title: Translational exposure-efficacy modeling to optimize the dose and schedule of taxanes combined with the investigational Aurora A kinase inhibitor MLN8237 (alisertib).
abstract: Aurora A kinase orchestrates multiple key activities, allowing cells to transit successfully into and through mitosis. MLN8237 (alisertib) is a selective Aurora A inhibitor that is being evaluated as an anticancer agent in multiple solid tumors and heme-lymphatic malignancies. The antitumor activity of MLN8237 when combined with docetaxel or paclitaxel was evaluated in in vivo models of triple-negative breast cancer grown in immunocompromised mice. Additive and synergistic antitumor activity occurred at multiple doses of MLN8237 and taxanes. Moreover, significant tumor growth delay relative to the single agents was achieved after discontinuing treatment; notably, durable complete responses were observed in some mice. The tumor growth inhibition data generated with multiple dose levels of MLN8237 and paclitaxel were used to generate an exposure-efficacy model. Exposures of MLN8237 and paclitaxel achieved in patients were mapped onto the model after correcting for mouse-to-human variation in plasma protein binding and maximum tolerated exposures. This allowed rank ordering of various combination doses of MLN8237 and paclitaxel to predict which pair would lead to the greatest antitumor activity in clinical studies. The model predicted that 60 and 80 mg/m(2) of paclitaxel (every week) in patients lead to similar levels of efficacy, consistent with clinical observations in some cancer indications. The model also supported using the highest dose of MLN8237 that can be achieved, regardless of whether it is combined with 60 or 80 mg/m(2) of paciltaxel. The modeling approaches applied in these studies can be used to guide dose-schedule optimization for combination therapies using other therapeutic agents.
authors: Department of Cancer Pharmacology, Takeda Pharmaceuticals International Co., Cambridge, Massacheusetts.
authors: Jessica J
authors: JJ
authors: Huck
authors: Department of Cancer Pharmacology, Takeda Pharmaceuticals International Co., Cambridge, Massacheusetts.
authors: Mengkun
authors: M
authors: Zhang
authors: Department of DMPK, Takeda Pharmaceuticals International Co., Cambridge, Massacheusetts.
authors: Jerome
authors: J
authors: Mettetal
authors: Department of DMPK, Takeda Pharmaceuticals International Co., Cambridge, Massacheusetts.
authors: Arijit
authors: A
authors: Chakravarty
authors: Department of Clinical Pharmacology, Takeda Pharmaceuticals International Co., Cambridge, Massacheusetts.
authors: Karthik
authors: K
authors: Venkatakrishnan
authors: Department of Clinical Pharmacology, Takeda Pharmaceuticals International Co., Cambridge, Massacheusetts.
authors: Xiaofei
authors: X
authors: Zhou
authors: Department of Drug Development Management, Takeda Pharmaceuticals International Co., Cambridge, Massacheusetts.
authors: Rob
authors: R
authors: Kleinfield
authors: Department of Cancer Pharmacology, Takeda Pharmaceuticals International Co., Cambridge, Massacheusetts.
authors: Marc L
authors: ML
authors: Hyer
authors: Department of Cancer Pharmacology, Takeda Pharmaceuticals International Co., Cambridge, Massacheusetts.
authors: Karuppiah
authors: K
authors: Kannan
authors: Department of Molecular Pathology, Takeda Pharmaceuticals International Co., Cambridge, Massacheusetts.
authors: Vaishali
authors: V
authors: Shinde
authors: Department of Translational Medicine, Takeda Pharmaceuticals International Co., Cambridge, Massacheusetts.
authors: Andy
authors: A
authors: Dorner
authors: Department of Cancer Pharmacology, Takeda Pharmaceuticals International Co., Cambridge, Massacheusetts.
authors: Mark G
authors: MG
authors: Manfredi
authors: Department of DMPK, Takeda Pharmaceuticals International Co., Cambridge, Massacheusetts.
authors: Wen Chyi
authors: WC
authors: Shyu
authors: Department of Translational Medicine, Takeda Pharmaceuticals International Co., Cambridge, Massacheusetts. jeffrey.ecsedy@takeda.com.
authors: Jeffrey A
authors: JA
authors: Ecsedy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D019540:Area Under Curve; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors*; D001381:Azepines / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage*; D043823:Taxoids / Q000008:administration & dosage*; D057170:Translational Research, Biomedical
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; C550258:MLN 8237; D011743:Pyrimidines; D043823:Taxoids; D000077143:Docetaxel; D064096:Aurora Kinase A; D017239:Paclitaxel