A phase II, randomized, placebo-controlled study of vismodegib as maintenance therapy in patients with ovarian cancer in second or third complete remission

Stanley B. Kaye, Louis Fehrenbacher, Robert Holloway, Amnon Amit, Beth Karlan, Brian Slomovitz, Paul Sabbatini, Ling Fu, Robert L. Yauch, Ilsung Chang, Josina C. Reddy

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Purpose: 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). 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 three to 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 [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. 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 Hedgehog ligand expression was lower than expected.

Original languageEnglish (US)
Pages (from-to)6509-6518
Number of pages10
JournalClinical Cancer Research
Volume18
Issue number23
DOIs
StatePublished - Dec 1 2012
Externally publishedYes

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HhAntag691
Ovarian Neoplasms
Placebos
Disease-Free Survival
Confidence Intervals
Therapeutics
Ageusia
Dysgeusia
Medulloblastoma
Second Primary Neoplasms
Fallopian Tubes
Basal Cell Carcinoma
Alopecia
Spasm
Research Design
Maintenance
Research Personnel

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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A phase II, randomized, placebo-controlled study of vismodegib as maintenance therapy in patients with ovarian cancer in second or third complete remission. / Kaye, Stanley B.; Fehrenbacher, Louis; Holloway, Robert; Amit, Amnon; Karlan, Beth; Slomovitz, Brian; Sabbatini, Paul; Fu, Ling; Yauch, Robert L.; Chang, Ilsung; Reddy, Josina C.

In: Clinical Cancer Research, Vol. 18, No. 23, 01.12.2012, p. 6509-6518.

Research output: Contribution to journalArticle

Kaye, Stanley B. ; Fehrenbacher, Louis ; Holloway, Robert ; Amit, Amnon ; Karlan, Beth ; Slomovitz, Brian ; Sabbatini, Paul ; Fu, Ling ; Yauch, Robert L. ; Chang, Ilsung ; Reddy, Josina C. / A phase II, randomized, placebo-controlled study of vismodegib as maintenance therapy in patients with ovarian cancer in second or third complete remission. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 23. pp. 6509-6518.
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abstract = "Purpose: 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). 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 three to 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 [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. 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 Hedgehog ligand expression was lower than expected.",
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T1 - A phase II, randomized, placebo-controlled study of vismodegib as maintenance therapy in patients with ovarian cancer in second or third complete remission

AU - Kaye, Stanley B.

AU - Fehrenbacher, Louis

AU - Holloway, Robert

AU - Amit, Amnon

AU - Karlan, Beth

AU - Slomovitz, Brian

AU - Sabbatini, Paul

AU - Fu, Ling

AU - Yauch, Robert L.

AU - Chang, Ilsung

AU - Reddy, Josina C.

PY - 2012/12/1

Y1 - 2012/12/1

N2 - Purpose: 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). 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 three to 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 [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. 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 Hedgehog ligand expression was lower than expected.

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