Safety, tolerability, and pharmacokinetics of the anti-IGF-1R monoclonal antibody figitumumab in patients with refractory adrenocortical carcinoma

Abstract

Purpose-Insulin-like growth factor 1 receptor signaling through upregulation of the stimulatory ligand IGF-II has been implicated in the pathogenesis of adrenocortical carcinoma. As there is a paucity of effective therapies, this dose expansion cohort of a phase 1 study was undertaken to determine the safety, tolerability, pharmacokinetics, and effects on endocrine markers of figitumumab in patients with adrenocortical carcinoma. NIH Public Access Author ManuscriptCancer Chemother Pharmacol. Author manuscript; available in PMC 2011 March 1. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptMethods-Figitumumab was administered on day 1 of each 21-day cycle at the maximal feasible dose (20 mg/kg) to a cohort of patients with metastatic, refractory adrenocortical carcinoma. Serum glucose, insulin, and growth hormone were measured pre-study, at cycle 4 and study end. Pharmacokinetic evaluation was performed during cycles 1 and 4.Results-Fourteen patients with adrenocortical carcinoma received 50 cycles of figitumumab at the 20 mg/kg. Treatment-related toxicities were generally mild and included hyperglycemia, nausea, fatigue, and anorexia. Single episodes of grade 4 hyperuricemia, proteinuria, and elevated gammaglutamyltransferase were observed. Pharmacokinetics of figitumumab was comparable to patients with solid tumors other than adrenocortical carcinoma. Treatment with figitumumab increased serum insulin and growth hormone levels. Eight of 14 patients (57%) had stable disease.Conclusions-The side effect profile and pharmacokinetics of figitumumab were similar in patients with adrenocortical carcinoma in comparison to patients with other solid tumors. While hyperglycemia was the most common adverse event, no clear patterns predicting severity were observed. The majority of patients receiving protocol therapy with single agent figitumumab experienced stability of disease, warranting further evaluation.

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

“…Figitumumab mean AUC 0-d22 was 86,110 AE 16,811 mg hr/L for the population (n ¼ 19). This is slightly lower than what has been reported previously, although the confidence intervals remain wide and overlapping (9,21).…”

Szlaki molekularne w raku kory nadnercza — od wiedzy o sygnalizacji komórkowej do metod diagnostyki i leczenia

“…Obiecujące dane przedkliniczne opisujące zmniejszenie proliferacji w ACC w wyniku hamowania IGF1R [34] były podstawą I fazy badań klinicznych inhibitorów IG-F1R. W przypadku monoklonalnego przeciwciała anty-IGF1R, figitumumabu, opisano aktywność biologiczną w ACC opornym na leczenie [169]. W innym badaniu klinicznym (I faza) oceniono skuteczność kombinacji inhibitora IGF1R, cixutumumabu, z inhibitorem mTOR,…”

“…Promising pre-clinical data of anti-proliferative effects of IGF1R inhibition in ACC [34] provided the basis for phase I trials of IGF1R inhibitors. The anti-IGF1R monoclonal antibody figitumumab has demonstrated biological activity in refractory ACC [169]. Another phase I trial assessed a combination of IGF1R inhibitor cixutumumab with mTOR inhibitor temsirolimus in metastatic ACC patients.…”

Genetics of tumors of the adrenal cortex

“…IGF1-R kinase inhibitor has therefore been developed and were shown to have antitumor effects in both adult and pediatric adrenocortical tumor cell lines (Almeida et al 2008). However, phase I trials evaluating the feasibility of IGF1-R (Figitumumab and OSI-906) and insulin receptor (OSI-906) inhibition were quite disappointing, only one of 25 patients showing a partial response by RECIST criteria (Haluska et al 2010, Drelon et al 2013. This result is concordant with mouse models in which IGF-II overexpression is not sufficient to promote tumorigenesis, even in association with beta-catenin activation (Heaton et al 2012, Drelon et al 2013.…”