SUCCINCT: An Open-label, Single-arm, Non-randomised, Phase 2 Trial of Gemcitabine and Cisplatin Chemotherapy in Combination with Sunitinib as First-line Treatment for Patients with Advanced Urothelial Carcinoma

Abstract

Gemcitabine and cisplatin chemotherapy (GC regimen) represents a standard treatment for advanced urothelial carcinoma. We performed an open-label, single-arm, non-randomised, phase 2 trial evaluating the addition of sunitinib to standard GC chemotherapy (SGC regimen). Overall, 63 treatment-naïve participants were recruited and received up to six 21-d cycles of cisplatin 70 mg/m2 (intravenously [IV], day 1) and gemcitabine 1000 mg/m2 (IV, days 1 and 8) combined with sunitinib 37.5 mg (orally, days 2–15). Following review of toxicity after the first six patients, the sunitinib dose was reduced to 25 mg for all patients. Overall response rate was 64%, with response noted in 37 of 58 patients. At 6 mo, 30 of 58 assessable patients (52%; 90% confidence interval [CI], 40–63%) were progression free. Median overall survival was 12 mo (95% CI, 9–15) and was heavily influenced by Bajorin prognostic group. Grade 3–4 toxicities were predominantly haematologic and limited the deliverability of the triple SGC regimen. The trial did not meet its prespecified primary end point of >60% patients progression free at 6 mo. Cumulative myelosuppression led to treatment delays of gemcitabine and cisplatin and dose reduction and/or withdrawal of sunitinib in the majority of cases. The triple-drug combination was not well tolerated. Phase 3 evaluation of the triple SGC regimen in advanced transitional cell carcinoma is not recommended.Patient summaryThe addition of sunitinib to standard cisplatin and gemcitabine chemotherapy was poorly tolerated and did not improve outcomes in advanced urothelial carcinoma. Treatment delivery was limited by myelotoxicity.

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“…In the SUCCINT study, an open-label, single-arm, nonrandomized Phase II trial by Geldart et al, comparable results were observed [44]. A total of 63 patients were enrolled and treated with 1 to 6 21-day cycles of i.v.…”

“…In all treatment groups, ki-67 and CD31 expression were reduced, and cleaved caspase-3 expression was higher compared with the untreated tumors, thus showing a decrease in proliferation and angiogenesis, and an increase in apoptosis, respectively [43]. The authors suggested that sunitinib could exert its oncologic effects by enhancing the activity of cisplatin in patients with metastatic urothelial carcinoma [ with advanced/metastatic urothelial carcinoma [44,45]. In both studies, this combination treatment was poorly tolerated (anemia, leukopenia, neutropenia, thrombocytopenia, nausea/ vomiting and fatigue) and did not improve outcomes [44,45].…”

“…The authors suggested that sunitinib could exert its oncologic effects by enhancing the activity of cisplatin in patients with metastatic urothelial carcinoma [ with advanced/metastatic urothelial carcinoma [44,45]. In both studies, this combination treatment was poorly tolerated (anemia, leukopenia, neutropenia, thrombocytopenia, nausea/ vomiting and fatigue) and did not improve outcomes [44,45].…”

“…It is entirely made of human proteic sequences, binds VEGF-A, VEGF-B and PDGF and has a much higher binding affinity to VEGF-A than the humanized monoclonal antibody bevacizumab (50 --100 folds higher) [37]. [44] GC + sunitinib 63 12 (95% CI 9 --15) 8 (95% CI 6 --11) 64%…”

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“…The single-arm phase 2 SUCCINCT study by Geldart et al [5], reported in this month's issue of European Urology, demonstrated poorer survival for patients given triplet therapy with sunitinib (an oral agent targeting multireceptor tyrosine kinase inhibition more commonly used in renal cell carcinoma) in combination with GC. The 6-mo PFS of <60% was lower than the expected PFS of 65%.…”