Toxicities
DLTs are summarized in Table 2 . Three dosage levels were
assessed in Stratum I. At dosage level 1 (50 mg/m2),
0/3 patients experienced a DLT. At dosage level 2 (75
mg/m2), there were no DLTs in the first 3 patients,
prompting dose escalation. At dosage level 3 (95
mg/m2), there were 6 patients enrolled, 4 of which
were evaluable (1 patient received less than the required amount of
study agent due to progressive disease and 1 patient voluntarily
withdrew after initiating protocol therapy). Two of the 4 patients
developed grade 4 neutropenia. Hence the MTD was exceeded at dosage
level 3, and a total of 9 additional patients were enrolled at dosage
level 2. An MTD of 75 mg/m2 was established for
Stratum I, with only 2/12 patients experiencing a DLT (Table
2 ).
We proceeded to Stratum II after establishing a MTD for Stratum I. Given
concern for myelosuppression in the heavily pretreated patients,
enrollment in Stratum II was started at 50 mg/m2 (1
dose level below the MTD of Stratum I). Four patients were enrolled at
50 mg/m2, all were evaluable with no DLTs. This
prompted a dose increase to 75 mg/m2 where a total of
10 subjects were enrolled and 7 were evaluable for DLT assessment (2
patients progressed before receiving sufficient study drug and 1 patient
withdrew prior to treatment initiation). No DLT was observed among the
first 6 evaluable subjects. There was no intent of escalating beyond the
MTD of Stratum I, so the cohort was expanded to include a total of 12
patients. However, slow accrual prompted closure of the study prior to
completing enrollment. One of 7 evaluable patients experienced a DLT,
establishing 75 mg/m2 as the MTD for both Stratum I
and II.
Adverse events associated with palbociclib in Stratum I and II are
outlined in Table 3 and Table 4 , respectively. Similar
to the side effect profile in adults,18 the most
common adverse events were related to myelosuppression with decrease in
white blood cells, neutrophils, lymphocytes, and platelets being the
most common.