Table 1.
Published clinical data with hedgehog signaling pathway inhibitors in the past five years.
| Disease Type | Clinical Trial Phase (# Patients) | Dosing and Schedule | Adverse Events (G3-5 ≥ 10%) | Activities |
|---|---|---|---|---|
| Extensive stage SCLC | II (152) [42] | Cisplatin/etoposide q3w, with or without vismodegib 150 mg daily x 4 cycles | G3-5 neutropenia (53%), febrile neutropenia (12%) | ORR 56%, PFS 4.4 months, OS 9.8 months, similar to cisplatin, etoposide arm |
| I (15) [41] | Cisplatin/etoposide q3w, sonidegib 400 mg and 800 mg daily (MTD: 800 mg) | G3/4 anemia (33%), neutropenia (53%), CK elevation (13%), fatigue (13%), nausea (13%). DLT: nausea, febrile neutropenia | PR: 79% | |
| Advanced solid tumors | I (103) [35] | Sonidegib 100 to 3000 mg daily and 250 to 750 mg twice daily (MTD: 800 mg daily and 250 mg twice daily) | G3/4 nausea (25%), dysgeusia (29%), anorexia (29%), muscle spasms (32%), fatigue or asthenia (27%). DLT: G3/4 CK elevation (18%) | CR/PR: 37% for BCC, 33% for medulloblastoma; SD: 23% |
| I (45) [36] | Sonidegib 400 to 800 mg daily (RD: 400 mg daily) | G3/4 elevated LFT (15%). DLT: G3/4 CK elevation (24%), rhabdomyolysis (10%) | SD: 33% | |
| I (94) [37] | IPI-926 20 to 210 mg daily (RD: 160 mg daily) | G3/4 anemia (18%), elevated LFT (66%), fatigue (37%). DLT: G3 LFT elevation, fatigue, anorexia | ORR 29% in BCC cohort | |
| I (23) [39] | Glasdegib 80 to 640 mg daily (MTD: 320 mg daily) | DLT: G2 fatigue, hypotension and G3 nausea, vomiting, dehydration at 640 mg daily | SD: 35% | |
| I (34) [40] | TAK-441 50 to 1600 mg daily (MTD: 1600 mg daily) | G3/4: hyponatremia (12%), DLT: muscle spasms and fatigue | PR: 3%, SD: 21% | |
| Advanced or metastatic BCC or Basal-cell nevus syndrome or Resectable BCC |
II (230) [53] | Sonidegib 200 mg vs. 800 mg daily | G3/4 elevated CK (13% in 800 mg arm) | ORR: 36% in 200 mg arm, 34% in 800 mg arm |
| II (41) [50,51] | Vismodegib 150 mg daily vs. placebo for 18 months | G3/4 weight loss (15%) | New surgically eligible BCC: 2 (vismodegib) vs. 29 (placebo) cases per year | |
| II (229) [52] | vismodegib 150 mg daily x 12 wks, then placebo x 24 wks, then 150 mg daily x 12 wks (arm A) vs. vismodegib 150 mg daily x 24 wks, then placebo x 24 wks, then 150 mg daily x 8 wks (arm B) | G3/4 muscle spasm (4% in arm A,11% in arm B) | Number of lesion reduction: 63% in arm A, 54% in arm B. | |
| II (1215) open-label safety trial [46,47] | Vismodegib 150 mg daily | ORR: 68% in locally advanced BCC, 37% in metastatic BCC | ||
| II (15), neoadjuvant [48] | Vismodegib 150 mg daily x 3-6 months before surgery | Surgical defect area reduction: 27% | ||
| II (24) before surgery [49] | Vismodegib 150 mg daily before surgery for cohort 1: 12 wks, cohort 2: 12 wks, then 24 wks observation, cohort 3: 8 wks on, 4 wks off, 8 wks on | Most frequent adverse events: muscle spasms (76%), alopecia (58%), and dysgeusia (50%). | Complete histologic clearance: 42% for cohort 1, 16% for cohort 2, 44% for cohort 3. | |
| II (29) open-label [54] | Itraconazole oral 200 mg twice daily x 1-month vs. 100 mg twice daily x 2.3 months | G4 congestive heart failure | cell proliferation reduction: 45%, Hh activity reduction: 65%, tumor size reduction: 24% | |
| Recurrent or refractory medulloblastoma | I/II (55) [57] | Adult: Sonidegib 800 mg daily, pediatric: 680 mg/m2 (RD) | In adult: G3/4 elevated CK (31%), elevated LFT (12%) | ORR: 50% in patients with activated Hh pathway |
| I (33) [55] | Vismodegib 85 to 170 mg/m2, revised to 150 and 300 mg daily (RD) | DLT: G3 γ-glutamyl transferase elevation, thrombocytopenia, G4 hypokalemia | One patient with SHH- subgroup had response | |
| II (43) [56] | Vismodegib 150 mg daily | G3/4 lymphopenia (30%), seizure (12%) | No response in non-SHH-subgroup. 15% in adult patients with SHH-subgroup, 41% with prolonged disease stabilization | |
| Advanced or metastatic pancreatic adenocarcinoma | I (15) [60] | FOLFIRINOX and IPI-926 130 to 160 mg daily (MTD: 130 mg daily) | G3/4 infection (13%), thrombocytopenia (13%), DLT: G3 elevated LFTs (20%) | ORR: 67% |
