438 Imidazotetrainone prodrugs (temozolomide analogues) with activity independent of mismatch repair and alkyltransferase

grade 4 neutropenia in cycle 1. Nadir occurred at 14 days (10−16) and median time to recovery was 5 days (1−8). Nonhematological toxicity was mild/moderate and reversible: fatigue (82%), nausea (50%), diarrhea (18%) and transaminase increase (50%). There was marked interindividual pharmacokinetic (PK) variability (clearance 11.0±5.5 L/hr), with a median terminal half-life at the RD of 58 hr. There was no significant association of dose or BSA with clearance, and there was a stronger correlation of AUC than dose (mg/m) with neutropenia (vs. log ANC, r = −0.92 vs. −0.72). Conclusions: PM01183 can be safely administered at the RD of 7.0mg (>200 times the starting dose), although intrapatient dose escalation may be warranted given the magnitude of interindividual PK variability and its association with neutropenia. Cohort expansion is ongoing at the RD to better define PK/pharmacodynamic relationships, and to screen for antitumor activity.