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Karthik Venkatakrishnan - One of the best experts on this subject based on the ideXlab platform.

  • population pharmacokinetics and exposure safety relationships of Alisertib in children and adolescents with advanced malignancies
    The Journal of Clinical Pharmacology, 2021
    Co-Authors: Xiaofei Zhou, Karthik Venkatakrishnan, Elizabeth Fox, Diane R Mould, Ying Yuan, Emily G Greengard, Douglas V Faller
    Abstract:

    Population pharmacokinetic (PK) and exposure-safety analyses of Alisertib were performed in children enrolled in two clinical trials: NCT024448841 and NCT01154816.2 NCT02444884 was a dose-finding study in children with relapsed/refractory solid malignancies (phase 1) or neuroblastomas (phase 2). Patients received oral Alisertib 45-‍100 mg/m2 as powder-in-capsule once daily (QD) or twice daily (BID) for 7 days in 21-day cycles. Serial blood samples were collected up to 24 hours post-dose on cycle 1, day 1. NCT01154816 was a phase 2 single-arm study evaluating efficacy in children with relapsed/refractory solid malignancies or acute leukemias. Patients received Alisertib 80 mg/m2 as enteric-coated tablets QD for 7 days in 21-day cycles. Sparse PK samples were collected up to 8 hours post-dose on cycle 1, day 1. Sources of Alisertib PK variability were characterized and quantified using nonlinear mixed-effects modeling to support dosing recommendations in children and adolescents. A 2-compartment model with oral absorption described by 3 transit compartments was developed using data from 146 patients. Apparent oral clearance and central distribution volume were correlated with body surface area (BSA) across the age range of 2-21 years, supporting the use of BSA-based Alisertib dosing in the pediatric population. The recommended dose of 80 mg/m2 QD enteric-coated tablets provided similar Alisertib exposures across pediatric age groups and comparable exposure to that in adults receiving 50 mg BID (recommended adult dose). Statistically significant relationships (p < .01) were observed between Alisertib exposures and incidence of grade ≥2 stomatitis and febrile neutropenia, consistent with antiproliferative mechanism-related toxicities. This article is protected by copyright. All rights reserved.

  • biotransformation pathways and metabolite profiles of oral 14c Alisertib mln8237 an investigational aurora a kinase inhibitor in patients with advanced solid tumors
    Drug Metabolism and Disposition, 2020
    Co-Authors: Sandeepraj Pusalkar, Xiaofei Zhou, Karthik Venkatakrishnan, Lawrence Cohen, Jun Johnny Yang, Suresh K Balani, Cindy Q Xia, Wen Chyi Shyu, Swapan K Chowdhury
    Abstract:

    Alisertib (MLN8237) is an investigational, orally available, selective aurora A kinase inhibitor in clinical development for the treatment of solid tumors and hematologic malignancies. This metabolic profiling analysis was conducted as part of a broader phase 1 study evaluating mass balance, pharmacokinetics, metabolism, and routes of excretion of Alisertib following a single 35-mg dose of [14C]Alisertib oral solution (∼80 μCi) in three patients with advanced malignancies. On average, 87.8% and 2.7% of the administered dose was recovered in feces and urine, respectively, for a total recovery of 90.5% by 14 days postdose. Unchanged [14C]Alisertib was the predominant drug-related component in plasma, followed by O-desmethyl Alisertib (M2), and Alisertib acyl glucuronide (M1), which were present at 47.8%, 34.6%, and 12.0% of total plasma radioactivity. In urine, of the 2.7% of the dose excreted, unchanged [14C]Alisertib was a negligible component (trace), with M1 (0.84% of dose) and glucuronide conjugate of hydroxy Alisertib (M9; 0.66% of dose) representing the primary drug-related components in urine. Hydroxy Alisertib (M3; 20.8% of the dose administered) and unchanged [14C]Alisertib (26.3% of the dose administered) were the major drug-related components in feces. In vitro, oxidative metabolism of Alisertib was primarily mediated by CYP3A. The acyl glucuronidation of Alisertib was primarily mediated by uridine 5'-diphospho-glucuronosyltransferase 1A1, 1A3, and 1A8 and was stable in 0.1 M phosphate buffer and in plasma and urine. Further in vitro evaluation of Alisertib and its metabolites M1 and M2 for cytochrome P450-based drug-drug interaction (DDI) showed minimal potential for perpetrating DDI with coadministered drugs. Overall, renal elimination played an insignificant role in the disposition of Alisertib, and metabolites resulting from phase 1 oxidative pathways contributed to >58% of the Alisertib dose recovered in urine and feces over 192 hours postdose. SIGNIFICANCE STATEMENT: This study describes the primary clearance pathways of Alisertib and illustrates the value of timely conduct of human absorption, distribution, metabolism, and excretion studies in providing guidance to the clinical pharmacology development program for oncology drugs, for which a careful understanding of sources of exposure variability is crucial to inform risk management for drug-drug interactions given the generally limited therapeutic window for anticancer drugs and polypharmacy that is common in cancer patients.

  • pharmacokinetics of the investigational aurora a kinase inhibitor Alisertib in adult patients with advanced solid tumors or relapsed refractory lymphoma with varying degrees of hepatic dysfunction
    The Journal of Clinical Pharmacology, 2019
    Co-Authors: Xiaofei Zhou, John Sarantopoulos, John Nemunaitis, Michael Bargfrede, Andreas Muehler, Craig A Lockhart, Lakshmi Rangachari, Karthik Venkatakrishnan
    Abstract:

    This clinical trial was designed to evaluate the effect of moderate or severe hepatic impairment on the single-dose pharmacokinetics (PK) of the investigational anticancer agent, Alisertib, in adult patients with advanced solid tumors or lymphoma. Patients with normal hepatic function (total bilirubin and alanine transaminase [ALT] ≤ upper limit of normal [ULN]), moderate hepatic impairment (1.5 × ULN 3 × ULN, with any ALT), received a single 50-mg oral dose of Alisertib. Blood samples for PK were collected up to 168 hours postdose. Predose samples were also used to assess Alisertib plasma protein binding. Patients could continue to receive Alisertib for 7 days in 21-day cycles (50, 30, or 10 mg twice daily for normal hepatic function, moderate hepatic impairment, and severe hepatic impairment, respectively). Alisertib was approximately 99% protein bound in all hepatic function groups. Alisertib exposure was similar in moderate and severe hepatic impairment groups, but higher than the normal hepatic function group. The geometric least-squares mean ratios (90% confidence intervals) for unbound Alisertib area under the curve extrapolated to infinity for moderate/severe impairment groups versus the normal hepatic function group was 254% (184%, 353%). Patients with moderate or severe hepatic impairment have approximately 150% higher unbound Alisertib exposures compared with patients with normal hepatic function. An approximately 60% reduction of the starting dose of Alisertib in patients with moderate/severe hepatic impairment is recommended based on pharmacokinetic considerations.

