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

• Published in: Clinical cancer research 2012-12, Vol.18 (23), p.6509-6518
• Main Authors: KAYE, Stanley B, FEHRENBACHER, Louis, REDDY, Josina C, HOLLOWAY, Robert, AMIT, Amnon, KARLAN, Beth, SLOMOVITZ, Brian, SABBATINI, Paul, LING FU, YAUCH, Robert L, CHANG, Ilsung
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Anilides - administration & dosage; Anilides - adverse effects; Anilides - therapeutic use; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Biomarkers - metabolism; Female; Female genital diseases; Gynecology. Andrology. Obstetrics; Humans; Maintenance Chemotherapy; Medical sciences; Middle Aged; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - mortality; Ovarian Neoplasms - pathology; Pharmacology. Drug treatments; Pyridines - administration & dosage; Pyridines - adverse effects; Pyridines - therapeutic use; Remission Induction; Treatment Outcome; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-12-1796

Hedgehog 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 Hedgehog 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). 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 three to 14 weeks after completing chemotherapy. Treatment continued until radiographic progression or toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS). 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 [HR 0.79; 95% confidence interval (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 in the vismodegib arm were dysgeusia/ageusia, muscle spasms, and alopecia. Grade 3/4 adverse events occurred in 12 patients (23.1%) with vismodegib and six (11.5%) with placebo. Hedgehog expression was detected in 13.5% of archival tissues. 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 Hedgehog ligand expression was lower than expected.