A phase 2 study of tasisulam sodium (LY573636 sodium) as second‐line treatment for patients with unresectable or metastatic melanoma

Kirkwood, John M.; González, René; Reintgen, Douglas S.; Clingan, Philip R.; McWilliams, Robert R.; Alwis, Dinesh P. de; Zimmermann, Annamaria H.; Brown, Michael P.; Ilaria, Robert; Millward, Michael

doi:10.1002/cncr.26068

Cited by 22 publications

(22 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Tasisulam is a promising drug which is used as an antiproliferative agent in patients with metastatic melanoma and other solid tumors [10,13,14,15,16]. A randomized, open-label clinical trial of tasisulam sodium versus paclitaxel as second-line treatment in patients with metastatic melanoma has recently been stopped early because of safety issues in the tasisulam arm.…”

Section: Discussionmentioning

confidence: 99%

“…An in vitro, antitumor screening analysis conducted by the National Cancer Institute (NCI COMPARE analysis) demonstrated a broad range of activity for tasisulam in 60 tumor cell lines including leukemia, melanoma, non-small-cell lung cancer, colon, ovarian, renal, and breast cancers [12]. Subsequently, tasisulam was evaluated as a single agent in several tumor types [10,13,14,15,16]. In this study we focused on the antiproliferative effect of tasisulam and a newly synthesized sulfonimidamide-based analog, which both were studied in melanoma cell lines in vitro.…”

Section: Introductionmentioning

confidence: 99%

“…Especially in chemotherapy new developments and insights are missing. A phase 2 study of tasisulam achieved partial response, with an objective response rate (RR) of 11.8% in 8 of 68 patients with second-line metastatic melanoma [10]. Tasisulam is an acyl sulfonamide with a unique antitumor dual mechanism of action, involving antiangiogenesis and mitotic inhibition [11].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Steinkamp¹,

Schmitt

Chen³

et al. 2016

Skin Pharmacol Physiol

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Steinkamp¹,

Schmitt

Chen³

et al. 2016

Skin Pharmacol Physiol

View full text Add to dashboard Cite

show abstract

“…Cells were lysed using a 2-step protocol adapted from ref. 48. Cells were directly lysed with lysis buffer (20 mM Tris-HCl, 1% Triton X-100, 10 mM MgCl 2 , 10 mM KCl, 2 mM EDTA, 1 mM NaF, 1 mM sodium orthovanadate, 2.5 mM β-glycerophosphate, 10% glycerol, pH 7.5), scraped off the culture dish, sonicated, supplemented to 400 mM NaCl, sonicated and diluted to 200 mM NaCl.…”

Section: Tumour Tissue Microarrays National Cancer Institute Cancer mentioning

confidence: 99%

“…Furthermore, TGFbneutralizing antibody GC-1008 showed promises in phase I trial for metastatic melanoma and renal cell carcinoma (45). Smallmolecule inhibitor, LY-573636, used in phase II clinical studies in patients with metastatic NSCLC, soft tissue sarcoma, and melanoma, has also shown modest activity as a second/third-line therapy (46)(47)(48). These studies showed that inhibiting TGFb signaling pathway is safe, well tolerated in patients and could provide promising new therapeutics against tumor invasion.…”

Section: Inflammatory Cytokinesmentioning

confidence: 99%

Regulation of Breast Cancer Stem Cell by Tissue Rigidity

Yang¹,

Engler²,

Fattet³

et al. 2015

View full text Add to dashboard Cite

Public reporting burden for the collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden, to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to a penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. SUPPLEMENTARY NOTESThe original document contains color images. ABSTRACTThe presence of a fibrotic focus in breast tumors is associated with a 10-50-fold increase in tissue stiffness and correlates with distant metastasis and poor outcome. Recent studies indicate that increasing tissue rigidity promotes breast cancer progression, however the underlying molecular mechanism is largely unknown. Breast cancer stem cells have both long-term self-renewal capacity and the ability to initiate tumors. In this proposal, we hypothesize that tissue rigidity regulates breast cancer stem cell properties and function, therefore assisting breast tumor development and promoting chemoresistance. REPORT DOCUMENTATION PAGEForm Approved OMB No. 0704-0188 Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERUniversity of California, San Diego 9500 Gilman Drive, MC0636 La Jolla, CA 92093 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel CommandFort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTThe presence of a fibrotic focus in breast tumors is associated with a 10-50-fold increase in tissue stiffness and correlates with distant metastasis and poor outcome. Recent studies indicate that increasing tissue rigidity promotes breast cancer progression, however the underlying molecular mechanism is largely unknown. Breast cancer stem cells have both long-term self-renewal capacity and the ability to initiate tumors. In this proposal, we hypothesize that tissue rigidity regulates breast cancer stem cell properties and function, therefore assisting brea...

show abstract

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

Hamid

Ilaria

Garbe

et al. 2014

Cancer

View full text Add to dashboard Cite

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).

show abstract

A phase 2 study of tasisulam sodium (LY573636 sodium) as second‐line treatment for patients with unresectable or metastatic melanoma

Cited by 22 publications

References 20 publications

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

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

Regulation of Breast Cancer Stem Cell by Tissue Rigidity

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

Contact Info

Product

Resources

About