Combination mTOR and IGF-1R Inhibition: Phase I Trial of Everolimus and Figitumumab in Patients with Advanced Sarcomas and Other Solid Tumors

Abstract

Purpose: Preclinical models demonstrate synergistic antitumor activity with combination blockade of mTOR and IGF-1R signaling. We aimed to determine the safety, tolerability, and recommended phase II dose (RP2D) of the combination of figitumumab, a fully human IgG 2 anti-insulin-like growth factor-1 receptor (IGF-1R) monoclonal antibody (Pfizer) and the mTOR inhibitor, everolimus (Novartis). Pharmacokinetics and preliminary antitumor effects of the combination were evaluated.Experimental Design: Phase I trial in patients with advanced sarcomas and other solid tumors. Initial cohort combined full phase 2 dose figitumumab (20 mg/kg IV every 21 days) with full dose everolimus (10 mg orally once daily). Intercohort dose de-escalation was planned for unacceptable toxicities. Dose modifications were allowed beyond cycle 1.Results: No DLTs were observed in the initial cohort during cycle one, therefore full dose figitumumab and everolimus was declared the RP2D. In total, 21 patients were enrolled on study. Most toxicities were grade 1 or 2, and were similar to reported toxicities of the single agents. Mucositis was the most frequently observed grade 3 toxicity. Median time on study was 104 days (range 17-300). Of 18 patients evaluable for response, best response was partial response in 1 patient with malignant solitary fibrous tumor and, stable disease in 15 patients. There were no apparent pharmacokinetic interactions between everolimus and figitumumab.Conclusions: Combination figitumumab plus everolimus at full doses appears safe and well tolerated with no unexpected toxicities. Dose reductions in everolimus may be required after prolonged drug administration. This regimen exhibits interesting antitumor activity warranting further investigation.

Characterization of the mTOR pathway in human normal adrenal and adrenocortical tumors

“…Few patients with advanced ACCs who received everolimus, as salvage treatment, did not receive any major benefit (Fraenkel et al 2013). Few ACC patients have been treated in registered clinical trials (Gangadhar et al 2011, Quek et al 2011, Naing et al 2013. These studies failed to prove the hoped efficacy of these compounds, and they also had limitations.…”

“…As mitotane can interfere with the metabolism of other drugs including mTOR inhibitors, it became necessary to determine mitotane levels in these patients. However, these early clinical experiences suggest that a subset of patients could benefit (more than 6 months of tumor stabilization) from combined treatment including mTOR inhibitors and IGF1R antagonists (Quek et al 2011, Naing et al 2013. In a previous study, we had demonstrated that, in H295 ACC cells, IGFs can activate mechanisms of escape from mTOR inhibitors, which could be responsible for a reduced sensitivity to the treatment with these drugs (De Martino et al 2012).…”

Molecular Predictors of Sensitivity to the Insulin-like Growth Factor 1 Receptor Inhibitor Figitumumab (CP-751,871)

“…A recent phase I combination study of figitumumab and the mTOR inhibitor, everolimus, in patients with advanced sarcomas and other solid tumors indicated that the combination was well tolerated with no unexpected toxicities. Stable disease was observed in the majority of patients and the combination also yielded a partial response in one patient with malignant solitary fibrous tumor (42). Furthermore, a phase I trial evaluating the humanized anti-IGF1R monoclonal antibody, dalotuzumab, combined with the mTOR inhibitor, ridaforolimus, demonstrated antitumor activity in patients with estrogen receptor-positive metastatic breast cancer (43).…”

Expression and Clinical Significance of mTOR in Surgically Resected Non-small Cell Lung Cancer Tissues: a Case Control Study

“…These findings raised the question whether the combination of IGF-1R and mTOR inhibitors in patients with NSCLC might be more effective. Several preclinical experiments had demonstrated synergistic antitumor activity with combination blockade of mTOR and IGF-1R signaling (Quek et al, 2011).…”