Tasisulam

Tasisulam is an antitumor agent [1].

Tasisulam is an antitumor agent that induced growth arrest and apoptosis of human solid tumours. In human malignant hematopoietic cell lines, tasisulam inhibited cells growth with ED50 values of 5, 7, 12, 13, 21 and 31 μM for BALL1, HL60, RCH, NCEB1, SP49 and Daudi cell lines, respectively. Tasisulam induced growth arrest in a dose-dependent way. Also, tasisulam caused induction of ROS, loss of mitochondrial membrane potential and induction of apoptosis. In HL60 and U937 cells, tasisulam induce granulocytic/monocytic differentiation. In solid tumor cell lines, tasisulam induced apoptosis that was mediated by the mitochondrial-mediated cell death pathways [1]. Tasisulam increased phospho-histone H3 expression and cells with 4N DNA, and led to G2-M accumulation and apoptosis. Tasisulam also inhibited endothelial cell cord formation induced by epidermal growth factor, VEGF and fibroblast growth factor with EC50 values of 34, 47 and 103 nM, respectively.

In mice bearing the Calu-6 non-small cell lung xenograft model, tasisulam exhibited antitumor efficacy in a dose-dependent way and reduced tumor volume by 77%. Tasisulam caused G2-M accumulation and increased nuclear fragmentation. Also, tasisulam induced vascular normalization [2].

References:
[1].  Haritunians T, Gueller S, O'Kelly J, et al. Novel acyl sulfonamide LY573636-sodium: effect on hematopoietic malignant cells. Oncol Rep, 2008, 20(5): 1237-1242.
[2].  Meier T, Uhlik M, Chintharlapalli S, et al. Tasisulam sodium, an antitumor agent that inhibits mitotic progression and induces vascular normalization. Mol Cancer Ther, 2011, 10(11): 2168-2178.

Synthesis of a Sulfonimidamide-Based Analog of Tasisulam and Its Biological Evaluation in the Melanoma Cell Lines SKMel23 and A375.[Pubmed:28013301]

Skin Pharmacol Physiol. 2016;29(6):281-290.

Tasisulam is a promising antitumor agent with complex pharmacology, which is used as an antiproliferative agent in patients with metastatic melanoma and other solid tumors. Phase 2 melanoma studies showed promising results but had to be stopped because of insufficient Tasisulam clearance leading to toxic side effects. To reduce the negative effects of Tasisulam, we synthesized a novel sulfonimidamide-based analog to evaluate its antiproliferative effects in comparison to the original compound by performing a cell proliferation assay in melanoma cell lines SKMel23 and A375. The results revealed that the analog had inhibitory effects on the proliferation comparable to Tasisulam in both investigated cell lines. These results could contribute to a reduced toxicity of Tasisulam and lead to further clinical trials in metastatic melanoma.

An innovative, multi-arm, complete phase 1b study of the novel anti-cancer agent tasisulam in patients with advanced solid tumors.[Pubmed:25260842]

Invest New Drugs. 2015 Feb;33(1):148-58.

BACKGROUND: This phase Ib study used a parallel, multi-arm design to examine Tasisulam-sodium (hereafter Tasisulam), a drug with complex pharmacology, combined with standard chemotherapies in patients with advanced solid tumors, with the ultimate goal of accelerating drug development. METHODS: Patients received escalating doses of Tasisulam (3 + 3 schema; target Cmax 300-400 mug/mL) every 28 days plus 1,000 mg/m(2) gemcitabine HCl (days 1 and 15), 60 mg/m(2) docetaxel, 200 mg/m(2)/day temozolomide, 75 mg/m(2) cisplatin, or 150 mg/day erlotinib. Following dose-escalation, patients were enrolled into specific tumor subtype arms, chosen based on the established activity of the standard agent. Because Tasisulam is highly albumin-bound, patients in the tumor-specific confirmation arms were dosed targeting specific albumin-corrected exposure ranges (AUCalb) identified during dose-escalation (3,500 h*mug/mL [75th percentile] for docetaxel, temozolomide, and cisplatin; 4,000 h*mug/mL for gemcitabine and erlotinib). RESULTS: A total of 234 patients were enrolled. The safety profile of Tasisulam with standard chemotherapies was sufficient to allow enrollment into the dose-confirmation phase in all arms. The primary dose-limiting toxicities were hematologic (thrombocytopenia and neutropenia). The most common grade >/=3 drug-related treatment-emergent adverse event was neutropenia, with the highest incidence in the docetaxel arm. CONCLUSIONS: The multi-arm design allowed the efficient determination of the maximum tolerated dose of Tasisulam across multiple combinations, and a preliminary characterization of pharmacokinetics, safety, and potential efficacy. Although enrollment into all planned groups was not completed due to termination of compound development, these data support the feasibility of this approach for accelerated cancer drug development, even for drugs with complex pharmacology.

A randomized, open-label clinical trial of tasisulam sodium versus paclitaxel as second-line treatment in patients with metastatic melanoma.[Pubmed:24676877]

Cancer. 2014 Jul 1;120(13):2016-24.

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).mug/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 = .048), and a median overall survival of 6.77 months versus 9.36 months (P = .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.

A phase I study of tasisulam sodium using an albumin-tailored dose in Japanese patients with advanced solid tumors.[Pubmed:23370664]

Cancer Chemother Pharmacol. 2013 Apr;71(4):991-8.

PURPOSE: This phase I study was designed to determine the maximum tolerated dose (MTD) and the dose to be recommended for a future phase II study of Tasisulam sodium in Japanese patients with advanced, refractory solid tumors. Safety, pharmacokinetics and preliminary anti-tumor activities were assessed. Due to high-affinity albumin binding, an albumin-tailored dose to reduce the variability in Tasisulam exposure was also studied. METHODS: A dose escalation scheme of Tasisulam was used over 4 dose levels. Dose levels 1-3 targeted the maximum plasma concentration (C max) of 300, 340, and 360 mug/mL. Dose level 4 used an albumin-tailored range of C max-targeted doses to achieve an albumin-corrected exposure (AUCalb) of 1,200-6,400 mug h/mL, the range chosen for global Tasisulam studies. Tasisulam was administered intravenously on day 1 of each 21-day (dose levels 1 and 2) or 28-day (dose levels 3 and 4) cycle. RESULTS: The major adverse events were related to bone marrow suppression, particularly neutropenia and thrombocytopenia. Dose-limiting toxicities (DLTs) were not observed until dose level 4, where 3 out of 6 patients experienced DLT, despite a tendency toward lower AUCalb variability (CV %) in the albumin-tailored dose group (38 %) compared with the targeted C max groups (50-236 %). CONCLUSIONS: Tasisulam in doses up to dose level 3 (target C max 360 mug/mL) was well tolerated. Although albumin-tailored dosing provided less AUCalb variability, a MTD that aligns with other global Tasisulam studies was not identified. A lower AUCalb range may be required for the Japan population.

Tasisulam is a anticancer agent and induces apoptosis via the intrinsic pathway, resulting in cytochrome c release and caspase-dependent cell death. Tasisulam inhibits mitotic progression and induces vascular normalization.

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