZD2171) is an oral, highly potent and selective inhibitor of vascular endothelial growth factor (VEGF) signaling, with activity against VEGFR-1, -2, and -3. AZD0530 is a potent, oral Src inhibitor with additional activity against Bcr-Abl. The primary objective of this ongoing study is to evaluate the safety and tolerability of treatment with cediranib in combination with AZD0530 and to define doses for further investigation. Secondary assessments include pharmacokinetics (PK) and preliminary efficacy. Methods: Patients with advanced solid tumors refractory to standard therapies received once-daily, oral cediranib (20, 30, or 45 mg) for 7 days followed by daily treatment with cediranib at the same dose in combination with AZD0530 175 mg. Cediranib 45 mg and AZD0530 175 mg were previously defined as the maximum tolerated doses (MTDs) as monotherapy. Safety data were reviewed when ≥3 patients were evaluable in a particular cohort. Dose escalation was based on the percentage of patients who experienced dose-limiting toxicities (DLTs [CTCAE ≥grade 3]). Results: By November 2007, 18 patients had been enrolled into the study (Table). Combined treatment with cediranib (20, 30 or 45 mg) and AZD0530 175 mg was well tolerated. During the evaluation period (first 28 days), there were no DLTs and common drug-related adverse events included diarrhea, hypertension and hoarseness. There does not appear to be a major effect of AZD0530 on the steady-state PK of cediranib and also no major effect of cediranib on the steady-state PK of AZD0530. Preliminary efficacy data are encouraging. Conclusions: Based on these initial data, cediranib 45 mg/day was defined as the MTD in combination with AZD0530 175 mg/day and this regimen has been selected for further assessment in an expanded cohort phase of the study. Summary of results Cediranib dose (mg/day) AZD0530 dose (mg/day) Number of patients (total/ evaluable * ) Safety (drug-related AEs during the 28-day evaluation period occurring in ≤1 patient † ) Efficacy (RECIST best response from day 43 onwards ‡ ) Maximum duration of response (days) Cediranib AZD0530 20 175 6/6 Abdominal pain; diarrhea; hoarseness; hypertension; TSH increase Diarrhea; DLCO decrease SD (n=6) [colorectal cancer, adenoid cystic carcinoma, adenocarcinoma, malignant mesenchymal tumor, leiomyosarcoma, carcinoid] 197 (n=1) 140 (n=3) 84 (n=1) 35 (n=1) 30 175 6/5 Diarrhea; hoarseness; hypertension None SD (n=3) [pleural mesothelioma, pancreatic carcinoma, rectal cancer] PD (n=3) 84 (n=3) 45 175 6/3 Diarrhea; hypertension None Not yet available Not yet available * Patients were considered evaluable once they had completed 28 days of treatment or had experienced a DLT prior to day 28; † All drug-related AEs were CTC grade ≤2; ‡ All patients AE, adverse event; CTCAE, Common Terminology Criteria for AEs; DLCO, diffusing capacity of the lung for CO; SD, stable disease; PD, progressive disease; TSH, thyroid-stimulating hormone Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca Oncology AstraZeneca Oncology, Bristol-Myers Squibb, Eli Lilly, Novartis, OSI Oncology, Pfizer Oncology, Roche AstraZeneca Oncology AstraZeneca Oncology, Bristol Myers, Eli Lilly, Novartis, Pfizer, Pierre Fabre, Roche