  • Mass balance, routes of excretion, and pharmacokinetics of investigational oral [^14C]-Alisertib (MLN8237), an Aurora A kinase inhibitor in patients with advanced solid tumors
    Investigational New Drugs, 2019
    Co-Authors: Xiaofei Zhou, Claudio Dansky Ullmann, Sandeepraj Pusalkar, Swapan K Chowdhury, Shawn Searle, Karthik Venkatakrishnan
    Abstract:

    Aims This two-part, phase I study evaluated the mass balance, excretion, pharmacokinetics and safety of the investigational aurora A kinase inhibitor, Alisertib, in three patients with advanced malignancies. Methods Part A; patients received a single 35-mg dose of [^14C]-Alisertib oral solution (~80 μCi total radioactivity [TRA]). Serial blood, urine, and fecal samples were collected up to 336 h post-dose for Alisertib mass balance and pharmacokinetics in plasma and urine by liquid chromatography–tandem mass spectrometry, and mass balance/recovery of [^14C]-radioactivity in urine and feces by liquid scintillation counting. Part B; patients received non-radiolabeled Alisertib 50 mg as enteric-coated tablets twice-daily for 7 days in 21-day cycles. Results In part A, absorption was fast (median plasma T_max, 1 h) for Alisertib and TRA. Mean plasma t_1/2 for Alisertib and TRA were 23.4 and 42.0 h, respectively. Mean plasma Alisertib/TRA AUC_0–inf ratio was 0.45, indicating presence of Alisertib metabolites in circulation. Mean TRA blood/plasma AUC_0–last ratio was 0.60, indicating preferential distribution of drug-related material in plasma. On average, 87.8% and 2.7% of administered radioactivity was recovered in feces and urine, respectively (total recovery, 90.5% by 14 days post-dose). In part B, patients received a median 3 cycles of Alisertib. The most common any-grade adverse events were fatigue and alopecia. Conclusions Findings suggest that Alisertib is eliminated mainly via feces, consistent with hepatic metabolism and biliary excretion of drug-related material. Further investigation of Alisertib pharmacokinetics in patients with moderate-severe hepatic impairment is warranted to inform dosing recommendations in these patient populations.

  • global population pharmacokinetics of the investigational aurora a kinase inhibitor Alisertib in cancer patients rationale for lower dosage in asia
    British Journal of Clinical Pharmacology, 2018
    Co-Authors: Xiaofei Zhou, Diane R Mould, Dirk Huebner, Takatoshi Takubo, Emily Sheldonwaniga, Ashley Milton, Karthik Venkatakrishnan
    Abstract:

    Aims This population pharmacokinetic analysis was conducted to describe quantitatively the regional differences and sources of interpatient variability on the apparent oral clearance of Alisertib. Methods A population pharmacokinetic analysis was performed on data from 671 cancer patients in Western countries and in Japan/East Asia to whom Alisertib 5–150 mg once or twice daily (b.i.d.) was administered in multiple dosing schedules. The final model was used to simulate Alisertib pharmacokinetics in patients in the West and East Asian regions in the single-agent schedule of 7 days of dosing in a 21-day cycle. Exposure–safety relationships for mechanism-related antiproliferative toxicities (neutropenia, mucositis and diarrhoea) were estimated by logistic regression. Results Alisertib pharmacokinetics were described by a two-compartment model with four-transit compartment absorption and linear elimination. The final model included a covariate effect of region on relative bioavailability, with patients in the East Asian region estimated to have a 52% higher bioavailability compared with Western patients. Population simulated exposure at 30 mg b.i.d. in patients in Asia was similar to that at 50 mg b.i.d. in Western patients [geometric mean (coefficient of variation) steady state area under the concentration-time curve over the dosing interval (AUC(0–τ)): 21.4 μM.h (52.3%) and 24.1 μM.h (53.6%), respectively]. Exposure–AE relationships could be described for neutropenia, stomatitis and diarrhoea, supporting the lower dosage of Alisertib in Asia for global clinical development. Conclusions Model-based simulations support the achievement of similar Alisertib exposures in patients in Asia who are administered a 40% lower dose compared with the Western population, thereby providing a quantitative clinical pharmacology bridging and regional dosing rationale for global drug development.

Xiaofei Zhou - One of the best experts on this subject based on the ideXlab platform.

  • population pharmacokinetics and exposure safety relationships of Alisertib in children and adolescents with advanced malignancies
    The Journal of Clinical Pharmacology, 2021
    Co-Authors: Xiaofei Zhou, Karthik Venkatakrishnan, Elizabeth Fox, Diane R Mould, Ying Yuan, Emily G Greengard, Douglas V Faller
    Abstract:

