Borealis-1: A Randomized, First Line, Placebo-Controlled Phase 2 Study Evaluating Apatorsen and Chemotherapy for Patients with Advanced Urothelial Cancer

Abstract

BackgroundFive year survival of patients with inoperable, advanced urothelial carcinoma (UC) treated with first line chemotherapy is 5 to 15%. We assessed whether the Hsp27 inhibitor apatorsen combined with gemcitabine plus cisplatin (GC) could improve overall survival (OS) in these patients.Patients and methodsThis placebo-controlled, double-blind phase 2 trial randomized 183 untreated UC patients (North America and Europe) to receive GC plus either placebo (N=62), apatorsen 600 mg (N= 60), or apatorsen 1000 mg (N=61). In the experimental arm, treatment included loading doses of apatorsen followed by up to 6 cycles of apatorsen plus GC. Patients receiving at least 4 cycles could continue apatorsen monotherapy as maintenance until progression or unacceptable toxicity. The primary endpoint was OSResultsOS was not significantly improved in the single or combined 600 mg or 1000 mg apatorsen arms versus placebo (hazard ratio [HR] 0.86 and 0.90, respectively). Exploratory study of specific statistical modeling showed a trend for improved survival in patients with baseline poor prognostic features treated with 600 mg apatorsen compared to placebo (HR = 0.72). Landmark analysis of serum Hsp27 (sHsp27) levels showed a trend towards survival benefit for poor-prognosis patients in apatorsen 600 mg and 1000 mg arms who achieved lower area-under-the-curve (AUC) sHsp27 levels, compared to the placebo arm (HR = 0.45, and 0.62 respectively). Higher baseline CTCs (≥5 cells/7.5 mL) was observed in patients with poor prognosis in correlation with poor survival. Treatment-emergent adverse events were manageable and more common in both apatorsen-treatment arms.ConclusionsEven though apatorsen combined with standard chemotherapy did not demonstrate a survival benefit in the overall study population, patients with poor prognostic features might benefit from this combination. Serum Hsp27 levels may act as a biomarker to predict treatment outcome. Further exploration of apatorsen in poor risk patients is warranted.

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