The Combination of InsulinLike Growth Factor Rece

Authors: Antonio M Lerario Francis P Worden Carole A Ramm Elizabeth A Hasseltine Walter M Stadler Tobias Else Manisha H Shah Edem Agamah Krishna Rao Gary D Hammer

Publish Date: 2014/05/22

Volume: 5, Issue: 4, Pages: 232-239

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Abstract

Adrenocortical carcinoma ACC is an aggressive malignancy which lacks an effective systemic treatment Abnormal activation of insulinlike growth factor receptor 1 IGF1R has been frequently observed Preclinical studies demonstrated that pharmacological inhibition of IGF1R signaling in ACC has antiproliferative effects A previous phase I trial with an IGF1R inhibitor has demonstrated biological activity against ACC The objective of this study is to assess the efficacy of the combination of the IGF1R inhibitor cixutumumab IMCA12 in association with mitotane as a firstline treatment for advanced/metastatic ACC We conducted a multicenter randomized doublearm phase II trial in patients with irresectable recurrent/metastatic ACC The original protocol included two treatment groups IMCA12 + mitotane and mitotane as a single agent after an initial singlearm phase for safety evaluation with IMCA12 + mitotane IMCA12 was dosed at 10 mg/kg intravenously every 2 weeks The starting dose for mitotane was 2 g daily subsequently adjusted according to serum levels/symptoms The primary endpoint was progressionfree survival PFS according to RECIST Response Evaluation Criteria in Solid Tumors This study was terminated before the randomization phase due to slow accrual and limited efficacy Twenty patients 13 males 7 females with a median age of 502 years range 219–796 were enrolled for the singlearm phase Therapeutic effects were observed in 8/20 patients including one partial response and seven stable diseases The median PFS was 6 weeks range 266–48 Toxic events included two grade 4 hyperglycemia and hyponatremia and one grade 5 multiorgan failure Although the regimen demonstrated activity in some patients the relatively low therapeutic efficacy precluded further studies with this combination of drugs

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