A phase 1 Bayesian dose selection study of bortezomib and sunitinib in patients with refractory solid tumor malignancies.

BACKGROUND: This phase 1 trial utilising a Bayesian continual reassessment method evaluated bortezomib and sunitinib to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and recommended doses of the combination. METHODS: Patients with advanced solid organ malignancies were enrolled and received bortezomib weekly with sunitinib daily for 4 weeks, every 6 weeks. Initial doses were sunitinib 25 mg and bortezomib 1 mg m(-2). Cohort size and dose level estimation was performed utilising the Escalation with Overdose Control (EWOC) adaptive method. Seven dose levels were evaluated; initially, sunitinib was increased to a goal dose of 50 mg with fixed bortezomib, then bortezomib was increased. Efficacy assessment occurred after each cycle using RECIST criteria. RESULTS: Thirty patients were evaluable. During sunitinib escalation, DLTs of grade 4 thrombocytopenia (14%) and neutropenia (6%) at sunitinib 50 mg and bortezomib 1.3 mg m(-2) were seen. Subsequent experience showed tolerability and activity for sunitinib 37.5 mg and bortezomib 1.9 mg m(-2). Common grade 3/4 toxicities were neutropenia, thrombocytopenia, hypertension, and diarrhoea. The recommended doses for further study are bortezomib 1.9 mg m(-2) and sunitinib 37.5 mg. Four partial responses were seen. Stable disease >6 months was noted in an additional six patients. CONCLUSION: Bortezomib and sunitinib are well tolerated and have anticancer activity, particularly in thyroid cancer. A phase 2 study of this combination in thyroid cancer patients is planned.

mRECIST and EASL responses at early time point by contrast-enhanced dynamic MRI predict survival in patients with unresectable hepatocellular carcinoma (HCC) treated by doxorubicin drug-eluting beads transarterial chemoembolization (DEB TACE).

BACKGROUND: We analyzed the magnetic resonance imaging (MRI) responses by world health organization (WHO), response evaluation criteria in solid tumor (RECIST), European Association for the Study of Liver (EASL), and modified RECIST (mRECIST) guidelines and correlated with survival after doxorubicin (Adriamycin; Pharmacia & Upjohn, Peapac, NJ). drug-eluting beads transarterial chemoembolization (DEB TACE) in patients with unresectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS: The early target and overall imaging responses were studied in 120 consecutive patients treated with DEB TACE for unresectable HCC, using RECIST, WHO, EASL, and mRECIST guidelines on contrast-enhanced dynamic liver MRI. The median period between the DEB TACE and assessment scan was 33.50 days. Survival analyses were carried out with the Kaplan-Meier method and the Cox proportional model. RESULTS: WHO and RECIST1.1 had poor correlation with survival. mRECIST and EASL had significant correlation with survival with target lesion response rates of 63.3% and 48.3% and with overall response rates of 52.5% and 39.2%, respectively. The responders of EASL and mRECIST had significant median survival (P ≤ 0.0001). Moreover, mRECIST was better than EASL in predicting survival, because the survival difference between responders and non-responders of overall response was statistically significant (P = 0.013) for mRECIST, but not for EASL (P = 0.064). CONCLUSIONS: EASL and mRECIST responses measured on MRI at an early time point after DEB TACE predicted survival. mRECIST response demonstrated higher survival correlation than EASL.