VinCaP: a phase II trial of vinflunine in locally advanced and metastatic squamous carcinoma of the penis.

BACKGROUND: We investigated the first-line activity of vinflunine in patients with penis cancer. Cisplatin-based combinations are commonly used, but survival is not prolonged; many patients are unfit for such treatment or experience toxicity that outweighs clinical benefit. METHODS: Twenty-five patients with inoperable squamous carcinoma of the penis were recruited to a single-arm, Fleming-A'Hern exact phase II trial. Treatment comprised 4 cycles of vinflunine 320 mg/m2, given every 21 days. Primary endpoint was clinical benefit rate (CBR: objective responses plus stable disease) assessed after 4 cycles. Seven or more objective responses or disease stabilisations observed in 22 evaluable participants would exclude a CBR of <15%, with a true CBR of >40% being probable. RESULTS: Twenty-two participants were evaluable. Ten objective responses or disease stabilisations were confirmed. CBR was 45.5%, meeting the primary endpoint; partial response rate was 27.3%. Seven patients received >4 cycles of vinflunine. Dose reduction or treatment delay was required for 20% of cycles. In all, 68% of patients experienced at least one grade 3 adverse event. Two deaths on treatment were not caused by disease progression. CONCLUSIONS: Pre-specified clinical activity threshold was exceeded. Toxicity was in keeping with experience in other tumours. Vinflunine merits further study in this disease. TRIAL REGISTRATION: NCT02057913.

Genetic deficiency or pharmacological inhibition of cyclooxygenase-1 or -2 induces mouse keratinocyte differentiation in vitro and in vivo.

Previously we demonstrated that genetic deficiency of the cyclooxygenases (COX-1 or COX-2) altered keratinocyte differentiation in mouse skin [Tiano et. al. (2002) Cancer Res. 62, 3395-3401]. In this study, we show that topical application of SC-560 (a COX-1 selective inhibitor) or celecoxib (COX-2 selective) to TPA-treated wild-type skin caused fivefold increases in the number of basal keratinocytes expressing the early differentiation marker keratin 1 (K1). In contrast to skin, COX-2 not COX-1 was the major isoform expressed in cultured primary keratinocytes. COX-1 was predominantly expressed in detached, differentiated cells, whereas COX-2 was found in the attached, proliferating cells. High Ca++ medium induced K1 and COX-1 in wild-type keratinocytes but did not change COX-2 expression. As observed in skin, COX-1-/- and COX-2-/- primary keratinocytes expressed fivefold more K1 than wild-type cells. K1 levels in cultured wild-type keratinocytes were also increased by treatment with celecoxib and indomethacin. However, unlike its in vivo effect, SC-560, possibly due to low COX-1 expression in cultured mouse keratinocytes, did not increase K1 levels. Furthermore, no increases in apoptotic cell numbers were observed in COX-deficient keratinocytes or COX-inhibitor treated wild-type cells. Thus, a major effect of COX inhibitors and COX-deficiency is the induction of keratinocyte differentiation.