ASP9853, an inhibitor of inducible nitric oxide synthase dimerization, in combination with docetaxel: preclinical investigation and a Phase I study in advanced solid tumors.

Abstract

PURPOSE:

ASP9853 is an inhibitor of inducible nitric oxide (NO) synthase (iNOS) dimerization, which results in decreased NO production. Here, we report preclinical pharmacology of ASP9853 and the impact of ASP9853 in combination with a taxane on tumor volume in vivo. In addition, a Phase I open-label study of ASP9853 plus docetaxel was conducted to assess this combination in patients with advanced solid tumors.

METHODS:

The preclinical efficacy of ASP9853 in combination with a taxane was studied in tumor-bearing mice. In the clinic, patients with solid tumors that had progressed or failed to respond to previous therapies were treated with once-daily ASP9853 in combination with docetaxel once every 3 weeks to assess safety and tolerability and to determine the maximum tolerated dose (MTD) and the recommended Phase II dose (RP2D) of the combination.

RESULTS:

ASP9853 in combination with docetaxel showed greater tumor growth inhibition than docetaxel alone against non-small lung cancer xenografts. Twenty patients were treated with ASP9853 and docetaxel. Five patients experienced neutropenic dose-limiting toxicities. Owing to overall toxicity that limited further dose escalation, the ASP9853 concentrations predicted for efficacy, based on the preclinical data, were not achieved. Due to toxicity and lack of clear efficacy, the study was terminated without determination of MTD or RP2D.

CONCLUSIONS:

Inhibition of iNOS by ASP9853 in combination with docetaxel was not tolerable and resulted in the possible potentiation of neutropenia. Manipulation of the iNOS pathway, with or without chemotherapy, appears to be more complicated than initially expected.

• Authors: Jason J Luke, Patricia LoRusso, Geoffrey I Shapiro, Andrew Krivoshik, Robin Schuster, Takao Yamazaki, Yukinori Arai, Allam Fakhoury, Carl Dmuchowski, Jeffrey R Infante
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 77 Issue 3 Pg. 549-58 (Mar 2016) ISSN: 1432-0843 [Electronic] Germany
• PMID: 26811179 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• ASP9853
• Acrylamides
• Pyrimidines
• Taxoids
• Docetaxel
• Nitric Oxide Synthase Type II

Topics

• Acrylamides (administration & dosage)
• Adult
• Aged
• Aged, 80 and over
• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, pathology)
• Dimerization
• Docetaxel
• Dose-Response Relationship, Drug
• Female
• Humans
• Lung Neoplasms (drug therapy, pathology)
• Male
• Maximum Tolerated Dose
• Mice
• Mice, Nude
• Middle Aged
• Neoplasms (drug therapy, pathology)
• Neutropenia (chemically induced)
• Nitric Oxide Synthase Type II (antagonists & inhibitors)
• Pyrimidines (administration & dosage)
• Taxoids (administration & dosage)
• Xenograft Model Antitumor Assays