Dataset Information

Sorafenib and dacarbazine as first-line therapy for advanced melanoma: phase I and open-label phase II studies.

ABSTRACT:

Method

The safety of oral sorafenib up to a maximum protocol-specified dose combined with dacarbazine in patients with metastatic, histologically confirmed melanoma was investigated in a phase I dose-escalation study and the activity of the combination was explored in an open-label phase II study.

Results

In the phase I study, three patients were treated with sorafenib 200 mg twice daily (b.i.d.) plus 1000 mg m(-2) dacarbazine on day 1 of a 21-day cycle and 15 patients had the sorafenib dose escalated to 400 mg b.i.d. without reaching the maximum tolerated dose of the combination. In the phase II study (n=83), the overall response rate was 12% (95% CI: 6, 21): one complete and nine partial, with median response duration of 46.7 weeks. Stable disease was the best response in 37%; median duration was 13.3 weeks. Median overall survival (OS) was 37.0 weeks (95% CI: 33.9, 46.0).

Conclusion

Oral sorafenib combined with dacarbazine had acceptable toxicity and some antineoplastic activity against metastatic melanoma.

SUBMITTER: Eisen T

PROVIDER: S-EPMC3172912 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Sorafenib and dacarbazine as first-line therapy for advanced melanoma: phase I and open-label phase II studies.

Eisen T T Marais R R Affolter A A Lorigan P P Robert C C Corrie P P Ottensmeier C C Chevreau C C Chao D D Nathan P D PD Jouary T T Harries M M Negrier S S Montegriffo E E Ahmad T T Gibbens I I James M G MG Strauss U P UP Prendergast S S Gore M E ME

British journal of cancer 20110712 3

<h4>Method</h4>The safety of oral sorafenib up to a maximum protocol-specified dose combined with dacarbazine in patients with metastatic, histologically confirmed melanoma was investigated in a phase I dose-escalation study and the activity of the combination was explored in an open-label phase II study.<h4>Results</h4>In the phase I study, three patients were treated with sorafenib 200 mg twice daily (b.i.d.) plus 1000 mg m(-2) dacarbazine on day 1 of a 21-day cycle and 15 patients had the sor ...[more]

PMID: 21750549

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Project description:Lessons learnedTrebananib leveraging anti-angiogenic mechanism that is distinct from the classic sorafenib anti-vascular endothelial growth factor inhibition did not demonstrate improved progression-free survival at 4 months in patients with advanced hepatocellular carcinoma (HCC).In support of previously reported high Ang-2 levels' association with poor outcome in HCC for patients, trebananib treatment with lower baseline Ang-2 at study entry was associated with improved overall survival to 22 months and may suggest future studies to be performed within the context of low baseline Ang-2.BackgroundAng-1 and Ang-2 are angiopoietins thought to promote neovascularization via activation of the Tie-2 angiopoietin receptor. Trebananib sequesters Ang-1 and Ang-2, preventing interaction with the Tie-2 receptor. Trebananib plus sorafenib combination has acceptable toxicity. Elevated Ang-2 levels are associated with poor prognosis in hepatocellular carcinoma (HCC).MethodsPatients with HCC, Eastern Cooperative Oncology Group ≤2, and Childs-Pugh A received IV trebananib at 10 mg/kg or 15 mg/kg weekly plus sorafenib 400 mg orally twice daily. The study was planned for ≥78% progression-free survival (PFS) rate at 4 months relative to 62% for sorafenib historical control (power = 80% α = 0.20). Secondary endpoints included safety, tolerability, overall survival (OS), and multiple biomarkers, including serum Ang-2.ResultsThirty patients were enrolled sequentially in each of the two nonrandomized cohorts. Demographics were comparable between the two arms and the historical controls. PFS rates at 4 months were 57% and 54% on the 10 mg/kg and 15 mg/kg trebananib cohorts, respectively. Median OS was 17 and 11 months, respectively. Grade 3 and above events noted in ≥10% of patients included fatigue, hypertension, diarrhea, liver failure, palmar-plantar erythrodysesthesia syndrome, dyspnea, and hypophosphatemia. One death was due to hepatic failure. Serum Ang-2 dichotomized at the median was associated with improved OS in both cohorts.ConclusionThere was no improvement in PFS rate at 4 months in either cohort, when compared with sorafenib historical control.

Dataset Information

Sorafenib and dacarbazine as first-line therapy for advanced melanoma: phase I and open-label phase II studies.

Method

Results

Conclusion

Publications

Sorafenib and dacarbazine as first-line therapy for advanced melanoma: phase I and open-label phase II studies.

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