A randomized, open‐label clinical trial of tasisulam sodium versus paclitaxel as second‐line treatment in patients with metastatic melanoma

Abstract

BACKGROUND: Tasisulam sodium (hereafter referred to as tasisulam) is a novel, highly albumin-bound agent that demonstrated activity in a phase 2 melanoma study. METHODS: In this open-label phase 3 study, patients with AJCC stage IV melanoma received tasisulam (targeting an albumin-corrected exposure of 1200-6400 h (hour).lg=mL on day 1) or paclitaxel (80 mg=m 2 on days 1, 8, and 15) every 28 days as second-line treatment. RESULTS: The study was placed on clinical hold after randomization of 336 patients when a safety review indicated an imbalance of possibly drug-related deaths in the tasisulam arm. Efficacy results for tasisulam versus paclitaxel revealed a response rate of 3.0% versus 4.8%, a median progression-free survival of 1.94 months versus 2.14 months (P 5.048), and a median overall survival of 6.77 months versus 9.36 months (P 5.121). The most common drug-related grade 3 laboratory toxicities (graded according to Common Terminology for Adverse Events [version 3.0]) were thrombocytopenia (18.9%) for patients treated with tasisulam and neutropenia=leukopenia (8.7%) among those receiving paclitaxel. There were 13 possibly related deaths reported to occur on the study, with the majority occurring during cycle 2 in the setting of grade 4 myelosuppression, all in the tasisulam arm. Investigation of the unexpectedly high rate of hematologic toxicity revealed a subset of patients with low tasisulam clearance, leading to drug accumulation and high albumin-corrected exposure in cycle 2. CONCLUSIONS: Although the study was stopped early because of safety issues in the tasisulam arm, tasisulam was considered unlikely to be superior to paclitaxel, and paclitaxel activity in the second-line treatment of melanoma was much lower than expected. The toxicity imbalance was attributed to an unexpectedly low tasisulam clearance in a subset of patients, underscoring the importance of pharmacokinetic monitoring of compounds with complex dosing, even in late-phase studies. INTRODUCTIONAlthough comprising only approximately 4% of skin cancer cases, melanoma is responsible for approximately 80% of all skin cancer deaths. 1,2 Targeted agents, such as BRAF inhibitors, can be used in approximately one-half of patients, most of whom will develop resistance after a few months. 3,4 Only 20% of patients might benefit from immunotherapy. 5 Thus, effective therapies for patients with metastatic melanoma remain a critical unmet need.In a phase 2 study of tasisulam, a novel acylsulfonamide compound with a unique dual mechanism of action involving mitotic catastrophe and antiangiogenesis, 6,7 8 of 68 patients with second-line metastatic melanoma achieved a partial response, for an overall response rate (RR) of 11.8%. 8 The median progression-free survival (PFS) was 2.6 months and the median overall survival (OS) was 9.6 months. Tasisulam was generally well tolerated, with thrombocytopenia reported to be the predominant treatment-related grade 3=4 toxicity (20.6% of patients).

Antitumorigenic effect of damnacanthal on melanoma cell viability through p53 and NF‑κB/caspase‑3 signaling pathways

“…Melanoma is the most common type of malignant tumor that occurs in the conjunctiva, accounting for between 2 and 5% cases of eye cancer, and between 5 and 7% cases of primary malignant melanoma of the eye (1). The incidence of melanoma is reported to have increased gradually, which may be associated with increased ultraviolet exposure (2). The high degree of tumor malignancy is associated with high recurrence rate and high incidence of adjacent lymph node and liver metastasis (3).…”

Synthesis of a Sulfonimidamide-Based Analog of Tasisulam and Its Biological Evaluation in the Melanoma Cell Lines SKMel23 and A375

“…Investigation of the unexpectedly high rate of hematological toxicity revealed a subset of patients with low tasisulam clearance, leading to drug accumulation and high albumin-corrected exposure in cycle 2 [79]. Because of high-affinity albumin binding and rapid, extensive metabolism of free tasisulam in vivo, preclinical studies had failed to identify a clearance mechanism for unbound tasisulam, which is the biologically active form.…”

“…Being considered as a promising anticancer agent [13,76], a robust process was introduced providing sufficient material for the initiated clinical trials [77,78]. Due to safety concerns, however, the compound development was terminated, which also affected a phase 3 study focused on tasisulam treatments of patients with metastatic melanoma [79]. …”

The Role of Chemotherapy in the Modern Management of Melanoma

“…This led to a Phase III study comparing tasisulam with paclitaxel. The study was suspended in 2010 after 336 patients had been randomized due to safety concerns because of an imbalance of pos sible treatmentrelated deaths (13 vs 0), which were thought to be due to low tasisulam clear ance [51]. The response rate was 3.0 versus 4.8%, with a median PFS of 1.94 versus 2.14 months (p = 0.048).…”