Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy

Table 3 mTOR Inhibitors: Phase I and Pharmacokinetic Data

mTOR Inhibitor	T_1/2 (h)	Primary Metabolite	Dose and Schedule	MTD	DLTs (all grade 3)	Suggested Phase II Dose
Ridaforolimus [22]	56-74	Not sirolimus pro-drug	3-28 mg/d IV × 5 d q 2 wk	18.75 mg	Mouth sores	12.5 mg IV × 5 d q 2 wk
Everolimus [25, 29]	~30	Not sirolimus pro-drug	Oral daily: 5-10 mg/d Oral weekly: 5-70 mg/wk	NR	Daily: hyperglycemia, stomatitis Weekly: stomatitis, fatigue, neutropenia, hyperglycemia	Daily: 10 mg Weekly: 50-70 mg
Temsirolimus [26]	13-22	Sirolimus	7.5-220 mg/m²/wk	Formal definition of MTD not met	Neutropenia, thrombocytopenia, hypophosphatemia; asthenia, diarrhea; manic-depressive syndrome, stomatitis; ALT elevation	25, 75, and 250 mg (flat dose) wkly

*In heavily pretreated patients.
^†In minimally pretreated patients, no MTD was established, but the maximum acceptable dose was 19 mg/m² due to grade 3 stomatitis and dose reductions in 2 patients.
NR = Not reached.

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