In addition, there are several ongoing phase 1 and 2 combination studies of IGFR inhibitors in adults with a variety of solid tumors

In addition, there are several ongoing phase 1 and 2 combination studies of IGFR inhibitors in adults with a variety of solid tumors. In summary, cixutumumab is well tolerated in children, adolescents and young adults like a single-agent at 9 mg/kg. accomplished a partial response: 4/20 with neuroblastoma (evaluable only) and 1/20 with rhabdomyosarcoma. Fourteen individuals had stable disease for any median of 10 cycles. Hematologic and non-hematologic toxicities were generally slight and infrequent. Serum IGF-1 and IGFBP-3 improved in response to therapy with cixutumumab. Conclusion Cixutumumab is definitely well tolerated in children with refractory solid tumors. Limited objective single-agent activity of cixutumumab was observed; however, prolonged stable disease was observed in 15% of individuals. Ongoing studies are evaluating the toxicity and good thing about cixutumumab in combination with additional providers that inhibit the IGF pathway. strong class=”kwd-title” Keywords: Investigational Rabbit Polyclonal to CLDN8 Providers, Insulin-like Growth Factor-I Receptor, Pediatric Malignancy, Monoclonal Antibody Intro The insulin-like growth factor-I receptor (IGF-IR) plays UNC 669 a role in the initiation and progression of a variety of cancers, including many malignancies of child years and young adults.1-9 Preclinical data suggest that inhibition of the IGF-IR may constitute an important therapeutic target in a variety of pediatric solid UNC 669 tumors, including rhabdomyosarcoma, neuroblastoma and Wilms tumor.10-15 Cixutumumab (IMC-A12; ImClone Systems, Inc., Branchburg, NJ), a human being IgG1/ monoclonal antibody (mAb) against the IGF-IR, binds to the IGF-IR with high affinity, decreases cell surface IGF-IR expression, and blocks relationships with IGF-I and IGF-II ligands.16-18 In preclinical malignancy models, cixutumumab has single-agent activity and potentiates UNC 669 the effect of cytotoxic therapy in vitro and in vivo.19-22 When evaluated from the Pediatric Preclinical Testing System, cixutumumab demonstrated single-agent activity in osteosarcoma, Ewing sarcoma (ES), neuroblastoma, glioblastoma, and rhabdomyosarcoma models.23 Inside a single-agent phase 1 study in adults, cixutumumab was well tolerated at doses from 3 to 15 mg/kg weekly, and a maximum tolerated dose (MTD) was not defined.24,25 Based on pharmacokinetic data, the recommended phase 2 dose in adults is 6 mg/kg when given weekly.24 A phase 1 study of cixutumumab (ADVL0712) conducted from the Children’s Oncology Group (COG) Phase 1 Consortium in children and adolescents individuals with refractory non-CNS sound tumors included a phase 2 expansion cohort for relapsed/refractory Ewing sarcoma (Sera). The recommended phase 2 dose defined with this trial, 9 mg/kg, was UNC 669 higher than that in adult phase 2 tests, which reflects a more quick clearance in children than adults.26 We now record the effects of the COG phase 2 study of cixutumumab in children, adolescents and young adults with relapsed/refractory non-CNS sound tumors. Individuals and Methods Patient Population Individuals between 1 and 31 years of age with measurable disease and relapsed refractory solid tumors including osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, synovial sarcoma, Wilms tumor, hepatoblastoma, and adrenocortical carcinoma were eligible for trial. Individuals with neuroblastoma and MIBG only evaluable disease were also qualified. Other eligibility criteria included standard organ function and overall performance status requirements as well as the absence diabetes mellitus and known metastatic disease to the central nervous system.26 Individuals receiving other anti-cancer providers, insulin, or growth hormone were not eligible. The trial was authorized by individual institutional review boards (IRBs) of participating sites, as well as the National Malignancy Institute Pediatric Central IRB. All individuals or their parent/legal guardian authorized a document of educated consent; assent was acquired as appropriate prior to enrollment. Drug Administration Cixutumumab was supplied in 250-mg (5 mg/ml) or 500-mg (10 mg/ml) solitary use vials from the UNC 669 NCI (Bethesda, MD). It was administered like a 1-hour intravenous infusion (at a rate 25 mg/min) through a 0.2 or 0.22 m protein-sparing filter once weekly in continuous 28 day time cycles. All individuals received the recommended phase 2 dose of 9 mg/kg. Cycles were repeated without interruption if the patient did not possess progressive disease and experienced recovered from the prior cycle with an ANC of 750/l, platelet count 50,000/l, and additional laboratory parameters meeting eligibility criteria. Individuals who experienced hyperglycemia could continue on protocol therapy if they were asymptomatic and their serum glucose was managed at 250 mg/dL ( grade 2) with or without the use of insulin or an oral hyperglycemic agent. Individuals could remain on protocol therapy with one dose reduction to 6 mg/kg,.