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. Mol Cancer Ther; 13(9); 2170-83. Ó2014 AACR.

Phase I study of the aurora A kinase inhibitor alisertib with induction chemotherapy in patients with acute myeloid leukemia

“…25 Others have found that the unique mitotic toxicity of alisertib may synergize with cytotoxic chemotherapy to enhance efficacy. 15–18 Herein we report the results of a phase I study of alisertib combined with conventional induction chemotherapy for newly diagnosed AML.…”

“…13,14 This process appears especially applicable to cells during or shortly following exposure to cytotoxic chemotherapy. 15–18 …”

“…Alisertib has also been studied in combination with other neoplastic agents, where it was also demonstrated to be safe and well-tolerated. 15–18 …”

On Command Drug Delivery via Cell‐Conveyed Phototherapeutics

“…In short, illumination of mRBCs conveying Cy5‐B12‐OH 2 has little or no effect on the integrity of the vasculature relative to that of mRBCs transporting Cy5‐B12‐TAX. Finally, we note that the maximum tolerated dose of docetaxel injected intravenously to mice is ≈250 µg per mouse (10 mg kg −1 ) . Typical dosage for treatment in mice is anywhere between 75 µg per mouse for low dosage up to the experimental maximum tolerated dose for high dosage .…”

The Aurora kinase A inhibitor TC-A2317 disrupts mitotic progression and inhibits cancer cell proliferation

“…Because pharmacological inhibition of Aurora kinase A overrides SAC-mediated mitotic arrest and aggravates chromosomal instability, the combination of anti-mitotic agents and Aurora kinase A inhibitor enhances chemosensitivity. Aurora kinase A inhibition by MK-5108 and alisertib increases the anti-tumor activity of docetaxel, paclitaxel, and vincristine [27, 48, 51, 64–66], whereas Aurora A overexpression increases resistance to taxol [67]. Overall, targeting the mitotic functions of Aurora A using pharmacological inhibitors increases the anti-cancer effect of anti-mitotic agents.…”