| General information |
| Database: | DB00584 |
| Objective: | Aurora A kinase (AAK) is a key regulator of mitosis and a target for anticancer drug development. Thisphase I study investigated the safety, pharmacokinetics, and pharmacodynamics of MLN8237 (alisertib), an investigational, oral, selective AAK inhibitor, in 59 adults with advanced solid tumors. |
| Authors: | Cervantes A, et al |
| Title: | Phase I pharmacokinetic/pharmacodynamic study of MLN8237, an investigational, oral, selective aurora a kinase inhibitor, in patients with advanced solid tumors. |
| Journal: | Clin Cancer Res. |
| Year: | 2012 |
| PMID: | 22753585 |
| Trial Design |
| Clinical Trial Id: | NCT00651664 |
| Agent: | alisertib
|
| Target: | NA
|
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | advanced solid tumors |
| Therapy Type: | mono |
| Therapeutic Combination Type: | NA |
| Therapeutic Combination Content: | NA |
| Study Type: | openlabel, phase I, dose-escalation study |
| Key Patients Feature: | Patients 18 years or older of age with histologically orcytologically confirmed metastatic and/or advanced solidtumors (including lymphomas) for which there was nostandard curative or lifeprolonging treatment were eligiblefor enrollment. Patients were required to have an EasternCooperative Oncology Group performance status of 0 or 1, radiographically or clinically evaluable disease, and adequate hematologic, renal, and hepatic function, defined asfollows: absolute neutrophil count 1, 500 cells/mm3 ormore; platelet count 100, 000/mm3 or more; serum creatinine 1.6 mg/dL or less; creatinine clearance 40 mL/min ormore; bilirubin 1.5 upper limit of normal (ULN) or less;aspartate and alanine aminotransferases and alkaline phosphatase 2.5 ULN or less. To meet the exposure-pharmacodynamic assessment goals of the study, it was requiredthat most patients had accessible tumors for sampling ofpre and posttreatment biopsies. |
| Biomarker: | AAK inhibition in skin and tumor biopsies |
| Biomark Analysis: | At steady state, pharmacodynamic effects were shown by accumulation of mitotic and apoptotic cells in skin, and exposurerelated increases in numbers of mitotic cells with characteristic spindle and chromosomal abnormalities in tumor specimens, supporting AAK inhibition by MLN8237. |
| Control Group Info: | single arm |
| Treatment Info: | Patients received MLN8237 once daily or twice daily for 7, 14, or 21 consecutive days, follotheyd by 14 days recovery, in 21, 28, or 35day cycles.Doselimiting toxicities (DLT) and the maximumtolerated dose (MTD) for the 7 and 21day schedules were determined. Pharmacokinetic parameters were derived from plasma concentrationtime profiles. AAK inhibition in skin and tumor biopsies was evaluated and antitumor activity assessed. |
| Primary End Point: | DLTs and the MTD |
| Secondary End Point: | pharmacokinetics, pharmacodynamic effects and antitumor activity. |
| Patients Number: | 59 |
| Trial Results |
| DLT_MTD: | Neutropenia and stomatitis were the most common DLTs. The MTD for the 7 and 21day schedules was 50 mg twice daily and 50 mg once daily, respectively. |
| Objective Response Rate: | Stable disease was observed and was durable with repeat treatment cycles, administered over 6 months, in 6 patients, without notable cumulative toxicity. |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | NA |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | Serious adverse events were reported in 26 (44%) patients across multiple dose levels, and those related to MLN8237 included diarrhea (5 patients, 8%), stomatitis (4 patients, 7%), and neutropenia (4 patients, 7%). |
| Conclusions: | The recommendedphase II dose of MLN8237 is 50 mg twice daily on the 7day schedule, which is being evaluated further in a variety of malignancies, including in aphase III trial in peripheral Tcell lymphoma. |