Phase II study of MLN8237 (alisertib), an investigational Aurora A kinase inhibitor, in patients with platinum-resistant or -refractory epithelial ovarian, fallopian tube, or primary peritoneal carcinoma

Matulonis, Ursula A.; Sharma, Sudarshan; Ghamande, Sharad; Gordon, Michael; Prete, Salvatore A. Del; Ray‐Coquard, Isabelle; Kutarska, E.; Liu, Hua; Fingert, Howard; Zhou, Xiaofei; Danaee, Hadi; Schilder, Russell J.

doi:10.1016/j.ygyno.2012.06.040

Cited by 127 publications

(92 citation statements)

References 25 publications

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“…Ali has been chosen as pharmacologic model for drug loading because of its effect as a selective AAK inhibitor and because its application against solid tumors (epi thelial ovarian, fallopian tube and primary peritoneal carcinoma) is well known [31][32][33]. In this work, we also studied the synergic effect of Ali and AgNPs.…”

Section: Discussionmentioning

confidence: 99%

Targeted Delivery of Silver Nanoparticles and Alisertib: In Vitro and In Vivo Synergistic Effect Against Glioblastoma

et al. 2014

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Aim: Targeted biocompatible nanoplatforms presenting multiple therapeutic functions have great potential for the treatment of cancer. Materials & methods: Multifunctional nanocomposites formed by polymeric nanoparticles (PNPs) containing two cytotoxic agents -the drug alisertib and silver nanoparticles -were synthesized. These PNPs have been conjugated with a chlorotoxin, an active targeting 36-amino acid-long peptide that specifically binds to MMP-2, a receptor overexpressed by brain cancer cells. Results:The individual and synergistic activity of these two cytotoxic agents against glioblastoma multiforme was tested both in vitro and in vivo. The induced cytotoxicity in a human glioblastoma-astrocytoma epithelial-like cell line (U87MG) was studied in vitro through a trypan blue exclusion test after 48 and 72 h of exposure. Subsequently, the PNPs' biodistribution in healthy animals and their effect on tumor reduction in tumor-bearing mice were studied using PNPs radiolabeled with 99m Tc. Conclusion: Tumor reduction was achieved in vivo when using silver/alisertib@PNPs-chlorotoxin.

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Section: Discussionmentioning

confidence: 99%

Targeted Delivery of Silver Nanoparticles and Alisertib: In Vitro and In Vivo Synergistic Effect Against Glioblastoma

et al. 2014

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“…MLN8237 has been evaluated in multiple PI and PII clinical studies (36,39,46,47). In the first-in-human P1 study, a partial response was achieved in one patient with platinum and radiation refractory ovarian cancer that lasted for greater than 1 year (38).…”

Section: Discussionmentioning

confidence: 99%

Translational Exposure–Efficacy Modeling to Optimize the Dose and Schedule of Taxanes Combined with the Investigational Aurora A Kinase Inhibitor MLN8237 (Alisertib)

Huck

Zhang

Mettetal

et al. 2014

Molecular Cancer Therapeutics

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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.

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“…4,5 Key toxicities in early-phase adult trials included myelosuppression, mucositis, and mood alterations. 6,7 Clinical experience with alisertib in combination with standard chemotherapy agents, to date, is limited and exclusive to adult malignancies.…”

Section: Introductionmentioning

confidence: 99%

Phase I Study of the Aurora A Kinase Inhibitor Alisertib in Combination With Irinotecan and Temozolomide for Patients With Relapsed or Refractory Neuroblastoma: A NANT (New Approaches to Neuroblastoma Therapy) Trial

DuBois

Marachelian

Fox

et al. 2016

JCO

117

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Purpose Alisertib is an oral Aurora A kinase inhibitor with preclinical activity in neuroblastoma. Irinotecan and temozolomide have activity in patients with advanced neuroblastoma. The goal of this phase I study was to determine the maximum tolerated dose (MTD) of alisertib with irinotecan and temozolomide in this population. Patients and Methods Patients age 1 to 30 years with relapsed or refractory neuroblastoma were eligible. Patients received alisertib tablets at dose levels of 45, 60, and 80 mg/m2 per day on days 1 to 7 along with irinotecan 50 mg/m2 intravenously and temozolomide 100 mg/m2 orally on days 1 to 5. Dose escalation of alisertib followed the rolling six design. Samples for pharmacokinetic and pharmacogenomic testing were obtained. Results Twenty-three patients enrolled, and 22 were eligible and evaluable for dose escalation. A total of 244 courses were administered. The MTD for alisertib was 60 mg/m2, with mandatory myeloid growth factor support and cephalosporin prophylaxis for diarrhea. Thrombocytopenia and neutropenia of any grade were seen in the majority of courses (84% and 69%, respectively). Diarrhea in 55% of courses and nausea in 54% of courses were the most common nonhematologic toxicities. The overall response rate was 31.8%, with a 50% response rate observed at the MTD. The median number of courses per patient was eight (range, two to 32). Progression-free survival rate at 2 years was 52.4%. Pharmacokinetic testing did not show evidence of drug-drug interaction between irinotecan and alisertib. Conclusion Alisertib 60 mg/m2 per dose for 7 days is tolerable with a standard irinotecan and temozolomide backbone and has promising response and progression-free survival rates. A phase II trial of this regimen is ongoing.

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Phase II study of MLN8237 (alisertib), an investigational Aurora A kinase inhibitor, in patients with platinum-resistant or -refractory epithelial ovarian, fallopian tube, or primary peritoneal carcinoma

Cited by 127 publications

References 25 publications

Targeted Delivery of Silver Nanoparticles and Alisertib: In Vitro and In Vivo Synergistic Effect Against Glioblastoma

Targeted Delivery of Silver Nanoparticles and Alisertib: In Vitro and In Vivo Synergistic Effect Against Glioblastoma

Translational Exposure–Efficacy Modeling to Optimize the Dose and Schedule of Taxanes Combined with the Investigational Aurora A Kinase Inhibitor MLN8237 (Alisertib)

Phase I Study of the Aurora A Kinase Inhibitor Alisertib in Combination With Irinotecan and Temozolomide for Patients With Relapsed or Refractory Neuroblastoma: A NANT (New Approaches to Neuroblastoma Therapy) Trial

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