Phase I Study of Carfilzomib in Combination with Cyclophosphamide and Etoposide for Children with Relapsed and Refractory Solid Tumors and Leukemias
Objective
Primary Objective:
To determine the DLTs and MTD of carfilzomib given in combination with cyclophosphamide and etoposide in pediatric patients with relapsed/refractory leukemias and solid tumors
Secondary Objectives: 1. To evaluate toxicities of carfilzomib in the pediatric population when combined with conventional chemotherapy 2. To gather preliminary efficacy data on the drug combination 3. To measure if circulating plasma proteasome (cProt) levels post treatment correlate with response to therapy and overall survival 4. To measure if the levels of proteasome activity and resistance to carfilzomib correlates with toxicity and/or response to treatment. 5. To measure if inhibition of proteasome activity by carfilzomib results in alteration in a number of autophagy and apoptosis related proteins, providing means to evaluate correlates of activity of carfilzomib. 6. To measure the level of proteasome inhibition in patient PBMCs before and during treatment by determination of the level of protein ubiquitination. 7. To determine in vitro sensitivity of patient leukemias and solid tumors to carfilzomib alone and in combination with study chemotherapeutic agents in order to generate a predictive model of drug sensitivity. 8. To expand patient leukemia and solid tumor samples in order to save tissue for future studies but also to serve as a pre-clinical in vivo model to be included in the generation and testing of a drug sensitivity predictive model. 9. To perform whole exome sequencing (WES) and RNA seq on patient leukemia and solid tumor samples and WES on germ line DNA in order to determine potential mechanisms of drug sensitivity or resistance as well as contribute to testing a computer learning engine (Bionet) for predicting clinical responsesfrom genomic and drug sensitivity data.
