Journal Article

A phase I study of bevacizumab, everolimus and panitumumab in advanced solid tumors

Bendell, Johanna C., Zafar, S. Yousuf, Hurwitz, Herbert I., Gockerman, Jon, Anderson, Elizabeth L., Alvarez-Secord, Angeles, Uronis, Hope E., Starodub, Alexander N., Blobe, Gerard C., Meadows, Kellen L., Morse, Michael A., Vlahovic, Gordana, Ready, Neal E., Riedel, Richard F.

2012

Overview

Purpose Preclinical data suggest concurrent inhibition of VEGF, mTOR and EGFR pathways may augment antitumor and antiangiogenic effects compared to inhibition of each pathway alone. This study evaluated the maximum tolerated dose/recommended phase II dose and safety and tolerability of bevacizumab, everolimus and panitumumab drug combination. Methods Subjects with advanced solid tumors received escalating doses of everolimus and flat dosing of panitumumab at 4.8 mg/kg and bevacizumab at 10 mg/kg every 2 weeks. Dose-limiting toxicities (DLTs) were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity. Results Thirty-two subjects were evaluable for toxicity; 31 subjects were evaluable for tumor response. DLTs were observed in cohorts with everolimus at 10 and 5 mg daily and included grade 3 mucositis, skin rash and thrombocytopenia. Therefore, everolimus was dose-reduced to 5 mg three times weekly, which improved the tolerability of the treatment regimen. Common adverse events were skin rash/pruritus (91 %), mucositis/stomatitis (75 %), hypomagnesemia (72 %), hypocalcemia (56 %) and hypokalemia (50 %). There were 3 partial responses; an additional 10 subjects had stable disease ≥6 months. Three subjects with ovarian cancer and one with endometrial cancer achieved prolonged disease control ranging from 11 to >40 months. Conclusions The recommended phase II dose is everolimus at 5 mg three times weekly plus panitumumab at 4.8 mg/kg and bevacizumab at 10 mg/kg every 2 weeks. This dosing regimen has an acceptable safety and tolerability profile and appears to have moderate the clinical activity in refractory tumors.

• Publisher: Springer-Verlag,Springer,Springer Nature B.V
• Subject: Adult / Aged / Antibodies, Monoclonal - administration & dosage / Antibodies, Monoclonal - adverse effects / Antibodies, Monoclonal, Humanized - administration & dosage / Antibodies, Monoclonal, Humanized - adverse effects / Antineoplastic agents / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Bevacizumab / Biological and medical sciences / Cancer Research / Dose-Response Relationship, Drug / Drug Administration Schedule / Everolimus / Exanthema - chemically induced / Female / Humans / Hypocalcemia - chemically induced / Hypokalemia - chemically induced / Male / Medical sciences / Medicine / Medicine & Public Health / Middle Aged / Mucositis - chemically induced / Multiple tumors. Solid tumors. Tumors in childhood (general aspects) / Neoplasms - drug therapy / Oncology / Original Article / Pharmacology. Drug treatments / Pharmacology/Toxicology / Sirolimus - administration & dosage / Sirolimus - adverse effects / Sirolimus - analogs & derivatives / Treatment Outcome / Tumors / Young Adult