MLN8054 and Alisertib (MLN8237): Discovery of Selective Oral Aurora A Inhibitors.
Ontology highlight
ABSTRACT:
SUBMITTER: Sells TB
PROVIDER: S-EPMC4468408 | biostudies-literature | 2015 Jun
REPOSITORIES: biostudies-literature
Similar Datasets
Project description: Not available
| S-EPMC4820359 | biostudies-literature
Project description:Alisertib (MLN8237) is an investigational, oral, selective, Aurora A kinase (AAK) inhibitor. In this phase 2 trial, 57 patients with acute myeloid leukemia (AML) or high-grade myelodysplastic syndrome received alisertib 50 mg BID for 7 days in 21-day cycles. Responses in 6/35 AML patients (17% response rate with an additional 49% stable disease, 34% transfusion independence) included 1 complete response lasting >1 year. No responses were observed in MDS patients. Adverse events >30% included diarrhea, fatigue, nausea, febrile neutropenia, and stomatitis. Results suggest modest activity in AML, supporting further research to better understand how AAK inhibition may induce leukemic cell senescence.
| S-EPMC4110881 | biostudies-literature
Project description:Alisertib, an Aurora kinase A inhibitor, was evaluated in a Phase 1 study in combination with the histone deacetylase inhibitor vorinostat, in patients with relapsed/refractory lymphoid malignancies (N = 34; NCT01567709). Patients received alisertib plus vorinostat in 21-day treatment cycles with escalating doses of alisertib following a continuous or an intermittent schedule. All dose-limiting toxicities (DLTs) were hematologic and there were no study-related deaths. The recommended phase 2 dose (RP2D) of the combination was 20 mg bid of alisertib and 200 mg bid of vorinostat on the intermittent schedule. A 13-patient expansion cohort was treated for a total of 18 patients at the RP2D. There were no DLTs at the RP2D, and toxicities were mainly hematologic. Two patients with DLBCL achieved a durable complete response, and two patients with HL achieved partial response. Alisertib plus vorinostat showed encouraging clinical activity with a manageable safety profile in heavily pretreated patients with advanced disease.
| S-EPMC6982547 | biostudies-literature
Project description:BackgroundAurora kinase A (AURKA) is commonly overexpressed in sarcoma. The inhibition of AURKA by shRNA or by a specific AURKA inhibitor blocks in vitro proliferation of multiple sarcoma subtypes. MLN8237 (alisertib) is a novel oral adenosine triphosphate-competitive AURKA inhibitor.Patients and methodsThis Cancer Therapy Evaluation Program-sponsored phase II study of alisertib was conducted through the Alliance for Clinical Trials in Oncology (A091102). Patients were enrolled into histology-defined cohorts: (i) liposarcoma, (ii) leiomyosarcoma, (iii) undifferentiated sarcoma, (iv) malignant peripheral nerve sheath tumor, or (v) other. Treatment was alisertib 50 mg PO b.i.d. d1-d7 every 21 days. The primary end point was response rate; progression-free survival (PFS) was secondary. One response in the first 9 patients expanded enrollment in a cohort to 24 using a Simon two-stage design.ResultsSeventy-two patients were enrolled at 24 sites [12 LPS, 10 LMS, 11 US, 10 malignant peripheral nerve sheath tumor (MPNST), 29 Other]. The median age was 55 years; 54% were male; 58%/38%/4% were ECOG PS 0/1/2. One PR expanded enrollment to the second stage in the other sarcoma cohort. The histology-specific cohorts ceased at the first stage. There were two confirmed PRs in the other cohort (both angiosarcoma) and one unconfirmed PR in dedifferentiated chondrosarcoma. Twelve-week PFS was 73% (LPS), 44% (LMS), 36% (US), 60% (MPNST), and 38% (Other). Grade 3-4 adverse events: oral mucositis (12%), anemia (14%), platelet count decreased (14%), leukopenia (22%), and neutropenia (42%).ConclusionsAlisertib was well tolerated. Occasional responses, yet prolonged stable disease, were observed. Although failing to meet the primary RR end point, PFS was promising.Trial registration idNCT01653028.
