ABSTRACT
Aim: This Phase I study investigated safety of navitoclax and docetaxel in patients (n = 41) with advanced solid tumors. Patients & methods: Two navitoclax plus docetaxel dosing schedules (21 and 28 days) were evaluated. Maximum tolerated dose, dose-limiting toxicities and preliminary antitumor activity were assessed. Results: Ten (24%) patients experienced dose-limiting toxicities; dose-escalation cohorts: n = 7 (21-day schedule: n = 5; 28-day schedule: n = 2) and 21-day expanded safety cohort: n = 3. Navitoclax 150-mg days 1-5 every 21 days with docetaxel 75 mg/m2 day 1 was the maximum tolerated dose and optimal schedule. Adverse events included thrombocytopenia (63%), fatigue (61%), nausea (59%) and neutropenia (51%). Four confirmed partial responses occurred. Conclusion: Navitoclax 150-mg orally once/day was safely administered with docetaxel. Myelosuppression limited dose escalation; antitumor activity was observed. Clinical trial registration: NCT00888108 (ClinicalTrials.gov).
Subject(s)
Aniline Compounds/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Docetaxel/adverse effects , Neoplasms/drug therapy , Sulfonamides/adverse effects , Administration, Oral , Adult , Aged , Aged, 80 and over , Aniline Compounds/administration & dosage , Aniline Compounds/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Docetaxel/administration & dosage , Docetaxel/pharmacokinetics , Drug Administration Schedule , Fatigue/chemically induced , Fatigue/epidemiology , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Nausea/chemically induced , Nausea/epidemiology , Neutropenia/chemically induced , Neutropenia/epidemiology , Sulfonamides/administration & dosage , Sulfonamides/pharmacokinetics , Thrombocytopenia/chemically induced , Thrombocytopenia/epidemiologyABSTRACT
INTRODUCTION: Drugs that interfere with the normal progression of mitosis belong to the most successful cytotoxic agents currently used for anticancer treatment. Aurora kinases are serine/threonine kinases that function as key regulators of mitosis and are frequently overexpressed in human cancers. The use of several small molecule aurora kinase inhibitors as potential anticancer therapeutic is being investigated. Danusertib (formerly PHA-739358) is a small ATP competitive molecule that inhibits aurora A, B and C kinases. Interestingly, danusertib also inhibits several receptor tyrosine kinases such as Abl, Ret, FGFR-1 and TrkA. These tyrosine kinases are involved in the pathogenesis of a variety of malignancies and the observed multi-target inhibition may increase the antitumor activity resulting in extending the indication. Danusertib was one of the first aurora kinase inhibitors to enter the clinic and has been studied in Phase I and II trials. AREAS COVERED: This review provides an updated summary of preclinical and clinical experience with danusertib up to July 2011. EXPERT OPINION: Future studies with danusertib should focus on the possibility of combining this agent with other targeted anticancer agents, chemotherapy or radiotherapy. As a single agent, danusertib may show more promise in the treatment of leukemias than in solid tumors.
