Abstract | PURPOSE:
AT9283 is a potent inhibitor of the mitotic regulators, Aurora-kinases A and B, and has shown anti- tumor activity in patients with solid and haematological malignancies. This phase I study assessed safety, tolerability, pharmacokinetic and pharmacodynamic properties of AT9283. PATIENTS AND METHODS: Patients with advanced, incurable solid tumors or non-Hodgkin's lymphoma received AT9283 as a continuous 24-hour infusion on days 1, 8 of a 21-day cycle. A 3 + 3 dose escalation design was used with a starting dose of 1.5 mg/m(2)/day. Pharmacokinetic samples were collected from all patients on cycle one, and pharmacodynamic samples were collected from 4 patients at the recommended phase II dose (RP2D). RESULTS: 35 patients were evaluable for toxicity and 32 were evaluable for response. AT9283 was well tolerated, with main toxicities being reversible dose-related fatigue, gastrointestinal disturbance, anemia, lymphocytopenia and neutropenia. The dose limiting toxicities were febrile neutropenia (two patients) and neutropenia with grade 3 infection (1 patient) at 47 mg/m(2)/day (established as the maximum tolerated dose). The RP2D was 40 mg/m(2)/day. Pharmacokinetic analyses showed AT9283 appeared to follow linear kinetics, with a mean elimination half-life of 8.2 h. Pharmacodynamic analyses showed no consistent or significant changes, but trends suggested evidence of AT9283 inhibition and anti-proliferative activity. One patient had partial response and four patients experienced RECIST stable disease (median 2.6 months). CONCLUSION: In this study, AT9283 was well tolerated. The RP2D is 40 mg/m(2)/day on days 1, 8 of a 21-day cycle. Ongoing AT9283 trials will assess efficacy and safety in solid and haematological cancers.
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Authors | S F Dent, K A Gelmon, K N Chi, D J Jonker, N Wainman, C A Capier, E X Chen, J F Lyons, L Seymour |
Journal | Investigational new drugs
(Invest New Drugs)
Vol. 31
Issue 6
Pg. 1522-9
(Dec 2013)
ISSN: 1573-0646 [Electronic] United States |
PMID | 24072436
(Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 1-cyclopropyl-3-(3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl)urea
- Antineoplastic Agents
- Benzimidazoles
- Histones
- Ki-67 Antigen
- Proliferating Cell Nuclear Antigen
- Protein Kinase Inhibitors
- Tumor Suppressor Protein p53
- Urea
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Topics |
- Adult
- Aged
- Aged, 80 and over
- Antineoplastic Agents
(administration & dosage, adverse effects, pharmacokinetics)
- Benzimidazoles
(administration & dosage, adverse effects, pharmacokinetics)
- Drug Administration Schedule
- Female
- Histones
(metabolism)
- Humans
- Infusions, Intravenous
- Ki-67 Antigen
(metabolism)
- Male
- Middle Aged
- Neoplasms
(drug therapy, metabolism)
- Proliferating Cell Nuclear Antigen
(metabolism)
- Protein Kinase Inhibitors
(administration & dosage, adverse effects, pharmacokinetics)
- Skin
(metabolism)
- Tumor Suppressor Protein p53
(metabolism)
- Urea
(administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics)
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