| S-EPMC5035789 | biostudies-literature
Project description:BackgroundThis phase 1b study evaluated an enteric-coated tablet (ECT) formulation of the investigational Aurora A kinase inhibitor, alisertib (MLN8237).MethodsPatients with advanced, non-hematologic malignancies received oral alisertib ECT for 7 d BID followed by 14 d treatment-free (21-day cycles; 3 + 3 dose escalation schema). Objectives were to assess safety, pharmacokinetics, and antitumor activity, and to define a recommended phase 2 dose (RP2D) of alisertib.Results24 patients were treated. Median age was 57 years. Patients received a median of 2 cycles (range 1-12). The RP2D was determined as 50 mg BID for 7 d (21-day cycles). A cycle 1 dose-limiting toxicity of grade 4 febrile neutropenia was observed in 1 of 13 patients at RP2D. The most common drug-related adverse event (AE) was neutropenia (50%). At doses ≥ 40 mg BID, 7 patients had drug-related AEs that were serious but largely reversible/manageable by dose reduction and supportive care, including 3 with febrile neutropenia. Pharmacokinetic data were available in 24 patients. Following administration of alisertib ECT, the plasma peak concentration of alisertib was achieved at ~3 h; systemic exposure increased with increasing dose over 10-60 mg BID. Mean t½ was ~21 h following multiple dosing. Renal clearance was negligible. Nine patients achieved stable disease (3.98*, 5.59, 1.28*, 2.56, 5.45*, 3.48, 3.15, 8.31, and 6.93* months; *censored).ConclusionsAlisertib ECT was generally well tolerated in adults with advanced, non-hematologic malignancies. The RP2D is 50 mg BID for 7 d and is being evaluated in ongoing phase 2 studies.
| S-EPMC4229392 | biostudies-literature
Project description:Lessons learnedTreatment with the Aurora kinase A inhibitor yields often durable disease control, but limited tumor regression, in heavily pretreated patients with unresectable malignant pleural or peritoneal mesothelioma. In a limited sample size, MYC copy-number gain or gene amplification, a candidate predictive biomarker for alisertib, did not correlate with improved response numbers or patient outcomes.BackgroundMalignant mesothelioma is an aggressive disease for which few effective therapies are available. The Aurora family kinases are critical for mitotic fidelity and highly expressed in mesothelioma, wherein their inhibition leads to growth arrest in vitro. We evaluated the efficacy of alisertib, an Aurora A kinase inhibitor, in relapsed malignant mesothelioma.MethodsTwenty-six patients with previously treated, unresectable pleural or peritoneal mesothelioma were enrolled on a single-arm, single-institution phase II trial of alisertib at a dosage of 50 mg twice daily for 7 of every 21 days. The primary endpoint was 4-month disease control rate. Secondary endpoints included overall response rate, progression free survival, overall survival, safety/toxicity, and correlation of endpoints with MYC copy number.ResultsOf the 25 evaluable patients treated on study, 8 (32%) experienced 4-month disease control, surpassing the futility endpoint. There were no confirmed partial or complete responses. Median progression-free and overall survival were 2.8 months and 6.3 months, respectively. No associations between MYC copy number and outcomes were observed.ConclusionAlisertib has modest activity in this unselected malignant mesothelioma population. Several patients achieved durable disease control. Although the study did meet its prespecified futility endpoint, the sponsor elected to close the trial at the interim analysis.
| S-EPMC7543335 | biostudies-literature
Project description:BackgroundThe Aurora kinases are a family of serine/threonine kinases comprised of Aurora A, B, and C which execute critical steps in mitotic and meiotic progression. Alisertib (MLN8237) is an investigational Aurora A selective inhibitor that has demonstrated activity against a wide variety of tumor types in vitro and in vivo, including CRC.ResultsCRC cell lines demonstrated varying sensitivity to alisertib with IC50 values ranging from 0.06 to > 5 umol/L. Following exposure to alisertib we observed a decrease in pAurora A, B and C in four CRC cell lines. We also observed an increase in p53 and p21 in a sensitive p53 wildtype cell line in contrast to the p53 mutant cell line or the resistant cell lines. The addition of alisertib to standard CRC treatments demonstrated improvement over single agent arms; however, the benefit was largely less than additive, but not antagonistic.MethodsForty-seven CRC cell lines were exposed to alisertib and IC50s were calculated. Twenty-one PDX models were treated with alisertib and the Tumor Growth Inhibition Index was assessed. Additionally, 5 KRAS wildtype and mutant PDX models were treated with alisertib as single agent or in combination with cetuximab or irinotecan, respectively.ConclusionAlisertib demonstrated anti-proliferative effects against CRC cell lines and PDX models. Our data suggest that the addition of alisertib to standard therapies in colorectal cancer if pursued clinically, will require further investigation of patient selection strategies and these combinations may facilitate future clinical studies.