    Population pharmacokinetic (PK) and exposure-safety analyses of Alisertib were performed in children enrolled in two clinical trials: NCT024448841 and NCT01154816.2 NCT02444884 was a dose-finding study in children with relapsed/refractory solid malignancies (phase 1) or neuroblastomas (phase 2). Patients received oral Alisertib 45-‍100 mg/m2 as powder-in-capsule once daily (QD) or twice daily (BID) for 7 days in 21-day cycles. Serial blood samples were collected up to 24 hours post-dose on cycle 1, day 1. NCT01154816 was a phase 2 single-arm study evaluating efficacy in children with relapsed/refractory solid malignancies or acute leukemias. Patients received Alisertib 80 mg/m2 as enteric-coated tablets QD for 7 days in 21-day cycles. Sparse PK samples were collected up to 8 hours post-dose on cycle 1, day 1. Sources of Alisertib PK variability were characterized and quantified using nonlinear mixed-effects modeling to support dosing recommendations in children and adolescents. A 2-compartment model with oral absorption described by 3 transit compartments was developed using data from 146 patients. Apparent oral clearance and central distribution volume were correlated with body surface area (BSA) across the age range of 2-21 years, supporting the use of BSA-based Alisertib dosing in the pediatric population. The recommended dose of 80 mg/m2 QD enteric-coated tablets provided similar Alisertib exposures across pediatric age groups and comparable exposure to that in adults receiving 50 mg BID (recommended adult dose). Statistically significant relationships (p < .01) were observed between Alisertib exposures and incidence of grade ≥2 stomatitis and febrile neutropenia, consistent with antiproliferative mechanism-related toxicities. This article is protected by copyright. All rights reserved.

  • biotransformation pathways and metabolite profiles of oral 14c Alisertib mln8237 an investigational aurora a kinase inhibitor in patients with advanced solid tumors
    Drug Metabolism and Disposition, 2020
    Co-Authors: Sandeepraj Pusalkar, Xiaofei Zhou, Karthik Venkatakrishnan, Lawrence Cohen, Jun Johnny Yang, Suresh K Balani, Cindy Q Xia, Wen Chyi Shyu, Swapan K Chowdhury
    Abstract:

    Alisertib (MLN8237) is an investigational, orally available, selective aurora A kinase inhibitor in clinical development for the treatment of solid tumors and hematologic malignancies. This metabolic profiling analysis was conducted as part of a broader phase 1 study evaluating mass balance, pharmacokinetics, metabolism, and routes of excretion of Alisertib following a single 35-mg dose of [14C]Alisertib oral solution (∼80 μCi) in three patients with advanced malignancies. On average, 87.8% and 2.7% of the administered dose was recovered in feces and urine, respectively, for a total recovery of 90.5% by 14 days postdose. Unchanged [14C]Alisertib was the predominant drug-related component in plasma, followed by O-desmethyl Alisertib (M2), and Alisertib acyl glucuronide (M1), which were present at 47.8%, 34.6%, and 12.0% of total plasma radioactivity. In urine, of the 2.7% of the dose excreted, unchanged [14C]Alisertib was a negligible component (trace), with M1 (0.84% of dose) and glucuronide conjugate of hydroxy Alisertib (M9; 0.66% of dose) representing the primary drug-related components in urine. Hydroxy Alisertib (M3; 20.8% of the dose administered) and unchanged [14C]Alisertib (26.3% of the dose administered) were the major drug-related components in feces. In vitro, oxidative metabolism of Alisertib was primarily mediated by CYP3A. The acyl glucuronidation of Alisertib was primarily mediated by uridine 5'-diphospho-glucuronosyltransferase 1A1, 1A3, and 1A8 and was stable in 0.1 M phosphate buffer and in plasma and urine. Further in vitro evaluation of Alisertib and its metabolites M1 and M2 for cytochrome P450-based drug-drug interaction (DDI) showed minimal potential for perpetrating DDI with coadministered drugs. Overall, renal elimination played an insignificant role in the disposition of Alisertib, and metabolites resulting from phase 1 oxidative pathways contributed to >58% of the Alisertib dose recovered in urine and feces over 192 hours postdose. SIGNIFICANCE STATEMENT: This study describes the primary clearance pathways of Alisertib and illustrates the value of timely conduct of human absorption, distribution, metabolism, and excretion studies in providing guidance to the clinical pharmacology development program for oncology drugs, for which a careful understanding of sources of exposure variability is crucial to inform risk management for drug-drug interactions given the generally limited therapeutic window for anticancer drugs and polypharmacy that is common in cancer patients.

  • pharmacokinetics of the investigational aurora a kinase inhibitor Alisertib in adult patients with advanced solid tumors or relapsed refractory lymphoma with varying degrees of hepatic dysfunction
    The Journal of Clinical Pharmacology, 2019
    Co-Authors: Xiaofei Zhou, John Sarantopoulos, John Nemunaitis, Michael Bargfrede, Andreas Muehler, Craig A Lockhart, Lakshmi Rangachari, Karthik Venkatakrishnan
    Abstract:

    This clinical trial was designed to evaluate the effect of moderate or severe hepatic impairment on the single-dose pharmacokinetics (PK) of the investigational anticancer agent, Alisertib, in adult patients with advanced solid tumors or lymphoma. Patients with normal hepatic function (total bilirubin and alanine transaminase [ALT] ≤ upper limit of normal [ULN]), moderate hepatic impairment (1.5 × ULN 3 × ULN, with any ALT), received a single 50-mg oral dose of Alisertib. Blood samples for PK were collected up to 168 hours postdose. Predose samples were also used to assess Alisertib plasma protein binding. Patients could continue to receive Alisertib for 7 days in 21-day cycles (50, 30, or 10 mg twice daily for normal hepatic function, moderate hepatic impairment, and severe hepatic impairment, respectively). Alisertib was approximately 99% protein bound in all hepatic function groups. Alisertib exposure was similar in moderate and severe hepatic impairment groups, but higher than the normal hepatic function group. The geometric least-squares mean ratios (90% confidence intervals) for unbound Alisertib area under the curve extrapolated to infinity for moderate/severe impairment groups versus the normal hepatic function group was 254% (184%, 353%). Patients with moderate or severe hepatic impairment have approximately 150% higher unbound Alisertib exposures compared with patients with normal hepatic function. An approximately 60% reduction of the starting dose of Alisertib in patients with moderate/severe hepatic impairment is recommended based on pharmacokinetic considerations.

