Phase Ib/II trial of gemcitabine, cisplatin, plus lenalidomide as first-line therapy for patients with metastatic urothelial carcinoma.

Abstract

321 Background: Cisplatin-based chemotherapy is standard in patients (pts) with metastatic urothelial carcinoma (MUC), though outcomes remain poor and novel approaches are needed. Lenalidomide, a potent thalidomide analog with antiangiogenic and immunomodulatory properties, has been shown to enhance the antiproliferative properties of standard chemotherapy in nonclinical studies of urothelial cancer (Apolo, ASCO 2011). In this phase Ib/II clinical trial we aimed to determine the safety and efficacy of gemcitabine, cisplatin, plus lenalidomide (GCL) in pts with MUC. Methods: Pts with chemotherapy-naïve MUC received gemcitabine 1000mg/m2 days 1 and 8 and cisplatin 70mg/m2 day 1, of a 21-day cycle. In the phase Ib portion, the dose of lenalidomide was to be dose escalated in successive cohorts starting at 10 mg PO daily, on days 1-14, using standard “3+3” dose escalation rules. The primary objective of the phase II portion was to determine the progression-free survival at one year. Results: A total of 7 pts received GCL (lenalidomide 10 mg dose level) in the phase 1b portion. A single pt experienced a dose limiting toxicity (DLT), grade 4 neutropenia. A decision was made to not dose escalate lenalidomide further due to the frequent need for dose delays and reductions of GC due to cytopenias. An additional 2 pts were enrolled in the phase II portion but the study was terminated due to frequent dose delays/reductions and slow accrual. Among the 9 pts enrolled, 5 required dose reductions of G (4 requiring >1), 4 required dose reductions of C (1 requiring >1), and 6 required at least one dose delay. The most frequent grade ≥ 3 adverse events were: neutropenia (n=7), anemia (n=3), thrombocytopenia (n=3), and diarrhea (n=2). Tumor responses included: partial response (n=3), stable disease (n=3), progressive disease (n=2), and unevaluable (n=1). Conclusions: Chronic administration of the combination of GCL was compromised by overlapping myelosuppression and the need for frequent dose reductions/delays of GC due to cytopenias. Despite promising nonclinical data, combining cytotoxic chemotherapy with “targeted” small molecules faces practical challenges. Clinical trial information: NCT01342172.