| Abstract | PURPOSE: To determine the maximum-tolerated dose (MTD) and assess the safety, pharmacokinetics, and preliminary evidence of antitumor activity of YM155, a small-molecule inhibitor of survivin. PATIENTS AND METHODS: Patients with advanced solid malignancies or lymphoma were treated with escalating doses of YM155 administered by 168-hour continuous intravenous infusion (CIVI). Plasma and urine samples were assayed to determine pharmacokinetic parameters and excretion. RESULTS: Forty-one patients received 127 cycles of YM155 at doses ranging from 1.8 to 6.0 mg/m(2)/d by 168-hour CIVI every 3 weeks. Overall, the most common grade 1 to 2 toxicities were stomatitis, pyrexia, and nausea, whereas grade 3 and 4 toxicities were rare. Reversible elevation in serum creatinine in two patients, with one developing acute tubular necrosis, was dose-limiting at 6.0 mg/m(2). The MTD was 4.8 mg/m(2). At the MTD, the mean steady-state concentration, clearance, volume of distribution at steady-state, and terminal elimination half-life were 7.7 ng/mL, 47.7 L/h, 1,763 L, and 26 hours, respectively. One complete and two partial responses lasting 8, 24+ and 48+ months occurred in three patients with non-Hodgkin's lymphoma, two patients with hormone- and docetaxel-refractory prostate cancer had prostate-specific antigen responses, and one patient with non-small-cell lung cancer had a minor response. CONCLUSION YM155 can be administered safely at 4.8 mg/m(2)/d 168 hours CIVI every 3 weeks. The absence of severe toxicities, attainment of plasma concentrations active in preclinical models, and compelling antitumor activity warrant further disease-directed studies of this agent alone and in combination with chemotherapy in a broad array of tumors. |
| Authors | Anthony W Tolcher, Alain Mita, Lionel D Lewis, Christopher R Garrett, Elizabeth Till, Adil I Daud, Amita Patnaik, Kyri Papadopoulos, Chris Takimoto, Pamela Bartels, Anne Keating, Scott Antonia
(Affiliation: Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX, USA. atolcher at start.stoh.com)
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| Journal | Journal of clinical oncology : official journal of the American Society of Clinical Oncology
(J Clin Oncol)
Vol. 26
Issue 32
Pg. 5198-203
(Nov 10 2008)
ISSN: 1527-7755 United States |
| PMID | 18824702
(Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- Antineoplastic Agents
- BIRC5 protein, human
- Imidazoles
- Microtubule-Associated Proteins
- Naphthoquinones
- Neoplasm Proteins
- YM 155
|
| Topics |
- Adult
- Aged
- Antineoplastic Agents
(administration & dosage, adverse effects, pharmacokinetics)
- Apoptosis
(drug effects)
- Dose-Response Relationship, Drug
- Drug Administration Schedule
- Female
- Humans
- Imidazoles
(administration & dosage, adverse effects, pharmacokinetics)
- Infusions, Intravenous
- Male
- Maximum Tolerated Dose
- Microtubule-Associated Proteins
(antagonists & inhibitors, metabolism)
- Middle Aged
- Naphthoquinones
(administration & dosage, adverse effects, pharmacokinetics)
- Neoplasm Proteins
(antagonists & inhibitors, metabolism)
- Neoplasms
(drug therapy, metabolism, pathology)
- Pilot Projects
- Treatment Outcome
|
