Phase II trial of sorafenib in combination with carboplatin and paclitaxel in patients with metastatic uveal melanoma: SWOG S0512.

BackgroundSorafenib, a multikinase inhibitor of cell proliferation and angiogenesis, inhibits the mitogen-activated protein kinase pathway that is activated in most uveal melanoma tumors. This phase II study was conducted by the SWOG cooperative group to evaluate the efficacy of sorafenib in combination with carboplatin and paclitaxel (CP) in metastatic uveal melanoma.MethodsTwenty-five patients with stage IV uveal melanoma who had received 0-1 prior systemic therapy were enrolled. Treatment included up to 6 cycles of carboplatin (AUC = 6) and paclitaxel (225 mg/m(2)) administered IV on day 1 plus sorafenib (400 mg PO twice daily), followed by sorafenib monotherapy until disease progression. The primary endpoint was objective response rate (ORR); a two-stage design was used with the study to be terminated if no confirmed responses were observed in the first 20 evaluable patients. Secondary efficacy endpoints included progression-free survival (PFS) and overall survival (OS).ResultsNo confirmed objective responses occurred among the 24 evaluable patients (ORR = 0% [95% CI: 0-14%]) and the study was terminated at the first stage. Minor responses (tumor regression less than 30%) were seen in eleven of 24 (45%) patients. The median PFS was 4 months [95% CI: 1-6 months] and the 6-month PFS was 29% [95% CI: 13%-48%]. The median OS was 11 months [95% CI: 7-14 months].ConclusionIn this study, the overall efficacy of CP plus sorafenib in metastatic uveal melanoma did not warrant further clinical testing when assessed by ORR, although minor tumor responses and stable disease were observed in some patients.Trial registrationClinicalTrials.govNCT00329641

Phase II Trial of Sorafenib in Combination with Carboplatin and Paclitaxel in Patients with Metastatic Uveal Melanoma: SWOG S0512

<div><h3>Background</h3><p>Sorafenib, a multikinase inhibitor of cell proliferation and angiogenesis, inhibits the mitogen-activated protein kinase pathway that is activated in most uveal melanoma tumors. This phase II study was conducted by the SWOG cooperative group to evaluate the efficacy of sorafenib in combination with carboplatin and paclitaxel (CP) in metastatic uveal melanoma.</p> <h3>Methods</h3><p>Twenty-five patients with stage IV uveal melanoma who had received 0–1 prior systemic therapy were enrolled. Treatment included up to 6 cycles of carboplatin (AUC = 6) and paclitaxel (225 mg/m²) administered IV on day 1 plus sorafenib (400 mg PO twice daily), followed by sorafenib monotherapy until disease progression. The primary endpoint was objective response rate (ORR); a two-stage design was used with the study to be terminated if no confirmed responses were observed in the first 20 evaluable patients. Secondary efficacy endpoints included progression-free survival (PFS) and overall survival (OS).</p> <h3>Results</h3><p>No confirmed objective responses occurred among the 24 evaluable patients (ORR = 0% [95% CI: 0–14%]) and the study was terminated at the first stage. Minor responses (tumor regression less than 30%) were seen in eleven of 24 (45%) patients. The median PFS was 4 months [95% CI: 1–6 months] and the 6-month PFS was 29% [95% CI: 13%–48%]. The median OS was 11 months [95% CI: 7–14 months].</p> <h3>Conclusion</h3><p>In this study, the overall efficacy of CP plus sorafenib in metastatic uveal melanoma did not warrant further clinical testing when assessed by ORR, although minor tumor responses and stable disease were observed in some patients.</p> <h3>Trial Registration</h3><p><a href="http://ClinicalTrials.gov">ClinicalTrials.gov</a><a href="http://www.clinicaltrials.gov/ct2/show/NCT00329641?term=NCT00329641&rank=1">NCT00329641</a></p> </div

Baseline Characteristics and Demographics of 24 Evaluable Patients.

<p>Baseline Characteristics and Demographics of 24 Evaluable Patients.</p

Best tumor response (waterfall plot) in evaluable patients (n = 24).

<p>The bars on each plot represent the largest decrease under baseline of the sum of longest diameters of all target measurable lesions, or if no decrease was observed, the smallest increase in the sum of longest diameters of target measurable lesions. Patients whose best response was progression due to new lesions, death (due to disease), or clear worsening of non-measurable disease are represented by a bar showing a 100% increase. In addition, patients whose best response could not be determined due to inadequate assessment are represented on the far left side of the plot as a solid bar showing 100% increase.</p

Summary of Grade 3 or 4 Treatment-related Adverse Events.

<p><i>Abbreviations</i>: ANC, Absolute Neutrophil Count; CTCAE, Common Terminology Criteria for Adverse Events; NCI, National Cancer Institute.</p

Kaplan-Meier curve for progression-free survival in evaluable patients (n = 24).

<p>Kaplan-Meier curve for progression-free survival in evaluable patients (n = 24).</p

Kaplan-Meier curve for overall survival in evaluable patients (n = 24).

<p>Kaplan-Meier curve for overall survival in evaluable patients (n = 24).</p