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Clinical Investigation 2013The oral taxanes are analogues of existing taxanes with a possible broad range of antitumor activity. They also have the potential advantages of ease of administration,...
The oral taxanes are analogues of existing taxanes with a possible broad range of antitumor activity. They also have the potential advantages of ease of administration, better efficacy and lesser toxicity than currently available taxanes. These drugs have been used in several Phase I clinical trials, the methodology and results of which will be reviewed here.
PubMed: 26146540
DOI: 10.4155/cli.13.18 -
Biological & Pharmaceutical Bulletin Mar 2004DJ-927, currently undergoing Phase I clinical trial, is a new orally effective taxane with potent antitumor effects. The absorption, tissue distribution, and excretion... (Comparative Study)
Comparative Study
DJ-927, currently undergoing Phase I clinical trial, is a new orally effective taxane with potent antitumor effects. The absorption, tissue distribution, and excretion of DJ-927 were investigated in mice, dogs, and monkeys after a single oral administration. After oral administration of [14C]DJ-927, radioactivity was rapidly absorbed, with the Cmax occurring within 1-2 h in all species. The blood and plasma radioactivity elimination was biphasic and species-dependent. Elimination half-life of plasma in dogs was much longer than those in monkeys or mice. In mice, radioactivity was rapidly distributed to all tissues except for the central nervous system, especially to adrenal glands, liver, pituitary glands, kidneys, lungs, and spleen. In all species, radioactivity was mainly excreted in feces. Following a single oral administration to mice, more than 80% of the radioactivity was excreted within 48 h; in dogs and monkeys, 80% of the radioactivity was excreted within 168 h. Urinary excretion was less than 7% of radioactive dose in all species. In vitro plasma protein binding of [14C]DJ-927 in the mouse, dog, and monkey plasma ranged from 92-98%. These studies showed that, the novel oral taxane DJ-927 was rapidly absorbed in all three species when administered by the oral route. The long biological half-life and slow elimination of radioactivity were distinctive in particular, compared with commercial taxanes. DJ-927 (as parent compound and its metabolites) is widely distributed to tissues except the brain. These preclinical data are useful for the design of clinical trials of DJ-927 and also for their interpretation.
Topics: Administration, Oral; Animals; Antineoplastic Agents; Area Under Curve; Blood Proteins; Carbon Radioisotopes; Dogs; Feces; Half-Life; In Vitro Techniques; Macaca fascicularis; Male; Mice; Protein Binding; Species Specificity; Taxoids; Time Factors; Tissue Distribution
PubMed: 14993800
DOI: 10.1248/bpb.27.345 -
Journal of Thoracic Oncology : Official... Jul 2008A phase I/II study was performed to assess the efficacy and toxicity of a new oral taxane in patients with recurrent, advanced Non-small Cell Lung Cancer.
INTRODUCTION
A phase I/II study was performed to assess the efficacy and toxicity of a new oral taxane in patients with recurrent, advanced Non-small Cell Lung Cancer.
PATIENTS AND METHODS
Patients who were treated with one prior, taxane free chemotherapy regimen, were eligible for this study. A single oral dose of DJ-927 (27 mg/m) was given every 3 weeks. In case of good tolerance, one dose escalation to 35 mg/m was allowed. Response and toxicity were measured and plasma pharmacokinetic analysis was performed during the first course.
RESULTS
From October 2004 to September 2005, 36 patients gave informed consent and 34 received medication. The mean age was 58 years (range, 33-75 years). The majority of patients were pretreated with a combination of cisplatin and gemcitabine. Median interval between end of first treatment and the registration of this study was 7 months (range, 0.8-22 months). Twelve patients died on study of which eight due to disease progression. In four patients with preexisting cardiac disease, toxicity led to cardiac worsening and subsequent death. Grade 3 and 4 toxicities according to the National Cancer Institute Common Toxicity Criteria were neutropenia in 18 patients (53%), anemia in six patients (18%), nausea and fatigue in two patients (6%), febrile neutropenia and neurotoxicity in one patient (3%). The overall response rate for all patients was 5.6% (Confidence Interval [CI] 0.7-18.7%). The percentage of patients with stabilization for >6 weeks was 47%. The median time to progression was 97 days (CI: 47-167 days) and the median survival time was 120 days (CI: 68-222 days) for the ITT group. Since only a minority of patients (3) tolerated the higher drug dose we omitted this dose level because of hematological toxicity. Pharmacokinetic analysis showed that the median area under the curve (t = 0-168 hours) was 1752 +/- 1355 ngr/ml/h and the half-life was 167 +/- 77 hours.
CONCLUSION
When administered once every 3 weeks, this oral taxane formulation of DJ-927 was well-absorbed with a long terminal half-life of 167 +/- 77 hour. DJ-927 has antitumor activity against Non-small Cell Lung Cancer when given as second-line monotherapy (overall response rate in 5.6%; CI 0.7-18.7%). Ten patients experienced SD for more than 8 weeks. Different types of dose administration (metronomic dosing) or combination with other cytotoxic agents should be considered in future studies.
Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Drug Administration Schedule; Female; Humans; Lung Neoplasms; Male; Middle Aged; Taxoids
PubMed: 18594320
DOI: 10.1097/JTO.0b013e31817c73ff -
Cancer Science May 2003DJ-927 is a novel taxane, which was selected for high solubility, non-neurotoxicity, oral bioavailability, and potent antitumor activity. In this study, we compared the... (Comparative Study)
Comparative Study
DJ-927 is a novel taxane, which was selected for high solubility, non-neurotoxicity, oral bioavailability, and potent antitumor activity. In this study, we compared the in vitro and in vivo efficacy of DJ-927 with those of paclitaxel and docetaxel. DJ-927 exhibited stronger cytotoxicity than paclitaxel and docetaxel in various tumor cell lines, especially against P-glycoprotein (P-gp)-expressing cells. The cytotoxicity of DJ-927, unlike those of other taxanes, was not affected by the P-gp expression level in tumor cells, or by the co-presence of a P-gp modulator. When intracellular accumulation of the three compounds was compared, intracellular amounts of DJ-927 were much higher than those of paclitaxel or docetaxel, particularly in P-gp-positive cells. In vivo, DJ-927 showed potent antitumor effects against two human solid tumors in male BALB/c-nu/nu mice, and yielded significant life-prolongation in a murine liver metastasis model with male C57BL/6 mice, in which neither paclitaxel nor docetaxel was effective. The results demonstrate the superior efficacy of orally administered DJ-927 over intravenously administered paclitaxel or docetaxel against P-gp-expressing tumors, probably due to higher intracellular accumulation. A phase I clinical trials of DJ-927 is currently ongoing in the US.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antineoplastic Agents; Cell Survival; Colony-Forming Units Assay; Docetaxel; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; In Vitro Techniques; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Neoplasms, Experimental; Paclitaxel; Taxoids; Tumor Cells, Cultured
PubMed: 12824894
DOI: 10.1111/j.1349-7006.2003.tb01465.x