TABLE 1.
SMO inhibitors in clinical trials for the treatment of AML.
| SMO inhibitor | SMO inhibitor dosage | Combination | (Preliminary) Results | Clinical trial | Phase | Status | References |
|---|---|---|---|---|---|---|---|
| Vismodegib | 150 mg/day | Ribavirin, decitabine | — | NCT02073838 | II | Unknown | — |
| 150 mg/day | (Cytarabine) | Vismodegib well-tolerated; lower-than-expected efficacy for vismodegib monotherapy; no combination therapy performed | NCT01880437 | Ib/II | Terminated | Bixby et al. (2019) | |
| Not defined | Not defined | — | NCT03878524 | Ib | Recruiting | — | |
| Sonidegib | 2 × 400 mg/day or 800 mg/day | — | 100% of patients experienced ≥1 AE, 71% of patients experienced serious AEs; low CR rate (1.45% of patients), disease progression in 62% of patients | NCT01826214 | II | Completed | — |
| 400 mg/day | Azacitidine | AEs within the expected range; remission rates comparable to azacitidine monotherapy, promising progression-free and overall survival | NCT02129101 | I/Ib | Completed | Tibes et al. (2017) | |
| Glasdegib | 5, 10, 20, 40, 80, 120, 180, 270, 400 or 600 mg/day | - | Established MTD: 400 mg/day; AEs within the expected range; two patients experienced DLT (80 and 600 mg/day); clinical activity in 49% of patients | NCT00953758 | I | Completed | Martinelli et al. (2015a) |
| 25, 50 or 100 mg/day | LDAC, azacitidine, cytarabine/daunorubicin | Glasdegib + LDAC, well-tolerated; glasdegib + azacitidine, well-tolerated; glasdegib + cytarabine/daunorubicin, manageable despite increased severe AEs; low remission rates in glasdegib only cohort, increased in combination cohorts | NCT02038777 | I | Active | Minami et al. (2017) | |
| Ib: 100 or 200 mg/day; II: 100 mg/day | LDAC, decitabine, cytarabine/daunorubicin | Phase Ib: glasdegib in combination with LDAC or decitabine, well-tolerated; glasdegib + cytarabine/daunorubicin, increased severe AEs, manageable; 31% remission rate across all groups; Phase II: Glasdegib + cytarabine/daunorubicin, high CR rate; glasdegib + LDAC, drastically improved CR rate and OS in combination compared to LDAC only (17 vs 2.3% and 8.8 vs. 4.9 months) | NCT01546038 | Ib/II | Completed | Cortes et al. (2016); Cortes et al. (2018); Savona et al. (2018); Cortes et al. (2019b) | |
| 100 mg/day | Azacitidine | Well-tolerated; 20% of AML patients achieved CR | NCT02367456 | Ib | Completed | Sekeres et al. (2019) | |
| — | Cytarabine/daunorubicin, azacitidine | No improvement of OS through addition of glasdegib | NCT03416179 | III | Completed | Cortes et al. (2019a) | |
| 50, 75 or 100 mg/day | Azacitidine | — | NCT04842604 | III | Active | — | |
| Not defined | Bosutinib, decitabine, enasidenib, ivosidenib, venetoclax, gilteritinib | — | NCT04655391 | Pilot/Ib | Withdrawn | — | |
| 100 mg/daily | CPX-351 (cytarabine/daunorubicin) | — | NCT04231851 | II | Recruiting | — | |
| 100 mg/day | Gemtuzumab ozogamicin | — | NCT04168502 | III | Recruiting | — | |
| 100 mg/day | Decitabine | — | NCT04051996 | II | Terminated | — | |
| 100 mg/day | Gemtuzumab ozogamicin | — | NCT04093505 | III | Recruiting | — | |
| Not defined | Gemtuzumab ozogamicin | — | NCT03390296 | Ib/II | Active | — | |
| 100 mg/day | Decitabine, azacitidine, venetoclax | — | NCT03226418 | II | Recruiting | — |
AE, adverse event; CR, complete remission; DLT, dose-limiting toxicity; LDAC, low-dose cytarabine; MTD, maximum-tolerated dose; OS, overall survival.