Safety and Pharmacokinetics of Ganitumab (AMG 479) Combined with Sorafenib, Panitumumab, Erlotinib, or Gemcitabine in Patients with Advanced Solid Tumors

Abstract

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 i.v. every 2 weeks) combined with either sorafenib 400 mg twice daily, panitumumab 6 mg/kg every 2 weeks, erlotinib 150 mg once daily, or gemcitabine 1,000 mg/m 2 on days 1, 8, and 15 of each 4-week cycle. The primary end points 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-binding 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.

MM-141, an IGF-IR– and ErbB3-Directed Bispecific Antibody, Overcomes Network Adaptations That Limit Activity of IGF-IR Inhibitors

“…The IGF-IR and ErbB3 signaling pathways have been implicated as potential escape pathways in cancers exhibiting resistance to targeted therapies and chemotherapies (18)(19)(20)(21)(41)(42)(43)(44)(45). We demonstrate that the IGF-IR pathway is often coactivated with ErbB3, another nonoverexpressed receptor.…”

“…We have previously shown that direct targeting of ErbB3 is optimal for blocking the ErbB3-PI3K cascade (32). Recent clinical strategies have combined IGF-IR inhibitors with EGFR-based therapies resulting in disappointing outcomes (19)(20)(21). We propose that the simultaneous blockade of IGF-IR and ErbB3 is necessary to maximize the potency of PI3K/ AKT/mTOR inhibition.…”

“…Addition of the IGF-I ligand has been shown to protect trastuzumab-sensitive cells from cell death (17), and patients treated with trastuzumab who also express IGF-IR have shorter progression-free survival (18). Not surprisingly, IGF-IR and EGFR/ErbB2 therapies were combined in multiple clinical trials (19)(20)(21). However, recent late-stage clinical failures have delayed proof-ofconcept that IGF-IR inhibitors, alone or in combination with EGFR-targeted agents, can be effective (19)(20)(21)(22).…”

The insulin-like growth factor (IGF) axis as an anticancer target in prostate cancer

“…A phase Ib study assessed the impact of ganitumab in advanced solid tumors including one patient with advanced PCa. The patient treated with the combination ganitumab 12 mg/m 2 + gemcitabine tolerated the drug without side effects [67]. Subsequently, another Phase I study was initiated including a higher number of patients with advanced PCa (NCT00562380).…”

Promising New Therapies in Advanced Pancreatic Adenocarcinomas

“…In human pancreatic cancer xenograft models, the combination of ganitumab with gemcitabine demonstrated inhibition of cell growth and proliferation [25]. In a Phase Ib study, this combination was associated with a disease control rate (complete response plus partial response plus stable disease) of 80% in patients with advanced solid tumors including pancreatic cancer [26]. A randomized Phase II study in untreated metastatic PDAC demonstrated tolerable toxicity with a trend toward improved OS [27].…”