  • Mass balance, routes of excretion, and pharmacokinetics of investigational oral [^14C]-Alisertib (MLN8237), an Aurora A kinase inhibitor in patients with advanced solid tumors
    Investigational New Drugs, 2019
    Co-Authors: Xiaofei Zhou, Claudio Dansky Ullmann, Sandeepraj Pusalkar, Swapan K Chowdhury, Shawn Searle, Karthik Venkatakrishnan
    Abstract:

    Aims This two-part, phase I study evaluated the mass balance, excretion, pharmacokinetics and safety of the investigational aurora A kinase inhibitor, Alisertib, in three patients with advanced malignancies. Methods Part A; patients received a single 35-mg dose of [^14C]-Alisertib oral solution (~80 μCi total radioactivity [TRA]). Serial blood, urine, and fecal samples were collected up to 336 h post-dose for Alisertib mass balance and pharmacokinetics in plasma and urine by liquid chromatography–tandem mass spectrometry, and mass balance/recovery of [^14C]-radioactivity in urine and feces by liquid scintillation counting. Part B; patients received non-radiolabeled Alisertib 50 mg as enteric-coated tablets twice-daily for 7 days in 21-day cycles. Results In part A, absorption was fast (median plasma T_max, 1 h) for Alisertib and TRA. Mean plasma t_1/2 for Alisertib and TRA were 23.4 and 42.0 h, respectively. Mean plasma Alisertib/TRA AUC_0–inf ratio was 0.45, indicating presence of Alisertib metabolites in circulation. Mean TRA blood/plasma AUC_0–last ratio was 0.60, indicating preferential distribution of drug-related material in plasma. On average, 87.8% and 2.7% of administered radioactivity was recovered in feces and urine, respectively (total recovery, 90.5% by 14 days post-dose). In part B, patients received a median 3 cycles of Alisertib. The most common any-grade adverse events were fatigue and alopecia. Conclusions Findings suggest that Alisertib is eliminated mainly via feces, consistent with hepatic metabolism and biliary excretion of drug-related material. Further investigation of Alisertib pharmacokinetics in patients with moderate-severe hepatic impairment is warranted to inform dosing recommendations in these patient populations.

  • Effects of rifampin, itraconazole and esomeprazole on the pharmacokinetics of Alisertib, an investigational aurora a kinase inhibitor in patients with advanced malignancies
    Investigational New Drugs, 2018
    Co-Authors: Xiaofei Zhou, Gerald S Falchook, John Sarantopoulos, Shubham Pant, John Nemunaitis, A. Craig Lockhart, Todd M. Bauer, Manish Patel, Michael Bargfrede, Andreas Muehler
    Abstract:

    Aim Two studies investigated the effect of gastric acid reducing agents and strong inducers/inhibitors of CYP3A4 on the pharmacokinetics of Alisertib, an investigational Aurora A kinase inhibitor, in patients with advanced malignancies. Methods In Study 1, patients received single doses of Alisertib (50 mg) in the presence and absence of either esomeprazole (40 mg once daily [QD]) or rifampin (600 mg QD). In Study 2, patients received single doses of Alisertib (30 mg) in the presence and absence of itraconazole (200 mg QD). Blood samples for Alisertib and 2 major metabolites were collected up to 72 h (Study 1) and 96 h (Study 2) postdose. Area under the curve from time zero extrapolated to infinity (AUC_0-inf) and maximum concentrations (C_max) were calculated and compared using analysis of variance to estimate least squares (LS) mean ratios and 90% confidence intervals (CIs). Results The LS mean ratios (90% CIs) for Alisertib AUC_0-inf and C_max in the presence compared to the absence of esomeprazole were 1.28 (1.07, 1.53) and 1.14 (0.97, 1.35), respectively. The LS mean ratios (90% CIs) for Alisertib AUC_0-inf and C_max in the presence compared to the absence of rifampin were 0.53 (0.41, 0.70) and 1.03 (0.84, 1.26), respectively. The LS mean ratios (90% CIs) for Alisertib AUC_0-inf and C_max in the presence compared to the absence of itraconazole were 1.39 (0.99, 1.95) and 0.98 (0.82, 1.19), respectively. Conclusions The use of gastric acid reducing agents, strong CYP3A inhibitors or strong metabolic enzyme inducers should be avoided in patients receiving Alisertib.

Gerald S Falchook - One of the best experts on this subject based on the ideXlab platform.

  • Effects of rifampin, itraconazole and esomeprazole on the pharmacokinetics of Alisertib, an investigational aurora a kinase inhibitor in patients with advanced malignancies
    Investigational New Drugs, 2018
    Co-Authors: Xiaofei Zhou, Gerald S Falchook, John Sarantopoulos, Shubham Pant, John Nemunaitis, A. Craig Lockhart, Todd M. Bauer, Manish Patel, Michael Bargfrede, Andreas Muehler
    Abstract:

    Aim Two studies investigated the effect of gastric acid reducing agents and strong inducers/inhibitors of CYP3A4 on the pharmacokinetics of Alisertib, an investigational Aurora A kinase inhibitor, in patients with advanced malignancies. Methods In Study 1, patients received single doses of Alisertib (50 mg) in the presence and absence of either esomeprazole (40 mg once daily [QD]) or rifampin (600 mg QD). In Study 2, patients received single doses of Alisertib (30 mg) in the presence and absence of itraconazole (200 mg QD). Blood samples for Alisertib and 2 major metabolites were collected up to 72 h (Study 1) and 96 h (Study 2) postdose. Area under the curve from time zero extrapolated to infinity (AUC_0-inf) and maximum concentrations (C_max) were calculated and compared using analysis of variance to estimate least squares (LS) mean ratios and 90% confidence intervals (CIs). Results The LS mean ratios (90% CIs) for Alisertib AUC_0-inf and C_max in the presence compared to the absence of esomeprazole were 1.28 (1.07, 1.53) and 1.14 (0.97, 1.35), respectively. The LS mean ratios (90% CIs) for Alisertib AUC_0-inf and C_max in the presence compared to the absence of rifampin were 0.53 (0.41, 0.70) and 1.03 (0.84, 1.26), respectively. The LS mean ratios (90% CIs) for Alisertib AUC_0-inf and C_max in the presence compared to the absence of itraconazole were 1.39 (0.99, 1.95) and 0.98 (0.82, 1.19), respectively. Conclusions The use of gastric acid reducing agents, strong CYP3A inhibitors or strong metabolic enzyme inducers should be avoided in patients receiving Alisertib.

