e13616 Background: TH-302 is essentially inactive in normoxic conditions and is activated in regions of severe hypoxia (<1% O2 saturation), releasing a bromo-isophosphoramide mustard that alkylates DNA. The epidermis and superficial mucosa contain areas of severe hypoxia; TH-302 can produce events in these regions that likely represent the local activation of TH-302.
METHODS
Tx guidelines to prevent and manage TH-302-induced events were empirically developed with research personnel during three phase I/II clinical trials (Table).
RESULTS
Dermatologic events associated with TH-302 in the three trials (n = 355) included rash (41%), stomatitis/mucosal inflammation (33%), hyperpigmentation (14%), hand foot syndrome (7%), and cheilitis (3%). Of these, 7% were grade 3; none were grade 4 or 5. The skin/mucosal events were dose-proportional, predictable, and reversible. Implementation of tx guidelines decreased the frequency and severity of these events.
CONCLUSIONS
The tx guidelines allow TH-302 administration at clinically active doses and should be prospectively investigated in future comparative studies. [Table: see text].