Abstract LB-138: Efficacy data of GDC-0449, a systemic Hedgehog pathway antagonist, in a first-in-human, first-in-class Phase I study with locally advanced, multifocal or metastatic basal cell carcinoma patients
Authors: Von Hoff Daniel D , Rudin Charles M , LoRusso Patricia M , Borad Mitesh J , Korn Ronald L , Heath Elisabeth I , Yauch Robert , Darbonne Walter C , Kadel Edward E , Zerivitz Kenn L , Nelson Lisa E , Mackey Howard , Marsters James C , de Sauvage Frederic J , Low Jennifer A 
Published: May 2019

Abstract
Background: Aberrant Hedgehog signaling due to PATCHED or SMOOTHENED mutations is critical to the development of both hereditary and sporadic human basal cell carcinomas (BCCs). GDC-0449 is a first-in-class, potent, oral systemic inhibitor of Hedgehog signal transduction. A dose escalation Phase I trial for refractory solid tumors was conducted. Because of activity seen in initial patients with BCC, an expansion cohort was added to evaluate activity in locally advanced, multifocal, or metastatic BCC patients.
Methods: Patients were enrolled in a first-in-human, 3+3 design Phase I study with modified dose doubling to evaluate safety, tolerability, maximum tolerated dose, pharmacokinetics, and pharmacodynamics. In the dose escalation portion, patients received 150, 270, or 540 mg GDC-0449 administered orally as a single dose on day 1, followed by a 1-week pharmacokinetics break, and then once daily on a continuous 28-day schedule (cycle 1=35 days). The expansion cohort BCC patients received 150 mg GDC-0449 daily without interruption beginning day 1. Surrogate tissues were assessed for expression levels of Hedgehog target gene, GLI1.
Results: Eight of 9 BCC patients enrolled have been evaluated. In 4 patients with measurable met disease, 2 confirmed RECIST partial responses, 1 stable disease, and 1 progressive disease have been observed. In 4 patients with clinically evaluable locally advanced or multifocal disease, 2 patients had complete response in subcutaneous masses by physical exam and 2 patients had stable disease in skin lesions. One met BCC patient is too early to assess. Metabolic responses by EORTC positron emission tomography (PET) criteria were achieved in 5 out of 5 patients to date. Durable clinical benefit (range 56+ to 375+ days, median 112+ days) was achieved in 8 out of 9 patients. GLI1 expression in skin biopsies was reduced &gt;2-fold in all patients tested to date.
Conclusions: GDC-0449 was evaluated in locally advanced, multifocal, and metastatic BCC patients on a continuous daily oral schedule and without significant toxicities. Antitumor activity was observed in almost all BCC patients enrolled, thereby confirming the importance of inhibiting aberrant Hedgehog signaling in BCC.
Table 1.BCC Patient Data for GDC-0449 Phase I StudyPt #Disease State (Site)Dose [mg] (Cohort)GLI1 Reduction (&gt;2-fold)PET ResponseRECIST ResponseComments1met150 (DE)++PR*375+ days on study, improved dyspnea, decreased bone pain2LA (ear)270 (DE)++CR (physical exam184+ days, reduced ear canal drainage, mutant PATCHED3met540 (DE)NDNDPD45 days on study, ear lesion healing4met150 (EC)++PR126+ days, improved dyspnea, reduced fatigue5LA (ear)150 (EC++CR (physical exam)112+ days, decreased ear bleeding6MF150 (EC)++SD113+ days, skin lesions healing7met150 (EC)NDNDSD67+ days, improved dyspnea8MF150 (EC)NDPET negSD60+ days, skin lesions healing9met150 (EC)NDTETE56+ days*PR, partial response; CR, complete response; SD, stable disease; PD, progressive disease.