TY - JOUR
T1 - Phase i study of ly2940680, a smo antagonist, in patients with advanced cancer including treatment-naïve and previously treated basal cell carcinoma
AU - Bendell, Johanna
AU - Andre, Valerie
AU - Ho, Alan
AU - Kudchadkar, Ragini
AU - Migden, Michael
AU - Infante, Jeffrey
AU - Tiu, Ramon V.
AU - Pitou, Celine
AU - Tucker, Trevor
AU - Brail, Les
AU - Hoff, Daniel Von
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/5/1
Y1 - 2018/5/1
N2 - Purpose: The purpose of this study was to determine a recommended phase II dose and schedule of LY2940680 (taladegib) for safe administration to patients with locally advanced/metastatic cancer. Experimental Design: This was a phase I, multicenter, open-label study of oral LY2940680. The maximum tolerable dose (MTD) was determined using a 3þ3 design, the dose was confirmed, and then treatment-na€ve and previously hedgehog (Hh)-inhibitor–treated patients with basal cell carcinoma (BCC) were enrolled. Results: Eighty-four patients were treated (dose escalation, n ¼ 25; dose confirmation, n ¼ 19; and BCC dose expansion, n ¼ 40). Common treatment-emergent adverse events were dysgeusia [41 (48.8%)], fatigue [40 (47.6%)], nausea [38 (45.2%)], and muscle spasms [34 (40.5%)]. Four patients experienced events (3 were grade 3; 1 was grade 2) that were considered dose-limiting toxicities (DLT). The MTD was determined to be 400 mg because of DLTs and dose reductions. Pharmacokinetic analyses showed no clear relationship between exposure and toxicity. Analysis of Gli1 mRNA from skin biopsies from unaffected areas suggested that all doses were biologically active [inhibition median of 92.3% (80.9% to 95.7%)]. All clinical responses (per RECIST 1.1) were in patients with BCC (n ¼ 47); the overall and estimated response rate was 46.8% (95% confidence interval, 32.1%–61.9%). Responses were observed in patients previously treated with Hh therapy (11/31) and in Hh treatment–na€ve (11/16) patients. Conclusions: LY2940680 treatment resulted in an acceptable safety profile in patients with advanced/metastatic cancer. Clinical responses were observed in patients with locally advanced/metastatic BCC who were previously treated with Hh therapy and in Hh treatment–na€ve patients.
AB - Purpose: The purpose of this study was to determine a recommended phase II dose and schedule of LY2940680 (taladegib) for safe administration to patients with locally advanced/metastatic cancer. Experimental Design: This was a phase I, multicenter, open-label study of oral LY2940680. The maximum tolerable dose (MTD) was determined using a 3þ3 design, the dose was confirmed, and then treatment-na€ve and previously hedgehog (Hh)-inhibitor–treated patients with basal cell carcinoma (BCC) were enrolled. Results: Eighty-four patients were treated (dose escalation, n ¼ 25; dose confirmation, n ¼ 19; and BCC dose expansion, n ¼ 40). Common treatment-emergent adverse events were dysgeusia [41 (48.8%)], fatigue [40 (47.6%)], nausea [38 (45.2%)], and muscle spasms [34 (40.5%)]. Four patients experienced events (3 were grade 3; 1 was grade 2) that were considered dose-limiting toxicities (DLT). The MTD was determined to be 400 mg because of DLTs and dose reductions. Pharmacokinetic analyses showed no clear relationship between exposure and toxicity. Analysis of Gli1 mRNA from skin biopsies from unaffected areas suggested that all doses were biologically active [inhibition median of 92.3% (80.9% to 95.7%)]. All clinical responses (per RECIST 1.1) were in patients with BCC (n ¼ 47); the overall and estimated response rate was 46.8% (95% confidence interval, 32.1%–61.9%). Responses were observed in patients previously treated with Hh therapy (11/31) and in Hh treatment–na€ve (11/16) patients. Conclusions: LY2940680 treatment resulted in an acceptable safety profile in patients with advanced/metastatic cancer. Clinical responses were observed in patients with locally advanced/metastatic BCC who were previously treated with Hh therapy and in Hh treatment–na€ve patients.
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U2 - 10.1158/1078-0432.CCR-17-0723
DO - 10.1158/1078-0432.CCR-17-0723
M3 - Article
C2 - 29483143
AN - SCOPUS:85047814227
SN - 1078-0432
VL - 24
SP - 2082
EP - 2091
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 9
ER -