Phase I dose-escalation and pharmacokinetic study of ispinesib, a kinesin spindle protein inhibitor, administered on days 1 and 15 of a 28-day schedule in patients with no prior treatment for advanced breast cancer.

Abstract

The objective of the study was to evaluate the safety, pharmacokinetics, and antitumor activity of ispinesib, a kinesin spindle protein inhibitor. Patients with locally advanced or metastatic breast cancer who had received only prior neoadjuvant or adjuvant chemotherapy were treated with escalating doses of ispinesib administered as a 1-h infusion on days 1 and 15 every 28 days until toxicity or progression of disease. Doses were escalated until dose-limiting toxicity was observed in two out of six patients during cycle 1. A total of 16 patients were treated at three dose levels: 10 mg/m (n=3), 12 mg/m (n=6), and 14 mg/m (n=7). Forty-four percent of the patients had locally advanced disease and 56% had metastatic disease; 50% were estrogen receptor positive, 44% were progesterone receptor positive, 25% human epidermal growth factor 2 were positive, and 31% triple (estrogen receptor, progesterone receptor, human epidermal growth factor 2) negative. Sixty-nine percent of patients were chemo-naive. The maximum tolerated dose was 12 mg/m and dose-limiting toxicity was grade 3 increased aspartate aminotransferase and alanine aminotransferase. The most common toxicities included neutropenia (88%; 38% grade 3 and 44% grade 4), increased alanine aminotransferase (56%), anemia (38%), increased aspartate aminotransferase (31%), and diarrhea (31%). No neuropathy, mucositis, or alopecia was reported. Among the 15 patients evaluable for antitumor activity, there were three partial responses, one confirmed by the response evaluation criteria in solid tumors (7% response rate). Nine patients (60%) had stable disease lasting at least 42 days, with four (27%) lasting for at least 90 days. Disease stabilization (partial responses+stable disease) was observed in 11 (73.3%) patients. In conclusion, ispinesib was well tolerated when administered on days 1 and 15 every 28 days. Limited activity was observed with this schedule in patients with previously untreated advanced breast cancer.

• Authors: Henry L Gomez, Manuel Philco, Patricia Pimentel, Miriam Kiyan, Maria Laura Monsalvo, Maureen G Conlan, Khalil G Saikali, Michael M Chen, Joseph J Seroogy, Andrew A Wolff, Rafael D Escandon
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 23 Issue 3 Pg. 335-41 (Mar 2012) ISSN: 1473-5741 [Electronic] England
• PMID: 22123335 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzamides
• Quinazolines
• Receptors, Estrogen
• Receptors, Progesterone
• ispinesib
• Aspartate Aminotransferases
• Alanine Transaminase
• ERBB2 protein, human
• Receptor, ErbB-2
• Kinesins

Topics

• Adult
• Alanine Transaminase (metabolism)
• Anemia (chemically induced)
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Aspartate Aminotransferases (metabolism)
• Benzamides (administration & dosage, adverse effects, pharmacokinetics)
• Breast Neoplasms (drug therapy, metabolism)
• Diarrhea (chemically induced)
• Drug Administration Schedule
• Female
• Humans
• Kinesins (antagonists & inhibitors)
• Maximum Tolerated Dose
• Middle Aged
• Quinazolines (administration & dosage, adverse effects, pharmacokinetics)
• Receptor, ErbB-2 (metabolism)
• Receptors, Estrogen (metabolism)
• Receptors, Progesterone (metabolism)
• Treatment Outcome