A phase I trial of the kinesin spindle protein (Eg5) inhibitor AZD4877 in patients with solid and lymphoid malignancies Journal Article
| Authors: | Gerecitano, J. F.; Stephenson, J. J.; Lewis, N. L.; Osmukhina, A.; Li, J.; Wu, K.; You, Z.; Huszar, D.; Skolnik, J. M.; Schwartz, G. K. |
| Article Title: | A phase I trial of the kinesin spindle protein (Eg5) inhibitor AZD4877 in patients with solid and lymphoid malignancies |
| Abstract: | Summary: Background This Phase I study assessed the safety and maximum tolerated dose (MTD) of the kinesin spindle protein inhibitor AZD4877 in patients with relapsed/refractory solid tumors and lymphoma. Methods In this multicenter study, a standard 3 + 3 dose-escalation design was used. AZD4877 was given as an intravenous infusion on days 1, 4, 8 and 11 of each 21-day cycle. Responses were assessed with CT scans +/- PET after 6 and 12 weeks, then every 12 weeks while on therapy. An additional four patients with lymphoma were enrolled at the MTD. Results 29 patients were enrolled and 22 patients received at least one dose of AZD4877 and were evaluable for safety. The MTD was 11 mg. Dose-limiting toxicity was neutropenia (n = 2 patients, 15 mg cohort). The most common adverse events were grade 1/2 fatigue, nausea, neutropenia and dyspnea. AZD4877 exposure generally increased with dose, with mean elimination half-life approximately 16 h at the MTD. Pharmacodynamic analyses demonstrated moderate correlation between plasma drug concentrations at 6 or 24 h and monoaster formation in peripheral blood mononuclear cells (PBMCs). Conclusions AZD4877 is generally well-tolerated with pharmacodynamic evidence of target inhibition in circulating PBMCs. © 2012 Springer Science+Business Media, LLC. |
| Keywords: | adult; treatment response; aged; middle aged; unclassified drug; fatigue; neutropenia; cancer recurrence; dose response; drug safety; solid tumor; treatment duration; positron emission tomography; follow-up studies; antineoplastic agent; anorexia; neoplasms; edema; computer assisted tomography; multiple cycle treatment; nausea; dehydration; antineoplastic activity; dose-response relationship, drug; pyrimidinones; backache; chill; drug dose escalation; dyspnea; pneumonia; hypoxia; lung embolism; lymphoma, b-cell; tissue distribution; multicenter study; lymphoma; urinary tract infection; sepsis; pleura effusion; safety; maximum tolerated dose; phase 1 clinical trial; drug half life; infusions, intravenous; protein inhibitor; peripheral blood mononuclear cell; pharmacokinetics; solid tumors; kinesin; cholestasis; hydronephrosis; drug elimination; benzamides; azd 4877; tolerability; azd4877; eg5; kinesin spindle protein |
| Journal Title: | Investigational New Drugs |
| Volume: | 31 |
| Issue: | 2 |
| ISSN: | 0167-6997 |
| Publisher: | Springer |
| Date Published: | 2013-04-01 |
| Start Page: | 355 |
| End Page: | 362 |
| Language: | English |
| DOI: | 10.1007/s10637-012-9821-y |
| PROVIDER: | scopus |
| PUBMED: | 22615058 |
| DOI/URL: | |
| Notes: | --- - Cited By (since 1996):2 - "Export Date: 19 July 2013" - "CODEN: INNDD" - "Source: Scopus" |
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