A Phase II, Randomized, Placebo-Controlled Study of Vismodegib as Maintenance Therapy in Patients with Ovarian Cancer in Second or Third Complete Remission.

Abstract

Abstract PURPOSE: Hedgehog (Hh) pathway inhibition has been suggested as a potential maintenance treatment approach in ovarian cancer through disruption of tumor-stromal interactions. Vismodegib is an orally available Hh pathway inhibitor with clinical activity in advanced basal cell carcinoma and medulloblastoma. This phase II, randomized, double-blind, placebo-controlled trial was designed to provide a preliminary estimate of efficacy in patients with ovarian cancer in second or third complete remission (CR).

EXPERIMENTAL DESIGN:

Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in second or third CR were randomized 1:1 to vismodegib (GDC-0449; 150 mg daily) or placebo 3-14 weeks after completing chemotherapy. Treatment continued until radiographic progression or toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS).

RESULTS:

One hundred four patients were randomized to vismodegib (n=52) or placebo (n=52); median PFS was 7.5 months and 5.8 months, respectively (hazard ratio [HR] 0.79 [95% CI, 0.46-1.35]). The HR was 0.66 (95% CI, 0.36-1.20) for second CR patients (n=84) and 1.79 (95% CI, 0.50-6.48) for third CR patients (n=20). The most common adverse events (AEs) in the vismodegib arm were dysgeusia/ageusia, muscle spasms, and alopecia. Grade 3/4 AEs occurred in 12 patients (23.1%) with vismodegib and six (11.5%) with placebo. Hh expression was detected in 13.5% of archival tissues.

CONCLUSIONS:

In this study the sought magnitude of increase in PFS was not achieved for vismodegib maintenance versus placebo in patients with ovarian cancer in second or third CR. The frequency of Hh ligand expression was lower than expected.