| S-EPMC5226583 | biostudies-literature
Project description:PurposeAurora kinases are overexpressed or amplified in numerous malignancies. This study was designed to determine the safety and tolerability of the Aurora A kinase inhibitor alisertib (MLN8237) when combined with weekly irinotecan.MethodsIn this single-center phase 1 study, adult patients with refractory advanced solid tumors received 100 mg/m2 irinotecan intravenously on day 1 and 8 of a 21-day cycle. Alisertib at planned escalating dose levels of 20-60 mg was administered orally twice per day on days 1-3 and 8-10. Patients homozygous for UGT1A1*28 were excluded. The primary objective was the safety of alisertib when combined with irinotecan to determine the maximum tolerated dose (MTD). Secondary objectives included overall response rate by RECIST and pharmacokinetics in a planned expansion cohort of patients with colorectal cancer treated at the MTD.ResultsA total of 17 patients enrolled at three dose levels. Dose-limiting toxicities included diarrhea, dehydration, and neutropenia. The MTD of alisertib combined with weekly irinotecan was 20 mg twice per day on days 1-3 and 8-10. One fatal cardiac arrest at the highest dose level tested was deemed possibly related to drug treatment. One partial response in 11 efficacy evaluable patients (9%) occurred in a patient with small cell lung cancer. The study was terminated prior to the planned expansion in patients with colorectal cancer.ConclusionIn contrast to prior results in a pediatric population, adult patients did not tolerate alisertib combined with irinotecan at clinically meaningful doses due to hematologic and gastrointestinal toxicities. The study was registered with ClinicalTrials.gov under study number NCT01923337 on Aug 15, 2013.
| S-EPMC8259450 | biostudies-literature
Project description:Alisertib (MLN8237, ALS), an Aurora kinase A (AURKA) inhibitor, exerts potent anti-tumor effects in the treatment of solid tumor and hematologic malignancies in preclinical and clinical studies. However, the fully spectrum of molecular targets of ALS and its anticancer effect in the treatment of chronic myeloid leukemia (CML) are not clear. This study aimed to examine the proteomic responses to ALS treatment and unveil the molecular interactome and possible mechanisms for its anticancer effect in K562 cells using stable-isotope labeling by amino acids in cell culture (SILAC) approach. The proteomic data identified that ALS treatment modulated the expression of 1541 protein molecules (570 up; 971 down). The pathway analysis showed that 299 signaling pathways and 459 cellular functional proteins directly responded to ALS treatment in K562 cells. These targeted molecules and signaling pathways were mainly involved in cell growth and proliferation, cell metabolism, and cell survival and death. Subsequently, the effects of ALS on cell cycle distribution, apoptosis, and autophagy were verified. The flow cytometric analysis showed that ALS significantly induced G2/M phase arrest and the Western blotting assays showed that ALS induced apoptosis via mitochondria-dependent pathway and promoted autophagy with the involvement of PI3K/Akt/mTOR, p38 MAPK, and AMPK signaling pathways in K562 cells. Collectively, this study provides a clue to quantitatively evaluate the proteomic responses to ALS and assists in globally identifying the potential molecular targets and elucidating the underlying mechanisms of ALS for CML treatment, which may help develop new efficacious and safe therapies for CML treatment.
| S-EPMC4697722 | biostudies-literature
Project description:PurposeAurora A kinase (AAK) is overexpressed in aggressive lymphomas and can correlate with more histologically aggressive forms of disease. We therefore designed a phase II study of alisertib, a selective AAK inhibitor, in patients with relapsed and refractory aggressive non-Hodgkin lymphomas.Patients and methodsPatients age ≥ 18 years were eligible if they had relapsed or refractory diffuse large B-cell lymphoma (DLBCL), mantle-cell lymphoma (MCL), transformed follicular lymphoma, Burkitt's lymphoma, or noncutaneous T-cell lymphoma. Alisertib was administered orally at 50 mg twice daily for 7 days in 21-day cycles.ResultsWe enrolled 48 patients. Histologies included DLBCL (n = 21), MCL (n = 13), peripheral T-cell lymphoma (n = 8), transformed follicular lymphoma (n = 5), and Burkitt's (n = 1). Most common grade 3 to 4 adverse events were neutropenia (63%), leukopenia (54%), anemia (35%), thrombocytopenia (33%), stomatitis (15%), febrile neutropenia (13%), and fatigue (6%). Four deaths during the study were attributed to progressive non-Hodgkin lymphoma (n = 2), treatment-related sepsis (n = 1), and unknown cause (n = 1). The overall response rate was 27%, including responses in three of 21 patients with DLBCL, three of 13 with MCL, one of one with Burkitt's lymphoma, two of five with transformed follicular lymphoma, and four of eight with noncutaneous T-cell lymphoma. The alisertib steady-state trough concentration (n = 25) revealed the expected pharmacokinetic variability, with a trend for higher incidence of adverse event-related dose reductions at higher trough concentrations. Analysis for AAK gene amplification and total AAK protein revealed no differences between histologies or correlation with clinical response.ConclusionThe novel AAK inhibitor alisertib seems clinically active in both B- and T-cell aggressive lymphomas. On the basis of these results, confirmatory single-agent and combination studies have been initiated.
| S-EPMC3867644 | biostudies-literature