Background Preclinical studies have shown synergistic antitumour activity by inhibition of

Background Preclinical studies have shown synergistic antitumour activity by inhibition of insulin-like growth factor-1 receptor (IGF-1R) and mTOR. to one of three treatment groups: IGF-1R-positive soft-tissue sarcoma (group A) IGF-1R-positive bone sarcomas (group B) or IGF-1R-negative bone KX1-004 and soft-tissue sarcoma (group C). Patients received weekly treatment with cixutumumab (6 mg/kg intravenous) and temsirolimus (25 mg intravenous flat dose) in 6-week cycles. A Simon optimal two-stage design was used for every arm. The primary endpoint was progression-free survival (PFS) at 12 weeks by intention-to-treat analysis in the first 54 patients assigned to every treatment arm. Although patients still remain on treatment this trial has completed enrolment and this represents the final analysis. This study is usually registered with number NCT01016015. Findings Between Nov 18 2009 and April 11 2012 388 patients were screened for IGF-1R expression and 54 were assigned to each arm. 17 of 54 patients in the IGF-1R-positive soft-tissue sarcoma group (31%; one-sided 95% CI lower bound 21%; two-sided 90% CI 21-43) 19 of 54 in IGF-1R-positive bone sarcoma KX1-004 group (35%; one-sided 95% CI lower bound 24%; two-sided 90% CI 24-47) and 21 of 54 in the IGF-1R-negative group (39% one-sided 95% CI lower bound 28%; two-sided 90% CI 28-51) were progression free at 12 weeks. On April 6 2011 the protocol was amended to include three additional patients in the IGF-1R-positive soft-tissue sarcoma group (total of 57 patients) and nine more in the IGF-1R-negative group (total of 63 patients). There were 2546 adverse events reported during the study 214 (8%) of which were grade 3-4. The most common grade 3-4 toxicities in the 174 treated patients were anaemia in 16 (9%) patients hyperglycaemia in 18 (10%) hypophosphataemia in 16 (9%) lymphopenia in 25 (14%) oral mucositis in 19 (11%) and thrombocytopenia KX1-004 in 19 (11%). Interpretation The combination of cixutumumab and Rabbit Polyclonal to p14 ARF. temsirolimus shows clinical activity in patients with sarcoma and forms a basis for future trials. However IGF-1R expression by immunohistochemistry is not predictive of clinical outcome after treatment with this combination. Funding National Malignancy Institute and Cycle for Survival Fund Memorial Sloan-Kettering Cancer Center. Introduction About 13 000 cases of soft-tissue and bone sarcoma are diagnosed annually in the USA.1 The median survival from diagnosis for patients with metastatic disease is about 10-18 months.2 In view of the toxicity and limited efficacy of chemotherapy patients with advanced and metastatic disease are appropriate candidates for investigational treatments. Insulin-like growth factor-1 (IGF-1) IGF-2 and IGF-binding protein (IGF-BP) are expressed in various sarcoma subtypes which suggests that IGF-1 receptor (IGF-1R) inhibition might be applicable in sarcomas.3 IGF-1R is activated by the growth factor ligands IGF-1 and IGF-2 resulting in receptor autophosphorylation which leads to the activation of many signalling cascades including the PI3K-Akt-mTOR pathway. Several lines of evidence have suggested that IGF-1R signalling is crucial to the biological changes in Ewing’s sarcoma and that targeting IGF-1R can inhibit tumour growth.4-8 However in two large phase 2 trials in Ewing’s sarcoma treatment with IGF-1R-targeting monoclonal antibodies R1507 and figitumumab resulted in overall response rates of only 10% and 14% and median progression-free survival (PFS) of 1 1.3 and 1.9 months respectively.9 10 Combined inhibition of both IGF-1R and mTOR signalling represents a novel approach for treatment of sarcoma.11 12 Blockade of mTOR alone paradoxically activates Akt.13 This finding might explain the disappointing single-drug activity with mTOR inhibitors such as temsirolimus in patients with soft-tissue sarcoma.14 However IGF-1R inhibition suppresses mTOR-induced Akt activation and sensitises tumour cells to mTOR inhibitors.13 Pretreatment of rhabdomyosarcoma cell lines with the IGF-1R antibody h7C10 resulted in blockade of rapamycin-induced Akt activation and in an enhanced antiproliferative effect compared with either drug alone.12 The IGF-1R antibody R1507 similarly enhanced the effect of rapamycin by downregulating IGF-1R and blocking the reactivation of phosphorylated Akt (p-Akt) in a broad range of sarcoma cell lines.15 For sarcoma cell lines in which there was no IGF-1R expression the combination of R1507 and rapamycin was ineffective.15 Based on such data phase 1 studies of the combination of IGF-1R and mTOR inhibitors in sarcoma KX1-004 have been undertaken.16 17 The fully.