Table 2.
Summary of clinical findings from Phase I trials of Smoothened inhibitors in cancer
| Parameter | GDC-0449 (vismodegib) Genentech |
IPI-926 Infinity |
LDE225 Novartis |
BMS-833923 (XL139) BMS/Exelexis |
PF-0449913 Pfizer |
|---|---|---|---|---|---|
| N (Phase I) | 68 | 104+ (ongoing) | 35+ (ongoing) | 27 | 39+ (ongoing) |
| Daily doses explored (mg) | 150–270–540 | 20–210 mg | 100–200–400–800–1500 | 30–60–120–240–360–540 | 5–10–20–40–80–120–180–270 |
| GLI1 inhibition | Yes | Yes | Yes | Yes | |
| Single dose t½ | >7d | ~4d (1–10)? | ~7d? | 17–35 hours | |
| MTD defined? | No (PK futility) | No | No | Yes | No |
| Grade 3 toxicities | ↓ Na, fatigue | ↑ LFTs, fatigue | Asthenia | ↓ phos, ↑ lipase | Hypoxia, pleural effusions, hemorrhagic gastritis |
| Most common toxicities | Muscle spasms Dysgeusia Fatigue |
Nausea, fatigue | Nausea Muscle spasms Fatigue |
Muscle spasms Dysgeusia |
Dysgeusia Arthralgias Alopecia Nausea Vomiting |