  • effect of food on the pharmacokinetics of the investigational aurora a kinase inhibitor Alisertib mln8237 in patients with advanced solid tumors
    Drugs in R & D, 2016
    Co-Authors: Gerald S Falchook, Devalingam Mahalingam, Razelle Kurzrock, Xiaofei Zhou, Karthik Venkatakrishnan, Jonathan W Goldman, Jungah A Jung, Claudio Dansky Ullmann, Catherine Milch, Lee S Rosen
    Abstract:

    Objective This study was conducted to characterize the effects of food on single-dose pharmacokinetics (PK) of the investigational Aurora A kinase inhibitor Alisertib (MLN8237) in patients with advanced solid tumors.

  • relative bioavailability of a prototype oral solution of the aurora a kinase inhibitor Alisertib mln8237 in patients with advanced solid tumors
    International Journal of Clinical Pharmacology and Therapeutics, 2015
    Co-Authors: Gerald S Falchook, Razelle Kurzrock, Xiaofei Zhou, Karthik Venkatakrishnan, Claudio Dansky Ullmann, Jungah Jung, John Sarantopoulos, Alain C Mita, Monica M Mita, Catherine Milch
    Abstract:

    OBJECTIVES Alisertib (MLN8237) is an investigational, oral, small-molecule, selective inhibitor of Aurora A kinase. Phase I/II studies of powder-in-capsule (PIC) and enteric-coated tablet formulations of Alisertib have determined the recommended phase II dose and have demonstrated anti-tumor activity. This phase I relative bioavailability study characterized the pharmacokinetics of a prototype oral solution (OS) of Alisertib (developed for patients unable to swallow solid dosage forms) in reference to the PIC formulation in adult cancer patients. MATERIALS AND METHODS A safety evaluation was undertaken first following a 3+3 design (OS starting dose, 15 mg). The relative bioavailability of Alisertib OS vs. PIC was then evaluated following single dose administration of Alisertib OS 25 mg and PIC 50 mg, using a 2-way crossover study design. RESULTS The relative bioavailability (geometric mean dose-normalized AUCinf ratio) of Alisertib OS vs. PIC formulation was 1.26 (90% confidence interval (CI): 1.09-1.47 (OS, n=17; PIC, n=18 evaluable patients)). These results support a distinguishable difference in bioavailability of Alisertib between the two formulations (lower bound of 90% CI>1), with an estimated 26% higher total systemic exposure with Alisertib OS vs. PIC. Alisertib absorption from OS was faster than from PIC, with a shorter median tmax (OS, 1 hour; PIC, 2 hours) and a geometric mean dose-normalized Cmax ratio (OS vs. PIC) of 1.90 (90% CI: 1.52 - 2.37). CONCLUSIONS These findings inform the starting dose of Alisertib OS to support further clinical evaluation of Alisertib in patients unable to swallow solid dosage forms.

  • investigational aurora a kinase inhibitor Alisertib mln8237 as an enteric coated tablet formulation in non hematologic malignancies phase 1 dose escalation study
    Investigational New Drugs, 2014
    Co-Authors: Gerald S Falchook, Razelle Kurzrock, Launce Gouw, David S Hong, Kimberly A Mcgregor, Xiaofei Zhou, Hongliang Shi, Howard Fingert, Sunil Sharma
    Abstract:

    Background This phase 1b study evaluated an enteric-coated tablet (ECT) formulation of the investigational Aurora A kinase inhibitor, Alisertib (MLN8237). Methods Patients 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. Results 24 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). Conclusions Alisertib 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.

  • abstract b194 phase 1 relative bioavailability study of a prototype oral solution os formulation of the investigational aurora a kinase aak inhibitor Alisertib mln8237 in reference to a powder in capsule pic formulation in patients with advanced soli
    Molecular Cancer Therapeutics, 2011
    Co-Authors: Gerald S Falchook, Razelle Kurzrock, Xiaofei Zhou, Karthik Venkatakrishnan, Catherine Milch, Jungah Jung, John Sarantopoulos, Alain C Mita, Monica M Mita, Lee S Rosen
    Abstract:

    Background: Alisertib is an investigational, oral, selective AAK inhibitor that has shown antitumor activity in both the PIC and enteric-coated tablet formulations in previously reported clinical trials. A prototype OS formulation of Alisertib has been developed for patient populations unable to swallow solid dosage forms (e.g. pediatric patients, patients with feeding tubes). We report preliminary data on safety and the relative bioavailability of Alisertib OS in reference to PIC. Methods: Patients ≥18 y with advanced solid tumors, ECOG PS 0–1, measurable disease by RECIST, and adequate hematologic, renal, and hepatic function were eligible. After initial safety evaluation of a single 15 mg dose of Alisertib OS in 4 patients, subsequent patients enrolled to the relative bioavailability cohort received a single dose of Alisertib as either 25 mg OS or 50 mg PIC on day 1 of cycle 1 (receiving alternative formulation on day 1 of cycle 2) on an empty stomach. Patients then continued on PIC 40 mg BID on days 3–9, followed by 14 days9 rest (23-day cycles). From cycle 3 onwards, patients received Alisertib PIC 40 or 50 mg BID for 7 days followed by 14 days9 rest (21-day cycles) until disease progression or unacceptable toxicity. The relative bioavailability of the OS in reference to PIC was estimated as the ratio of geometric mean of dose-normalized (DN) AUC0−inf (OS vs PIC) and associated 2-sided 90% CI. AEs were graded according to NCI-CTCAE v3.0. Response was assessed by RECIST v1.1 after every 2 cycles. Results: 19 patients were enrolled; 63% were male, 89% white, median age 58 y, mean weight 83.4 kg, and mean BSA 2.0 m2. The most common tumor types included colorectal (n=7), kidney (n=2), and NSCLC (n=2). Pharmacokinetic parameters were evaluable in 15 patients. Following single oral dosing of Alisertib, observed median Tmax was ∼1 hour for OS and ∼2 hours for PIC. The terminal half-life (T1/2) was similar following single dosing of OS or PIC (mean T1/2 ∼14 hours for OS; ∼16 hours for PIC). The geometric mean of DN AUCinf following single dose 25 mg OS was ∼135% of that following single dose 50 mg PIC (90% CI: 117, 156). The geometric mean of DN Cmax was 178% of that following single PIC dosing (90% CI: 143, 220). Patients received a median of 2 cycles (range 1–8). Dose-limiting toxicities were observed in 2 patients (PIC/OS): Gr 4 febrile neutropenia/Gr 3 oral mucositis and Gr 4 thrombocytopenia. Drug-related Gr ≥3 AEs occurred in 5 patients; the most common were neutropenia (n=3) and leukopenia (n=2). Most common drug-related AEs of any grade were fatigue (n=6); neutropenia, leukopenia, diarrhea, nausea (n=5 each); vomiting, and anorexia (n=4). All patients evaluable for taste assessment (cycle 1/2: n=12/n=5) indicated that the taste of Alisertib OS was “tolerable”. Four patients (ovarian, colorectal, colon, NSCLC) had a best response of stable disease; maximum duration of SD was 4.5 months. Conclusions: The relative bioavailability (geometric mean AUC) of Alisertib OS is approximately 135% in reference to PIC. The prototype Alisertib OS was generally well tolerated and the safety profile was consistent with that observed to date with solid formulations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B194.

