TABLE 3.
Small molecules targeting Hedgehog signaling and their clinical trials.
| Compound | Tumor type | Phase (Clinicaltrials.gov identifier) | Efficacy outcomes | Status | References |
|---|---|---|---|---|---|
| Vismodegib vs. placebo | Recurrent epithelial ovarian, primary peritoneal cancer or fallopian tube in second or third CR | Phase II (NCT00739661) | Median PFS: 7.5 months vs. 5.8 months with placebo | Magnitude of sought increase in PFS not achieved | 416 |
| Vismodegib or placebo in combination with FOLFOX or FOLFIRI plus bevacizumab | mCRC | Phase II | PFS: HR 1.25, 90% CI 0.89−1.76, p = 0.28; 1‐year OS: 81.4 vs. 80.1%; ORR: 51% in vismodegib arm vs. 46% in placebo arm | Development for CRC terminated | 417 |
| Vismodegib with gemcitabine | Advanced‐stage PDAC (25 with elevated SHH on pretreatment biopsy) | Phase II (NCT01195415) | Fibrosis decreased in 45.4% of 22 patients and Ki67 levels decreased in 52.9% of 17 patients; Gli1 and PTCH1 expression decreased in 95.6 and 82.6%, respectively, of 23 evaluable patients; Median OS: 5.3 months; DCR: 65.2%; Median PFS: 2.8 months; ORR: 21.7% | Development for PDAC terminated | 418 |
| Vismodegib or placebo with gemcitabine | Advanced‐stage PDAC | Phase I/II (NCT01064622) | Median OS: 6.9 months vs. 6.1 months (HR 1.04, 95% CI 0.69−1.58); PR rate: 8 vs. 11%; SD rate: 51 vs. 38%; Median PFS: 4.0 months vs. 2.5 months (HR 0.81, 95% CI 0.54−1.21); CR rate: 0% in vismodegib arm vs. 2% in placebo arm | Development for PDAC terminated | 419 |
| Vismodegib preoperatively and/or postoperatively | Recurrent resectable glioblastoma | Phase II (NCT00980343) | Median PFS and OS were 1.8 months and 8.3 months, respectively | Development for glioblastoma terminated | 420 |
| Vismodegib or placebo with FOLFOX | Advanced stage gastric or gastroesophageal junction adenocarcinoma | Phase II (NCT00982592) | Median PFS: 7.3 months vs. 8.0 months in the placebo group; ORR: 35% in both arms; Median OS: 11.5 months vs. 14.9 months with placebo | Development terminated for these diseases | 421 |
| Taladegib | Advanced‐stage cancer | Phase I (NCT01226485) | ORR: 26.2%; SD rate: 28.6%; | Clinical studies ongoing | 407 |
| Saridegib | Advanced‐stage solid tumors | Phase I | 6 PRs observed in 22 patients with HH inhibitor‐naïve BCC (27%) | Clinical studies ongoing | 422 |
| Saridegib (with cetuximab) |
Recurrent metastatic head and neck squamous cell carcinoma |
Phase I (NCT01255800) | Median PFS: 77 days; 12.5% evaluable patients had PR (1 of 8) and 50% had SD (4 of 8) | Clinical studies ongoing | 423 |
| Itraconazole | Biochemically relapsed prostate cancer | Phase II (NCT01787331) | 47% evaluable patients (9 of 19) had PSA declines by week 12 | Development for prostate cancer terminated | 424 |
| Itraconazole and pemetrexed | Metastatic nonsquamous non‐small cell lung cancer | Phase II | 15 patients received pemetrexed and itraconazole and 8 received pemetrexed alone); OS: 32 months vs. 8 months; Median PFS: 5.5 months vs. 2.8 months | Discontinued | 425 |
| Itraconazole with arsenic trioxide | Refractory metastatic BCC | Phase I | SD in 3 patients | Study ongoing, further results pending | 426 |
Abbreviations: ALT, alanine transaminase; AML, acute myeloid leukemia; AST, aspartate transaminase; BCC, basal cell carcinoma; CR, complete response; CRC, colorectal cancer; DCR, disease control rate; DoR, duration of response; FOLFIRI, folinic acid, 5‐fluorouracil and irinotecan; FOLFOX, folinic acid, 5‐fluorouracil and oxaliplatin; HH, Hedgehog; HR, hazard ratio; mCRC, metastatic colorectal cancer; ORR, objective response rate; OS, overall survival; PDAC, pancreatic ductal adenocarcinoma; PFS, progression‐free survival; PR, partial response; PSA, prostate‐specific antigen; SD, stable disease; SHH, Sonic hedgehog.