| General information |
| Database: | DB00583 |
| Objective: | Thisphase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of the investigational oral drug MLN8237 (alisertib), a smallmolecule Aurora A kinase (AAK) inhibitor, in 87 adult patients with advanced solid tumors. |
| Authors: | Dees EC, et al |
| Title: | Phase I study of aurora A kinase inhibitor MLN8237 in advanced solid tumors: safety, pharmacokinetics, pharmacodynamics, and bioavailability of two oral formulations. |
| Journal: | Clin Cancer Res. |
| Year: | 2012 |
| PMID: | 22767670 |
| Trial Design |
| Clinical Trial Id: | NCT00500903 |
| Agent: | alisertib
|
| Target: | aurora kinase A
|
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | advanced solid tumors |
| Therapy Type: | mono |
| Therapeutic Combination Type: | NA |
| Therapeutic Combination Content: | NA |
| Study Type: | phase I, openlabel, doseescalation study |
| Key Patients Feature: | Eligible patients were aged 18 years, and had histologically or cytologically confirmed metastatic and/oradvanced solid tumors (including lymphomas) refractoryto standard therapy, or for which no effective standardtreatment was available. Other inclusion criteria includedan Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and radiographically or clinicallyevaluable disease. Eligible patients were required to haveadequate organ function, including an absolute neutrophilcount (ANC) of 1, 500 cells/mm3; a platelet count of 100, 000/mm3; serum creatinine of 1.6 mg/dL or ameasured or estimated (Cockcroft-Gault formula) creatinine clearance of 40 mL/min; bilirubin of 1.5 upperlimit of normal (ULN); aspartate aminotransferase (AST) oralanine aminotransferase of 2.5 ULN; alkaline phosphatase (ALP) of 2.5 ULN (AST and ALP levels <5 ULN were permitted if reasonably ascribed to liver or bonemetastases); and a left ventricular ejection fraction (LVEF)of 50%. Patients could not have received more than 4prior cytotoxic chemotherapeutic regimens, prior stemcell transplant, or prior radiation therapy involving 25% of hematopoietically active bone marrow |
| Biomarker: | NA |
| Biomark Analysis: | NA |
| Control Group Info: | single arm |
| Treatment Info: | patients received MLN8237 5 to 150 mg orally once daily or twice daily for 7, 14, or 21 days, follotheyd by 14 days' rest per cycle. |
| Primary End Point: | the maximum tolerated dose (MTD) and doselimiting toxicities (DLT) ofMLN8237 |
| Secondary End Point: | pharmacokinetics, assessment of pharmacodynamic effects, measurementof the relative bioavailability, and the antitumor activity |
| Patients Number: | 87 |
| Trial Results |
| DLT_MTD: | At the maximum tolerated dose of 50 mg twice daily on the 7day schedule, the mitotic index of the skin basal epithelium was increased within 24 hours after MLN8237 administration on days 1 and 7, a finding consistent with AAK inhibition |
| Objective Response Rate: | One (1%) patient achieved a partial response lasting for more than 1 year and received MLN8237 for 51 cycles; 20 (23%) patients achieved stable disease for more than and equal to 3 months. |
| 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): | All patients reported at least 1 treatmentemergent adverse event, and 47 (54%) patients reported at least 1 grade 3 adverse event during the study. Drugrelated adverse events are summarized in Table 3. The most common drugrelated adverse events (all grades) were fatigue (n 40, 46%), nausea (n 40, 46%), and neutropenia (n 37, 43%). |
| Conclusions: | This firstinhuman trial of MLN8237 showed tolerability and favorable pharmacokinetics in this patient population. The recommendedphase II dose of MLN8237 is 50 mg twice daily orally for 7 days in 21day cycles, which is being evaluated further in the treatment of various solid tumors and hematologic malignancies. |