Jeffrey Ecsedy - One of the best experts on this subject based on the ideXlab platform.

  • Alisertib demonstrates significant antitumor activity in bevacizumab resistant patient derived orthotopic models of glioblastoma
    Journal of Neuro-oncology, 2017
    Co-Authors: Cheyne Kurokawa, Jeffrey Ecsedy, Hirosha Geekiyanage, Cory Allen, Ianko D Iankov, Mark A Schroeder, Brett L Carlson, Katrina K Bakken, Jann N Sarkaria, A B Dassoro
    Abstract:

    Aurora A kinase (AURKA), a member of the serine/threonine kinase family, plays a critical role in cell division, and it is widely overexpressed in a variety of tumors including glioblastoma (GBM). Alisertib (MLN8237) is an orally administered selective AURKA inhibitor with potent antiproliferative activity, currently undergoing clinical testing in different tumor types. In vitro evaluation of Alisertib against the primary GBM lines, GBM6, GBM10, GBM12 and GBM39 showed significant antitumor activity with IC50s ranging between 30 and 95 nM. Orthotopic xenografts of GBM10 and the bevacizumab resistant lines GBM6 and GBM39 were established by implantating 3 × 105 cells in the caudate nucleus of nude mice; animals were randomized to treatment with either Alisertib 30 mg/kg/day or vehicle. In all three models, treatment with Alisertib resulted in a statistically significant prolongation of survival (p < 0.0001). In addition, Alisertib administration in these mice decreased phosphorylated aurora-A, induced mitotic arrest and significantly decreased histone H3 phosphorylation in tumors. In conclusion, Alisertib displays significant antitumor activity against primary GBM lines and xenografts, including patient derived GBM lines resistant to bevacizumab; these data support clinical translation in GBM.

  • abstract 3887 proteomic profiling identifies cmyc and ttf1 as biomarkers of response to the aurora kinase inhibitor Alisertib in small cell lung cancer sclc
    Cancer Research, 2016
    Co-Authors: Robert J Cardnell, Jeffrey Ecsedy, Huifeng Niu, Fatemeh Masrorpour, Jing Wang, Lauren Averett Byers
    Abstract:

    Background: Small cell lung cancer (SCLC) is the most aggressive form of lung cancer, with a 5-year survival rate of only 6%. The treatment of SCLC has not changed in over 25 years, hence the development of new drugs for SCLC represents a major unmet need. A recent phase II trial of the aurora kinase inhibitor Alisertib showed single agent activity in a subset (21%) of SCLC (Melichar et al, 2015) and a second study is underway testing Alisertib in combination with chemotherapy (NCT02038647). However, there are currently no established biomarkers to identify patients likely to have the greatest benefit from Alisertib. We have previously demonstrated the utility of proteomic profiling to identify targets and markers in SCLC. Here we use proteomics to identify markers of response to Alisertib in SCLC. Methods: The sensitivity (IC50) of 51 SCLC cell lines to Alisertib was assayed in 5-day proliferation assays. Expression levels of 171 total and/or phosphorylated proteins were measured by reverse phase protein array (RPPA) and correlated with IC50’s. Using two approaches – 1) Spearman correlation of IC50 to protein data for all cell lines and 2) t-test comparing protein data between the most and least sensitive cell lines – we generated consensus markers of response. Results: Proliferation assays showed sensitivity to Alisertib at clinically achievable doses in 14/51 (27%) cell lines (based on Cmax = 1.8uM, Phase I single agent trial). High cMyc protein was the top marker of sensitivity to Alisertib (R = -0.47, p = 0.0006 as continuous variables; fold difference = 3.52, p = 0.008 by t-test comparing extremes). Further analysis revealed a bi-modal distribution of cMyc protein, defined as high and low using a bimodality index. The cMyc protein high group (25%) included cell lines that were both cMyc amplified and non-amplified. While cMyc amplified cell lines (11%) are more sensitive to Alisertib than non-amplified (p = 0.002), high cMyc protein captures a larger population of SCLC that is sensitive to Alisertib. In contrast, expression of thyroid transcription factor 1 (TTF1, a standard IHC marker used in the diagnosis of lung cancer) was the top marker of Alisertib resistance (R = 0.38, p = 0.006; fold difference = -4.22, p = 0.003). TTF1 protein expression was also bi-modal, with 32% of cell lines falling into a distinct TTF1-low (more sensitive to Alisertib) group. Conclusions: High cMyc and low TTF1 protein expression identify a subset of SCLC cell lines (27%) that are sensitive to single agent Alisertib. cMyc protein as a marker of response is consistent with other preclinical findings suggesting that cMyc amplified SCLC may be more sensitive to aurora kinase inhibition. The association of low TTF1 expression with Alisertib sensitivity may prove to be of particular value in selecting patients for treatment given that immunohistochemical assessment of TTF1 is commonly used in the diagnosis of SCLC. Citation Format: Robert J. Cardnell, Lerong Li, Fatemeh Masrorpour, Huifeng Niu, Jeffrey Ecsedy, Jing Wang, Lauren A. Byers. Proteomic profiling identifies cMyc and TTF1 as biomarkers of response to the aurora kinase inhibitor Alisertib in small cell lung cancer (SCLC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3887.

