A study of carfilzomib in combination with cyclophosphamide and etoposide for children with relapsed and refractory solid tumors and leukemias
The proteasome is a multicatalytic proteinase complex that is responsible for degradation of a
wide variety of protein substrates within normal and transformed cells. Intracellular proteins
targeted for degradation by the proteasome are first ubiquitinated via the ubiquitin conjugation
system. Ubiquitinated proteins are cleaved within the proteasome by one or more of three
separate threonine protease activities: a chymotrypsin-like activity, a trypsin-like activity, and a caspase-like activity. Carfilzomib (PR-171) is a tetrapeptide ketoepoxide-based inhibitor specific for the chymotrypsin-like active site of the 20S proteasome.
Carfilzomib has not yet been evaluated in children. It will be a phase I combination study
looking at carfilzomib in combination with a standard chemotherapy backbone for both solid
tumors/lymphomas and leukemias. Solid tumors/lymphomas and leukemias will be analyzed and
dose-escalated independently as separate cohorts.
The backbone will consist of cyclophosphamide and etoposide, both given daily for 5 days. The
rationale for use of this backbone includes the following: 1) As described above, in vitro studies have shown synergy of carfilzomib in combination with etoposide and other studies have evaluated synergy between cyclophosphamide and proteasome inhibitors; 2) Both cyclophosphamide and etoposide are active agents in pediatric leukemias [both lymphoid and myeloid] and solid tumors; 3) The combination has been used as a standard regimen to treat both solid tumors and leukemias; 4) Because of extensive experience with this regimen, the baseline toxicities are well known. This will be crucial in distinguishing toxicities of the backbone versus the carfilzomib; 5) There are multiple current adult combination trials with carfilzomib, some of which include cyclophosphamide or etoposide; 6) By the time of study enrollment, patients often will have received the maximum cumulative doses of anthracyclines, ruling out the use of anthracycline-containing treatment regimens; 7) Because of the rapid clearance in vivo in adult trials, it is thought that giving carfilzomib back-to-back with the standard chemotherapy will maximize synergy. Since the cyclophosphamide and etoposide regimen is given daily for 5 days, it can be given on the same days as the carfilzomib, utilizing the 5-day dosing schedule of theinitial Phase I adult carfilzomib trial.