| Ib/II (113) [59] | Gemcitabine with or without vismodegib 150 mg daily | G3-5 neutropenia (28%), fatigue (13%), thrombocytopenia (11%) | Similar ORR, PFS, and OS | |
| I (25) [58] | Vismodegib 150 mg daily x 3 wks, then vismodegib + gemcitabine | G3 anemia (12%), LFT elevation (12%) | GLI1 inhibition: 96%, PTCH1 inhibition: 83%, ORR 22%, disease control rate: 65%. | |
| Metastatic castration-resistant prostate cancer | I (9) [61] | Vismodegib 150 mg daily x 4 wks | G3/4 anemia (11%), dehydration (11%), dyspnea (11%), pain (22%), pneumonia (11%), vomiting (11%) | GLI1 inhibition: 57% in tumor, 75% in normal skin. No response. Median PFS 1.9 months, OS 7.0 months |
| II (46) [25] | Itraconazole 200 mg vs. 600 mg daily | G3 (600 mg arm) hypokalemia (10%) | PSA PFS at 24 weeks (200 vs. 600 mg): 12% vs. 48%. | |
| Metastatic colorectal cancer | II (199) [63] | Vismodegib 150 mg daily or placebo with FOLFOX or FOLFIRI and bevacizumab | G3-5 neutropenia (22%), diarrhea (12%), nausea (10%), fatigue (18%), weight loss (10%), dehydration (12%) | median PFS HR 1.25 (p = 0.3), ORR 46% vs. 51% for vismodegib vs. placebo |
| Advanced chondrosarcoma | II (45) [65] | Vismodegib 150 mg daily | 6-month clinical benefit rate 25.6%. median PFS 3.5 months | |
| Advanced gastric or GEJ adenocarcinoma | II (124), [64] | FOLFOX with or without vismodegib 150 mg daily | G3-5 neutropenia (83%), neuropathy (32%), fatigue (25%), thrombosis (23%), anemia (17%), GI bleeding (13%), hypokalemia (17%), nausea (13%). | ORR 58%, median PFS 7.3 months, OS 11.5 months. |
| Lung adenocarcinoma | II (23), 2nd-line setting [27] | Pemetrexed with or without itraconazole 200 mg daily (stopped early due to 1st-line pemetrexed | G3/4 (itraconazole arm) lymphopenia (20%) | PFS at 3 months (itraconazole vs. no itraconazole): 67% vs. 29% |
| Hematologic malignancies or myelofibrosis | I (13), Japanese patients [68] | Glasdegib 25 to 100 mg daily (RD: 100 mg daily) | G3-4 thrombocytopenia (23%), hypokalemia (15%), DLT: none | AML: CR 8%, SD 31%; MDS: CR 8%, SD 16%. |
| I (47) [69] | Glasdegib 5 to 600 mg daily (MTD: 400 mg daily, RD: 200 mg daily or lower) | G3-4 anorexia (11%) DLT: G3 hypoxia, pleural effusion, peripheral edema | CML: partial cytogenetic response 20%; MDS/CMML: SD 57%; myelofibrosis: improvement 29%; AML: ORR 32%, SD 25% | |
| II (14) [72] | IPI-926 160 mg daily | G3-4 bilirubin elevation (21%) | <50% spleen size reduction: 86%; 64% had no response | |
| NHL and CLL | II (31) [73] | Vismodegib 150 mg daily | G3-5 29% | Indolent lymphoma: (17%) |
| AML and high risk MDS | II (35) [70] | Glasdegib 100 mg daily x 4 months, 200 mg daily allowed for SD | G3-4 infection (11%) | ORR: 6%; SD: 54%; median OS: 10.2 months |
| Ib (52) [74] | Glasdegib 100 or 200 mg daily with low-dose cytarabine (arm A) or decitabine (arm B) or cytarabine/daunorubicin (arm C). RD: 100 mg daily | G3-4 febrile neutropenia (A: 39%, C: 54%), fatigue (A: 22%), neutropenia (A: 22%, B: 57%), anemia (B: 29%), thrombocytopenia (A: 30%, B: 43%), pyrexia (C: 18%). No DLT in arms A, B, grade 4 neuropathy in arm C. | Arm A: CR 8.7% Arm B: CR 29% Arm C: CR 54% |
|
| II (132), ineligible for intensive chemotherapy [71] | Glasdegib 100 mg daily and low-dose cytarabine versus low-dose cytarabine alone | Glasdegib arm: more frequent febrile neutropenia. | Glasdegib + cytarabine vs. cytarabine: CR 15% vs. 2%; median OS: 8.3 vs. 4.9 months |
DLTs: dose limiting toxicities; MTD: maximum tolerated dose; RD: recommended dose; ORR: overall response rate; CR: complete response; PR: partial response; SD: stable disease; PFS: progression-free survival; OS: overall survival; G: grade; CK: creatine kinase; LFT: liver function tests; SHH: sonic hedgehog; PSA: prostate-specific antigen; FOLFIRINOX: 5-FU, leucovorin, oxaliplatin, irinotecan; FOLFOX: 5-FU, leucovorin, oxaliplatin; FOLFIRI: 5-FU, leucovorin, irinotecan; SCLC: small cell lung cancer; BCC: basal cell carcinoma; GEJ: gastroesophageal junction; AML: acute myeloid leukemia; MDS: myelodysplastic syndrome; CMML: chronic monocytic leukemia; NHL: non-Hodgkin lymphoma; CLL: chronic lymphocytic leukemia. Wks: weeks.