This pediatric phase I trial establishes the MTD of MK-0752 as 260 mg/m2
/dose orally daily for 3 consecutive days of every 7 days. Observed DLTs included increased ALT and AST. Two of the initial six patients experienced DLTs at the MTD that was defined by CRM. The traditional 3 + 3 design would have resulted in finding this dose level to be too toxic and thus would have led to a de-escalation to 200 mg/m2
/dose. However, the extended cohort of 12 patients at the 260 mg/m2
/dose dose level led to only one additional DLT, thus confirming the safety of the recommended dose by CRM. Unlike in adult studies,33,34
dose-limiting diarrhea and GI symptoms were not observed in this study. A recent study by Real et al35
reported that, in a xenograft model of glucocorticoid resistant T-cell acute lymphatic leukemia, GSI treatment resulted in accumulation of goblet cells in the gut, while glucocorticoid therapy led to transcriptional upregulation of cyclin D2 and protected mice from developing the intestinal goblet cell metaplasia typically induced by inhibition of NOTCH signaling with GSIs. These data suggest that the use of steroids may reduce the gut toxicity of GSIs. In the current cohort, seven patients (30%) were receiving steroids while on study, which may in part explain the lack of GI toxicity noted in this study compared with that in adults. Although increased fatigue did occur in some patients, the fatigue was not dose-limiting, as reported in adult studies. No objective responses were observed, and only two patients had SD for ≥ 3 months.
To the best of our knowledge, this is the first description of MK-0752 disposition in children with cancer, and since no pharmacokinetic studies of MK-0752 have been published in adults, it is unknown how they compare. However, data from two meeting abstracts33,34
suggest that the disposition (eg, AUC, Cmax
) is similar. MK-0752 was absorbed slowly, with a range of 2.2 to 17 hours required to reach maximum plasma concentrations. Although some variability was observed in the maximum MK-0752 plasma concentration at the 260 mg/m2
dosage level, it was not as much as that observed for other phase I drugs (ie, 2.4-fold v
Finally, measures of MK-0752 systemic exposure (eg, AUC and Cmax
) were related to pharmacodynamic measures, but no relation was observed. It should be noted that total drug (bound and unbound) was used in this analysis, and for a highly protein-bound drug such as MK-0752 (percent unbound, 0.4%; unpublished results), exposure to the unbound drug may be more informative.
IHC analyses confirmed frequent and high-level expression of the NOTCH family and active downstream signal intermediates in pediatric brain tumors. Particularly high-level expression of cleaved nuclear NOTCH1 was observed in a patient with choroid plexus carcinoma. These data are compatible with reports that Notch signaling critically regulates choroid plexus development39,40
and drives tumorigenesis in the choroid plexus.41
The mechanism that mediates this high level of NOTCH signaling in relapsed tumors and its pathogenic significance remain to be determined. Our study also confirms prior reports42
that cleaved NOTCH1 and its downstream targets can be readily detected in PBMCs; however, our initial studies indicate this is not likely to be a useful assay for detecting in vivo activity of MK-0752. Further work will be required to determine whether PBMC NICD1 correlates with in vivo drug activity in patients with brain tumors.
This study demonstrates that MK-0752 is well-tolerated in children at the dose and schedule studied. However, there were no objective responses, and only two patients experienced prolonged stabilization of disease for at least three cycles. Preclinical models indicate that a once-weekly regimen of MK-0752 is well-tolerated and efficacious with no significant difference in efficacy in rodent models between 3 days on and 4 days off and once weekly dosing.43,44
On the basis of these data, a once-weekly schedule for MK-0752 is currently being explored in adults with recurrent CNS malignancies.