Phase I and pharmacokinetic study of 3′-C-ethynylcytidine (TAS-106), an inhibitor of RNA polymerase I, II and III,in patients with advanced solid malignancies

Hammond-Thelin, Lisa A.; Thomas, Melanie B.; Iwasaki, Michiko; Abbruzzese, James L.; Lassere, Yvonne; Meyers, Christina A.; Hoff, Paulo M.; Bono, Johann S. de; Norris, J.; Matsushita, Hitoshi; Mita, Akira; Rowinsky, Eric K.

doi:10.1007/s10637-010-9535-y

Cited by 8 publications

(13 citation statements)

References 40 publications

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“…It was concluded that the safety profile of TAS-106 administered via weekly 4-hour intravenous infusion is similar to the toxicity profile of TAS-106 when administered as a weekly bolus; peripheral neuropathy was acceptable at the recommended phase II dose. Infusion regimens of TAS-106 were further evaluated in another clinical trial [41] in order to characterize the drug safety profile and identify a phase II dose. A review of the safety and drug exposure data from this trial suggested that the best regimen for phase II testing was TAS-106 administered as a 24-hour infusion.…”

Section: Clinical Trialsmentioning

confidence: 99%

TAS-106: Preclinical, Clinical and Beyond

2013

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5-Fluorouracil, other fluorinated pyrimidines and their derivatives are frequently used in chemotherapy to treat different types of cancer. These agents are classified as metabolic antagonists that target the DNA synthesis phase of the cell cycle. Therefore, these agents are more effective in rapidly growing tumors than in more indolent cancers. In order to develop new drugs that interfere with both DNA and RNA synthesis, the metabolism of pyrimidines was investigated, and new compounds were developed by the molecular design method, which analyzes the biochemical properties of the compounds. The nucleoside 3′-C-ethynylcytidine (TAS-106) was designed to inhibit RNA synthesis by blocking RNA polymerases I, II, and III, which occur throughout the cell cycle except for the M phase. This review article discusses the antitumor activity of TAS-106 as a single agent or in combination therapy with the focus on preclinical and clinical findings.

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Section: Clinical Trialsmentioning

confidence: 99%

TAS-106: Preclinical, Clinical and Beyond

2013

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“…One of the other safety concerns closely monitored on this trial was based on prior observations in the early phase I trials of significant peripheral neuropathy and neurologic AEs. In this phase II trial, there was only one patient who reported grade 3 peripheral neuropathy, which suggests that the 24‐h continuous infusion schedule of administration was successful in limiting the amount of neurologic toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…Four early clinical trials have assessed the safety and tolerability of bolus and infusional schedules for TAS‐106 . Hammond‐Thelin et al.…”

Section: Introductionmentioning

confidence: 99%

“…Four early clinical trials have assessed the safety and tolerability of bolus and infusional schedules for TAS-106 [19,20]. Hammond-Thelin et al [20] reported the average terminal elimination half-life (t 1/2 ) as 11.3 h and mean half-life between 8.2 and 13.8 h. A prior phase 1 study (9904) of TAS-106 monotherapy in solid tumor patients established the recommended dose of TAS-106 as 6.85 mg/m 2 over 24 h as continuous infusion on day 1 of each 3-week cycle [17]. This 24-h continuous infusion schedule of administration was shown to have higher TAS-106 patient exposure compared with an intravenous push [20] or 4-h continuous infusion evaluated in other phase 1 studies [17].…”

Section: Introductionmentioning

confidence: 99%

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Phase II study of TAS‐106 in patients with platinum‐failure recurrent or metastatic head and neck cancer and nasopharyngeal cancer

et al. 2013

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TAS-106, a RNA polymerase inhibitor, was studied in solid tumors with potential clinical benefit and reasonable tolerability. We conducted a multicenter, international phase II trial of TAS-106 in salvage metastatic or recurrent head and neck squamous cell cancer (HNSCC) and nasopharyngeal cancer (NPC) patients. TAS-106 monotherapy was given at 6.5 mg/m2 over 24-h continuous infusion every 3 weeks. Translational studies for blood and tissue were included. Twenty-seven enrolled patients experienced the most common drug-related adverse events of neutropenia, fatigue, non-neutropenic fever, injection site reaction, and skin rash/dermatitis. The greater than or equal to grade 3 adverse events included neutropenia (14.8%), febrile neutropenia (7.4%), pneumonia (7.4%), and peripheral neuropathy (3.7%). The overall response rate was 0% in both subgroups; five HNSCC patients had stable disease (median duration 99 days) and four NPC patients had stable disease (median duration of 92.5 days). Median progression-free survival (PFS) for HNSCC patients was 52 days (95% CI 43.0–99.0 days) and 48 days (95% CI 41.0–83.0 days) for NPC. Median overall survival (OS) for HNSCC patients was 175 days (95% CI 92.0–234.0 days) and 280 days (95% CI 107.0–462.0 days) for NPC. The TAS-106 plasma levels were equivalent between Asian and Caucasian patients. There was no significant correlation of tumor UCK2 protein expression levels to TAS-106 efficacy. TAS-106 was reasonably tolerated in patients with platinum-failure HNSCC and NPC. The administration schedule of 24-h continuous infusion prevented neurologic toxicity, but had myelosuppression as its main toxicity. There was no anti-tumor efficacy seen with TAS-106 monotherapy. Future studies will focus on TAS-106 combinations and mechanisms of drug resistance.

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“…TAS-106 has been tested in multiple phase I and phase II clinical trials. The phase I studies have concluded that TAS-106 can be administered either as an infusion or as a bolus injection, and that the main dose-limiting adverse effect is its neurotoxicity (Friday et al, 2012;Hammond-Thelin et al, 2012;Naing et al, 2014). So far, the phase II clinical trials have not shown significant benefits for TAS-106 monotherapy and no new clinical trials have been started in the last years because of the lack of efficacy and the possibility of adverse effects (Tsao et al, 2013).…”

Section: Tas-106mentioning

confidence: 99%

Transcription and Translation Inhibitors in Cancer Treatment

et al. 2020

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Transcription and translation are fundamental cellular processes that govern the protein production of cells. These processes are generally up regulated in cancer cells, to maintain the enhanced metabolism and proliferative state of these cells. As such cancerous cells can be susceptible to transcription and translation inhibitors. There are numerous druggable proteins involved in transcription and translation which make lucrative targets for cancer drug development. In addition to proteins, recent years have shown that the "undruggable" transcription factors and RNA molecules can also be targeted to hamper the transcription or translation in cancer. In this review, we summarize the properties and function of the transcription and translation inhibitors that have been tested and developed, focusing on the advances of the last 5 years. To complement this, we also discuss some of the recent advances in targeting oncogenes tightly controlling transcription including transcription factors and KRAS. In addition to natural and synthetic compounds, we review DNA and RNA based approaches to develop cancer drugs. Finally, we conclude with the outlook to the future of the development of transcription and translation inhibitors.

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Phase I and pharmacokinetic study of 3′-C-ethynylcytidine (TAS-106), an inhibitor of RNA polymerase I, II and III,in patients with advanced solid malignancies

Cited by 8 publications

References 40 publications

TAS-106: Preclinical, Clinical and Beyond

TAS-106: Preclinical, Clinical and Beyond

Phase II study of TAS‐106 in patients with platinum‐failure recurrent or metastatic head and neck cancer and nasopharyngeal cancer

Transcription and Translation Inhibitors in Cancer Treatment

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