Safety and Pharmacokinetics of Ganitumab (AMG 479) Combined With Sorafenib, Panitumumab, Erlotinib, or Gemcitabine in Patients With Advanced Solid Tumors
Mené sur 14 cohortes de 3 à 9 patients atteints de tumeurs solides de stade avancé, cet essai de phase 1b évalue le ganitumab, un anticorps monoclonal ciblant le récepteur IGF1, en combinaison avec le sorafenib, le panitumumab, l'erlotinib ou la gemcitabine
Purpose: This phase 1b dose-escalation study assessed safety, tolerability, and pharmacokinetics of ganitumab, a fully human monoclonal antibody against the insulin-like growth factor 1 (IGF1) receptor, combined with targeted agents or cytotoxic chemotherapy in patients with advanced solid tumors. Experimental Design: Patients with treatment-refractory advanced solid tumors were sequentially enrolled at 2 ganitumab dose levels (6 or 12 mg/kg intravenously every 2 weeks [Q2W]) combined with either sorafenib 400 mg twice daily, panitumumab 6 mg/kg Q2W, erlotinib 150 mg once daily, or gemcitabine 1000 mg/m2 on days 1, 8, and 15 of each 4-week cycle. The primary endpoints were safety and pharmacokinetics of ganitumab. Results: Ganitumab up to 12 mg/kg appeared well tolerated combined with sorafenib, panitumumab, erlotinib, or gemcitabine. Treatment-emergent adverse events were generally mild and included fatigue, nausea, vomiting, and chills. Three patients had dose-limiting toxicities: grade 3 hyperglycemia (ganitumab 6 mg/kg and panitumumab), grade 4 neutropenia (ganitumab 6 mg/kg and gemcitabine), and grade 4 thrombocytopenia (ganitumab 12 mg/kg and erlotinib). Ganitumab- and panitumumab-binding antibodies were detected in 5 and 2 patients, respectively; neutralizing antibodies were not detected. The pharmacokinetics of ganitumab and each cotherapy did not appear affected by coadministration. Circulating total IGF1 and IGF binding protein 3 increased from baseline following treatment. Four patients (9%) had partial responses. Conclusions: Ganitumab up to 12 mg/kg was well tolerated, without adverse effects on pharmacokinetics in combination with either sorafenib, panitumumab, erlotinib, or gemcitabine. Ganitumab is currently under investigation in combination with some of these and other agents.