Initial testing of the aurora kinase a inhibitor MLN8237 by the Pediatric Preclinical Testing Program (PPTP)

Maris, John M.; Morton, Christopher L.; Görlick, Richard; Kolb, E. Anders; Lock, Richard B.; Carol, Hernán; Keir, Stephen T.; Reynolds, C. Patrick; Kang, Min H.; Wu, Jianrong; Smith, Malcolm A.; Houghton, Peter J.

doi:10.1002/pbc.22430

Cited by 182 publications

(181 citation statements)

References 32 publications

(35 reference statements)

Supporting

Mentioning

172

Contrasting

Unclassified

Order By: Relevance

“…In clinical studies, similar pharmacodynamic effects were reported, indicating AAK inhibition in skin and tumor tissues (34)(35)(36); however, dose escalation was stopped, and the MLN8054 development program discontinued, based on benzodiazepine-like somnolence and neurocognitive changes (34). Consistent with the expected activity of an AAK inhibitor, treatment with the second-generation agent MLN8237 has been shown to be associated with an accumulation of cells with abnormal mitotic spindles, leading to decreased proliferation and apoptosis in a range of human tumor cell lines (37)(38)(39)(40)(41)(42)(43). MLN8237 has shown promising single-agent antitumor activity in animal xenograft models (32,41,44) and enhanced antitumor activity in combination with standard agents in hematologic and solid tumor models (39,40,42,43,45).…”

Section: Introductionmentioning

confidence: 74%

Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors

Cervantes

Élez

Roda

et al. 2012

Clinical Cancer Research

130

159

View full text Add to dashboard Cite

Purpose: Aurora A kinase (AAK) is a key regulator of mitosis and a target for anticancer drug development. This phase I study investigated the safety, pharmacokinetics, and pharmacodynamics of MLN8237 (alisertib), an investigational, oral, selective AAK inhibitor, in 59 adults with advanced solid tumors.Experimental Design: Patients received MLN8237 once daily or twice daily for 7, 14, or 21 consecutive days, followed by 14 days recovery, in 21-, 28-, or 35-day cycles. Dose-limiting toxicities (DLT) and the maximum-tolerated dose (MTD) for the 7-and 21-day schedules were determined. Pharmacokinetic parameters were derived from plasma concentration-time profiles. AAK inhibition in skin and tumor biopsies was evaluated and antitumor activity assessed.Results: Neutropenia and stomatitis were the most common DLTs. The MTD for the 7-and 21-day schedules was 50 mg twice daily and 50 mg once daily, respectively. MLN8237 absorption was fast (median time to maximum concentration, 2 hours). Mean terminal half-life was approximately 19 hours. At steady state, pharmacodynamic effects were shown by accumulation of mitotic and apoptotic cells in skin, and exposure-related increases in numbers of mitotic cells with characteristic spindle and chromosomal abnormalities in tumor specimens, supporting AAK inhibition by MLN8237. Stable disease was observed and was durable with repeat treatment cycles, administered over 6 months, in 6 patients, without notable cumulative toxicity.Conclusions: The recommended phase II dose of MLN8237 is 50 mg twice daily on the 7-day schedule, which is being evaluated further in a variety of malignancies, including in a phase III trial in peripheral T-cell lymphoma.

show abstract

Section: Introductionmentioning

confidence: 74%

Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors

Cervantes

Élez

Roda

et al. 2012

Clinical Cancer Research

130

159

View full text Add to dashboard Cite

show abstract

“…MLN8237 is an ATP-competitive and reversible inhibitor of AAK with an inhibition constant (K i ) of 0.43 nmol/L (Millennium Pharmaceuticals, Inc. data on file), and was designed to minimize the benzodiazepine-like effects seen with MLN8054 (24). In preclinical studies, MLN8237 has showed both in vitro and in vivo activity in a broad range of tumor types (21,22,(25)(26)(27)(28). In vitro, MLN8237 showed antiproliferative activity across a broad range of both solid tumor and lymphoma cell lines (22).…”

Section: Introductionmentioning

confidence: 99%

Phase I Study of Aurora A Kinase Inhibitor MLN8237 in Advanced Solid Tumors: Safety, Pharmacokinetics, Pharmacodynamics, and Bioavailability of Two Oral Formulations

