A randomized phase II trial of vismodegib versus placebo with FOLFOX or FOLFIRI and bevacizumab in patients with previously untreated metastatic colorectal cancer.
Clin Cancer Res
; 19(1): 258-67, 2013 Jan 01.
Article
en En
| MEDLINE
| ID: mdl-23082002
PURPOSE: Vismodegib, a Hedgehog pathway inhibitor, has preclinical activity in colorectal cancer (CRC) models. This trial assessed the efficacy, safety, and pharmacokinetics of adding vismodegib to first-line treatment for metastatic CRC (mCRC). EXPERIMENTAL DESIGN: Patients were randomized to receive vismodegib (150 mg/day orally) or placebo, in combination with FOLFOX or FOLFIRI chemotherapy plus bevacizumab (5 mg/kg) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Key secondary objectives included evaluation of predictive biomarkers and pharmacokinetic drug interactions. RESULTS: A total of 199 patients with mCRC were treated on protocol (124 FOLFOX, 75 FOLFIRI). The median PFS hazard ratio (HR) for vismodegib treatment compared with placebo was 1.25 (90% CI: 0.89-1.76; P = 0.28). The overall response rates for placebo-treated and vismodegib-treated patients were 51% (90% CI: 43-60) and 46% (90% CI: 37-55), respectively. No vismodegib-associated benefit was observed in combination with either FOLFOX or FOLFIRI. Increased tumor tissue Hedgehog expression did not predict clinical benefit. Grade 3 to 5 adverse events reported for more than 5% of patients that occurred more frequently in the vismodegib-treated group were fatigue, nausea, asthenia, mucositis, peripheral sensory neuropathy, weight loss, decreased appetite, and dehydration. Vismodegib did not alter the pharmacokinetics of FOLFOX, FOLFIRI, or bevacizumab. CONCLUSIONS: Vismodegib does not add to the efficacy of standard therapy for mCRC. Compared with placebo, treatment intensity was lower for all regimen components in vismodegib-treated patients, suggesting that combined toxicity may have contributed to lack of efficacy.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias Colorrectales
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Protocolos de Quimioterapia Combinada Antineoplásica
Tipo de estudio:
Clinical_trials
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Guideline
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Prognostic_studies
Límite:
Adult
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Aged
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Aged80
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Año:
2013
Tipo del documento:
Article