Carfilzomib in Combination With Cyclophosphamide and Etoposide for Children

Titre officiel

Phase I Study of Carfilzomib in Combination With Cyclophosphamide and Etoposide for Children With Relapsed and Refractory Solid Tumours and Leukemias

Sommaire:

Cette étude évalue l’utilisation du carfilzomib en association avec le cyclophosphamide et l’étoposide chez les enfants atteints de tumeurs solides ou de leucémie récidivantes/réfractaires. Le cyclophosphamide et l’étoposide sont des médicaments standards souvent utilisés conjointement pour le traitement du cancer chez les enfants atteints de tumeurs solides ou de leucémie.

Le carfilzomib est approuvé par la FDA (Food and Drug Administration) aux États-Unis pour les adultes atteints de myélome multiple (un type de cancer). Toutefois, ce médicament n’est pas approuvé pour la maladie traitée dans cette étude. Comme le carfilzomib n’a pas encore été utilisé dans ce contexte pour traiter cette affection, les investigateurs doivent d’abord déterminer la meilleure dose à administrer. Les investigateurs veulent cerner la dose la plus élevée du carfilzomib pouvant être administrée en toute sécurité. Par conséquent, les enfants prenant part à cette étude ne recevront pas tous la même dose du médicament à l’étude lors de la première partie de l’essai.

Description de l'essai

Primary Outcome:

• To determine the DLTs and MTD of carfilzomib given in combination with cyclophosphamide and etoposide in pediatric patients with relapsed/refractory leukemias and solid tumours

Secondary Outcome:

• To evaluate toxicities of carfilzomib in the pediatric population when combined with conventional chemotherapy.
• Determine patient response rate (CR, PR, SD, PD) with this regimen
• To measure if circulating plasma proteosome (cProt) levels post treatment correlate with response to therapy and overall survival.
• To measure if the levels of proteasome activity and resistance to carfilzomib correlates with toxicity and/or response to treatment
• 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
• To measure the level of proteosome inhibition in patient PBMCs before and during treatment by determination of the level of protein ubiquitination
• To determine in vitro sensitivity of patient leukemias and solid tumours to carfilzomib alone and in combination with study chemotherapeutic agents in order to generate a predictive model of drug sensitivity
• To perform whole exome sequencing (WES) and RNA seq on patient leukemia and solid tumour samples and WES on germ line DNA in order to determine potential mechanisms of drug sensitivity or resistance

Part 1 of the study will include a dose escalation based on Dose limiting toxicities (DLTs) until the MTD or highest dose level is reached, whichever comes first. At the MTD or highest dose level (if no MTD is reached), an additional 6 patients will be enrolled to further evaluate safety of the regimen (Part 2). Part 2 of this study will enroll additional patients at the highest tolerable dose found in Part 1 in order to get more information on side effects and make sure the dose is tolerable Once an MTD is determined for Strata A or B, if the Study Principal Investigator determines that the study treatment should not be further pursued due to safety or enrollment barriers, the expansion Part or the study will be discontinued.

Voir cet essai sur ClinicalTrials.gov