Dees

Cohen

Mehren

et al. 2012

Clinical Cancer Research

142

169

View full text Add to dashboard Cite

Purpose: This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of the investigational oral drug MLN8237 (alisertib), a small-molecule Aurora A kinase (AAK) inhibitor, in 87 adult patients with advanced solid tumors.Experimental Design: Sequential cohorts of patients received MLN8237 5 to 150 mg orally once daily or twice daily for 7, 14, or 21 days, followed by 14 days' rest per cycle. MLN8237 pharmacokinetics was characterized, and the relative bioavailability of an enteric-coated tablet (ECT) formulation was evaluated in reference to the original powder-in-capsule (PIC) formulation. Pharmacodynamic effects of MLN8237 on inhibition of AAK activity were evaluated in skin biopsies. Tolerability and response to treatment were assessed.Results: Common toxicities included fatigue, nausea, and neutropenia. Plasma exposures increased dose proportionally (5-150 mg/d), and were similar for PIC and ECT. The terminal half-life was 23 hours. At the maximum tolerated dose of 50 mg twice daily on the 7-day 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. 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 !3 months.Conclusions: This first-in-human trial of MLN8237 showed tolerability and favorable pharmacokinetics in this patient population. The recommended phase II dose of MLN8237 is 50 mg twice daily orally for 7 days in 21-day cycles, which is being evaluated further in the treatment of various solid tumors and hematologic malignancies.

show abstract

“…The best studied proteins of the two identified machineries, AURKA and MAD2L1, were already demonstrated to be important NB prognostic genes when at high expression levels. AURKA overexpression in NBs is actually associated with high-risk and high-stage tumors, unfavorable histology, MNA, disease relapse and decreased progression-free survival (Shang et al, 2009) and offers a promising target for NB therapy (Shang et al, 2009;Maris et al, 2010). MAD2L1 overexpression has also been associated to NB poor prognosis (Hernando et al, 2004).…”

Section: Discussionmentioning

confidence: 98%

Segmental chromosome aberrations converge on overexpression of mitotic spindle regulatory genes in high‐risk neuroblastoma

Ooi

Sidarovich

et al. 2012

Genes Chromosomes & Cancer

View full text Add to dashboard Cite

Integration of genome-wide profiles of DNA copy number alterations (CNAs) and gene expression variations (GEVs) could provide combined power to the identification of driver genes and gene networks in tumors. Here we merge matched genome and transcriptome microarray analyses from neuroblastoma samples to derive correlation patterns of CNAs and GEVs, irrespective of their genomic location. Neuroblastoma correlation patterns are strongly asymmetrical, being on average 10 CNAs linked to 1 GEV, and show the widespread prevalence of long range covariance. Functional enrichment and network analysis of the genes covarying with CNAs consistently point to a major cell function, the regulation of mitotic spindle assembly. Moreover, elevated expression of 14 key genes promoting this function is strongly associated to high-risk neuroblastomas with 1p loss and MYCN amplification in a set of 410 tumor samples (P < 0.00001). Independent CNA/GEV profiling on neuroblastoma cell lines shows that increased levels of expression of these genes are linked to 1p loss. By this approach, we reveal a convergence of clustered neuroblastoma CNAs toward increased expression of a group of prognostic and functionally cooperating genes. We therefore propose gain of function of the spindle assembly machinery as a lesion potentially offering new targets for therapy of high-risk neuroblastoma.

show abstract

Initial testing of the aurora kinase a inhibitor MLN8237 by the Pediatric Preclinical Testing Program (PPTP)

Abstract: Background-MLN8237 is a small molecule inhibitor of Aurora Kinase A (AURKA) that is currently in early phase clinical testing. AURKA plays a pivotal role in centrosome maturation and spindle formation during mitosis.

Cited by 182 publications

References 32 publications

Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors

Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors

Phase I Study of Aurora A Kinase Inhibitor MLN8237 in Advanced Solid Tumors: Safety, Pharmacokinetics, Pharmacodynamics, and Bioavailability of Two Oral Formulations

Segmental chromosome aberrations converge on overexpression of mitotic spindle regulatory genes in high‐risk neuroblastoma

Contact Info

Product

Resources

About