  • scientific rationale supporting the clinical development strategy for the investigational aurora a kinase inhibitor Alisertib in cancer
    Frontiers in Oncology, 2015
    Co-Authors: Huifeng Niu, Mark Manfredi, Jeffrey Ecsedy
    Abstract:

    Alisertib (MLN8237) is a selective small molecule inhibitor of Aurora A kinase that is being developed in multiple cancer indications as a single agent and in combination with other therapies. A significant amount of research has elucidated a role for Aurora A in orchestrating numerous activities of cells transiting through mitosis and has begun to shed light on potential non-mitotic roles for Aurora A as well. These biological insights laid the foundation for multiple clinical trials evaluating the antitumor activity of Alisertib in both solid cancers and heme-lymphatic malignancies. Several key facets of Aurora A biology as well as empirical data collected in experimental systems and early clinical trials have directed the development of Alisertib toward certain cancer types, including neuroblastoma, small cell lung cancer, neuroendocrine prostate cancer, atypical teratoid/rhabdoid tumors, and breast cancer among others. In addition, these scientific insights provided the rationale for combining Alisertib with other therapies, including microtubule perturbing agents, such as taxanes, EGFR inhibitors, hormonal therapies, platinums, and HDAC inhibitors among others. Here, we link the key aspects of the current clinical development of Alisertib to the originating scientific rationale and provide an overview of the Alisertib clinical experience to date.

  • mln8054 and Alisertib mln8237 discovery of selective oral aurora a inhibitors
    ACS Medicinal Chemistry Letters, 2015
    Co-Authors: Todd B Sells, Jeffrey Ecsedy, Kara Hoar, Jessica Huck, Ryan Chau, Rachel E Gershman, David A Janowick, V Kadambi, Patrick J Leroy, Matthew Stirling
    Abstract:

    The Aurora kinases are essential for cell mitosis, and the dysregulation of Aurora A and B have been linked to the etiology of human cancers. Investigational agents MLN8054 (8) and Alisertib (MLN8237, 10) have been identified as high affinity, selective, orally bioavailable inhibitors of Aurora A that have advanced into human clinical trials. Alisertib (10) is currently being evaluated in multiple Phase II and III clinical trials in hematological malignancies and solid tumors.

  • dose selection for the investigational anticancer agent Alisertib mln8237 pharmacokinetics pharmacodynamics and exposure safety relationships
    The Journal of Clinical Pharmacology, 2015
    Co-Authors: Karthik Venkatakrishnan, Xiaofei Zhou, Howard Fingert, Hua Liu, Jeffrey Ecsedy, Hadi Danaee, Diane R Mould, Robert W Kleinfield, Ashley Milton
    Abstract:

    We report population pharmacokinetic, pharmacodynamic, and pharmacokinetic-safety analyses to support phase II/III dose/regimen selection of Alisertib, a selective Aurora A kinase (AAK) inhibitor. Phase I studies in adult cancer patients evaluated dosing on Days 1-7 in 21-day cycles or Days 1-21 in 35-day cycles, with corresponding maximum tolerated doses of 50 mg twice daily (BID) and 50 mg QD, respectively. Population pharmacokinetic analyses supported dose- and time-linear pharmacokinetics without identification of clinically meaningful covariates. Exposure-related increases in skin mitotic index and decreases in chromosomal alignment/spindle bipolarity in tumor mitotic cells confirmed AAK inhibition. Exposures in the 7-day schedule at or near 50 mg BID are expected to result in tumor AAK inhibition based on pharmacodynamic assessment in patient tumors. Exposure-safety analyses of data from patients receiving doses of 5-200 mg/day in the 7-day schedule support a low (∼7%) predicted incidence of dose-limiting toxicity at 50 mg BID. Taken together, these analyses support a pharmacologically active and acceptably tolerated dose range of Alisertib for future clinical development.

Jane E Leonard - One of the best experts on this subject based on the ideXlab platform.

  • open label multicenter phase 1 study of Alisertib mln8237 an aurora a kinase inhibitor with docetaxel in patients with solid tumors
    Cancer, 2016
    Co-Authors: Julie N Graff, Xiaofei Zhou, Karthik Venkatakrishnan, Jane E Leonard, Bin Zhang, Celestia S Higano, Noah M Hahn, Matthew H Taylor, John Sarantopoulos
    Abstract:

    Background This study was designed to determine the safety, tolerability, and pharmacokinetics (PK) of Alisertib (MLN8237) in combination with docetaxel and to identify a recommended dose for the combination. Methods Adults with metastatic cancer were treated on 21-day cycles with Alisertib (10, 20, 30, or 40 mg) twice daily on days 1 to 7 or days 1 to 5 and with docetaxel (75 or 60 mg/m(2) ) on day 1. The primary objectives were to assess the safety and tolerability of the combination and to determine the recommended phase 2 dose (RP2D) for future studies. Secondary objectives included an efficacy assessment and PK analyses of docetaxel and Alisertib. Results Forty-one patients participated. Eight dose levels were explored with various doses of Alisertib and docetaxel. The dose-limiting toxicities were neutropenic fever, neutropenia without fever, stomatitis, and urinary tract infection. The RP2D of this combination was 20 mg of Alisertib twice daily on days 1 to 7 and intravenous docetaxel at 75 mg/m(2) on day 1 in 21-day cycles. Eight of the 28 patients (29%) who were efficacy-evaluable had objective responses. These included 1 complete response in a patient with bladder cancer, 6 partial responses in patients with castration-resistant prostate cancer, and 1 partial response in a patient with angiosarcoma. Concomitant administration of Alisertib did not produce any clinically meaningful change in docetaxel PK. Conclusions Alisertib at 20 mg twice daily on days 1 to 7 with intravenous docetaxel at 75 mg/m(2) on day 1 in a 21-day cycle was well tolerated, and the combination demonstrated antitumor activity. Cancer 2016;122:2524-33. © 2016 American Cancer Society.

  • an exploratory phase 2 study of investigational aurora a kinase inhibitor Alisertib mln8237 in acute myelogenous leukemia and myelodysplastic syndromes
    Leukemia research reports, 2014
    Co-Authors: Stuart L Goldberg, Pierre Fenaux, Michael Craig, Emmanuel Gyan, John Lister, Jeannine Kassis, Arnaud Pigneux, Gary J Schiller, Jungah Jung, Jane E Leonard
    Abstract:

    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.

  • phase ii study of Alisertib a selective aurora a kinase inhibitor in relapsed and refractory aggressive b and t cell non hodgkin lymphomas
    Journal of Clinical Oncology, 2014
    Co-Authors: Jonathan W Friedberg, Xiaofei Zhou, Jungah Jung, Daruka Mahadevan, Erin Cebula, Daniel O Persky, Izidore S Lossos, Amit Agarwal, Richard Burack, Jane E Leonard
    Abstract:

    Purpose Aurora 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 Methods Patients 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. Results We 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 s...

  • phase 2 trial of Alisertib mln8237 an investigational potent inhibitor of aurora a kinase aak in patients pts with aggressive b and t cell non hodgkin lymphoma nhl
    Blood, 2011
    Co-Authors: Jonathan W Friedberg, Xiaofei Zhou, Hadi Danaee, Jungah Jung, Jane E Leonard, Daruka Mahadevan, Daniel O Persky, Izidore S Lossos, Steven H Bernstein
    Abstract:

    Abstract 95 Background: Aurora kinases are a family of oncogenic serine-threonine kinases that regulate multiple phases of the mitotic signaling cascade. Inhibition of aurora A kinase (AAK) leads to mitotic errors, followed by aneuploidy, apoptosis, and senescence. Investigational drug Alisertib is an ATP-competitive, orally available inhibitor of AAK, that has been evaluated for safety and efficacy in Phase I hematological malignancies. We conducted the first phase II multicenter trial of Alisertib in adult patients with aggressive B- and T- cell NHL. Methods: Eligible patients had normal organ function, ANC ≥1250/mm3, platelets ≥ 75,000/mm3 and no prior allogeneic transplant. Patients were treated with Alisertib at a dose of 50mg twice daily for 7 days on 21 day cycles until either documented progression or unacceptable treatment-related toxicity. Using fluorescent in situ hybridization (FISH), gene amplification was assessed in archived tumors by a dual assay measuring AAK copy number on chromosome 20q13 as well as the ratio to a control probe located on chromosome 20q11. Immunohistochemistry (IHC) was performed on archived paraffin embedded diagnostic tissue using a dual assay measuring the protein levels of total AAK and that of phospho histone H3. PK sampling was performed with inclusion of steady-state trough plasma PK samples on the morning of Cycle 1 Day 8. Results: 48 pts were enrolled, including 41 response-evaluable. Histologies included DLBCL (n=21, 44%), mantle cell (MCL; n=13, 27%), peripheral T- cell (n=8, 17%), transformed follicular (n=5, 10%) and Burkitt (n=1, 2%). Median age was 68 y (range 32–85). Pts received median 3 prior regimens (range 1–11); 11 pts received prior ASCT. Most common Grade 3/4 adverse events were neutropenia (63%), thrombocytopenia (31%), stomatitis (15%), febrile neutropenia (13%) and fatigue (6%). Four deaths on study were attributed to progressive NHL (2), treatment-related sepsis (1), and unknown cause (1). 11 pts discontinued and 24 reduced dose due to adverse events (AEs). Evaluation of steady state trough concentration of Alisertib (N=25) revealed that PK variability was consistent with that observed in other trials with Alisertib, and there was a trend toward higher levels in patients who required AE-related dose reductions compared to those who did not (geometric mean 2375 nM [n=10, CV: 54%] vs. 1504 nM [n=15, CV: 35%]). FISH analysis for AAK gene amplification did not reveal differences between histologies (N=31). When total AAK protein was evaluated by immunohistochemistry (N=32), marked variability in both proportion of expression as well as intensity was observed both between and within histologies; there was no correlation of AAK protein expression and clinical response. The overall response rate (ORR) was 32% (95% CI 0.181–0.481); response by histology: DLBCL 20%; MCL 23% and T- cell NHL 57%. Conclusion: Current data suggests that Alisertib is generally well-tolerated, with responses observed in heavily pretreated patients with aggressive NHL, including patients after ASCT. Emerging data supports single agent activity in several histologies, with proportionally more responses observed in relapsed/refractory T-cell NHL. Some patients have now been treated for up to two years with this agent, and the generally manageable toxicity profile suggests an opportunity to combine this drug with other agents. IHC of aggressive lymphoma histologies suggests heterogeneity in AAK protein expression and intensity. The geometric mean of Alisertib steady-state trough concentration was 1.8 μM (CV= 47%, N = 25), which was above the 1 μM steady-state plasma concentrations associated with saturating levels of pharmacodynamics and antitumor activity in preclinical xenograft models. The observed trend for association between trough concentration of Alisertib and AEs supports the dose modification scheme implemented in this trial. Based upon these results, planned future trials include a single-agent study in T-cell NHL, and a combination study exploring Alisertib with rituximab and vincristine in aggressive B-cell NHL. Disclosures: Friedberg:Genentech: Consultancy; astellas:; Lilly:; Abbott/Trubion:; Seattle Genetics: Honoraria; Cephalon: Consultancy. Off Label Use: novel agents for relapsed DLBCL. Jung:Millennium: Employment. Danaee:Millennium Pharmaceuticals Inc.: Employment. Zhou:millennium: Employment. Leonard:millennium: Employment.