Xiaofei Zhou

Phase II Study of Alisertib, a Selective Aurora A Kinase Inhibitor, in Relapsed and Refractory Aggressive B- and T-Cell Non-Hodgkin Lymphomas

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, Burkitts 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 Burkitts (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 Burkitts 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. CONCLUSION The 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.

Translational Exposure–Efficacy Modeling to Optimize the Dose and Schedule of Taxanes Combined with the Investigational Aurora A Kinase Inhibitor MLN8237 (Alisertib)

Aurora A kinase orchestrates multiple key activities, allowing cells to transit successfully into and through mitosis. MLN8237 (alisertib) is a selective Aurora A inhibitor that is being evaluated as an anticancer agent in multiple solid tumors and heme-lymphatic malignancies. The antitumor activity of MLN8237 when combined with docetaxel or paclitaxel was evaluated in in vivo models of triple-negative breast cancer grown in immunocompromised mice. Additive and synergistic antitumor activity occurred at multiple doses of MLN8237 and taxanes. Moreover, significant tumor growth delay relative to the single agents was achieved after discontinuing treatment; notably, durable complete responses were observed in some mice. The tumor growth inhibition data generated with multiple dose levels of MLN8237 and paclitaxel were used to generate an exposure–efficacy model. Exposures of MLN8237 and paclitaxel achieved in patients were mapped onto the model after correcting for mouse-to-human variation in plasma protein binding and maximum tolerated exposures. This allowed rank ordering of various combination doses of MLN8237 and paclitaxel to predict which pair would lead to the greatest antitumor activity in clinical studies. The model predicted that 60 and 80 mg/m2 of paclitaxel (every week) in patients lead to similar levels of efficacy, consistent with clinical observations in some cancer indications. The model also supported using the highest dose of MLN8237 that can be achieved, regardless of whether it is combined with 60 or 80 mg/m2 of paciltaxel. The modeling approaches applied in these studies can be used to guide dose-schedule optimization for combination therapies using other therapeutic agents. Mol Cancer Ther; 13(9); 2170–83. ©2014 AACR.

Dose selection for the investigational anticancer agent alisertib (MLN8237): Pharmacokinetics, pharmacodynamics, and exposure–safety relationships

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.

Open-label, multicenter, phase 1 study of alisertib (MLN8237), an aurora A kinase inhibitor, with docetaxel in patients with solid tumors

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.

Abstract B216: Mass balance, routes of excretion and pharmacokinetics of investigational oral [14C]alisertib (MLN8237) in patients with advanced solid tumors or lymphoma.

Background: Alisertib (MLN8237) is an investigational, orally administered, selective oral Aurora A kinase inhibitor under clinical development for treatment of solid tumors and hematologic malignancies. We herein report the mass balance, routes of excretion and pharmacokinetics (PK) of alisertib following oral administration of radiolabeled [14C]alisertib in cancer patients. Material and methods: This was a two-part, open-label, single oral dose (Part A) followed by multiple-dose (Part B) study in patients with advanced malignancies. Eligible patients were aged ≥ 18 years with histologic or cytologic diagnosis of advanced solid tumors or lymphoma, ECOG PS 0-1. In Part A, patients received a single 35 mg dose of 14C-labeled alisertib (approximately 80 μCi) administered as oral solution. Serial blood samples were collected over a 10-day period for analysis of plasma and whole blood PK of alisertib and total radioactivity (drug-related material). Complete urinary and fecal outputs were collected until at least 80% of the administered radioactivity was recovered or excretion of radioactivity fell below 1% per day for assessment of drug-related material recovery in excreta and products of alisertib biotransformation. In Part B, patients received 50 mg of nonradiolabeled alisertib twice daily administered as enteric-coated tablets for 7 days in 21-day cycles until disease progression or unacceptable toxicity. Results: Three patients with ovarian cancer, bladder cancer and mesothelioma, respectively, completed Part A of the study. Demographic features of patients enrolled in the study were: 2 males and 1 female, median age 66 years, mean body weight 79 kg. Following single dose of [14C]alisertib oral solution, the median time to first reach maximal plasma concentration of alisertib and drug-related material was 1 hr. The mean terminal half-life for alisertib and drug-related material were 22 and 39 hrs, respectively. The mean plasma exposure (AUC0-inf) ratio of alisertib versus total drug-related material was 0.46, indicating the presence of alisertib metabolites in circulation. The apparent oral clearance of alisertib was 3.9 L/hr and renal clearance of the parent drug was negligible. Following a single oral dose of [14C]alisertib, 87% and 2.7% of administered radioactivity were recovered in feces and urine, respectively, by 2 weeks post-dose. Grade 1 fatigue was the most frequent adverse event (2/3) during the study. One patient experienced grade 3 neutropenia. Conclusions: The predominant route of elimination for drug-related material was fecal, consistent with hepatic metabolism and biliary excretion of alisertib. Renal clearance of unchanged alisertib was negligible. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B216. Citation Format: Xiaofei Zhou, Sandeepraj Pusalkar, Swapan Chowdhury, Shawn Searle, Yuexian Li, Jaime Mertz, Bin Zhang, Yong Ben, Karthik Venkatakrishnan. Mass balance, routes of excretion and pharmacokinetics of investigational oral [14C]alisertib (MLN8237) in patients with advanced solid tumors or lymphoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B216.

Relative bioavailability of a prototype oral solution of the Aurora A kinase inhibitor alisertib (MLN8237) in patients with advanced solid tumors

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.

Abstract A217: Impact of pharmacokinetic (PK) variability on dose finding in phase 1 oncology studies.

Background: The key objective of Phase 1 dose escalation studies in patients for oncology compounds is to define the maximum tolerated dose (MTD) or biologically active dose range with high confidence. Small patient numbers and inter-patient heterogeneity are unavoidable factors in traditional “3+3” designs and contribute to uncertainty in MTD determination. It is hypothesized that PK variability in systemic exposures can increase uncertainty in defining the dose-toxicity (and dose-pharmacodynamics) relationship, thereby impacting the accuracy of dose finding in Ph 1. We herein performed simulations to quantitatively assess the impact of PK variability on MTD selection. Materials and Methods: Three virtual scenarios of varying steepness of the exposure-toxicity relationship and 4 scenarios of PK variability (coefficient of variation [CV]: 80% [High], 40% [Moderate], 20% [Low], 0% [None]) were considered for simulations. Dose-linear PK was assumed and a standard “3+3” escalation design was used for simulations. The hypothetical starting dose was 1 mg and dose escalations used a modified Fibonacci scheme. 10,000 simulations were performed for each of the 12 scenarios, and the frequency of each dose selected as MTD was reported. The selected MTD was defined to have 20-33% dose-limiting toxicity rate. Results: The simulation results are summarized as follows: ![Figure][1] Regardless of the dose-toxicity relationship, increases in PK variability lead to a higher likelihood of underestimation of the MTD. Selecting the correct MTD is approximately 3 - 4 times more likely with low PK variability than with high PK variability. Conclusions: Substantial PK variability can compromise the accuracy of MTD or recommended phase 2 dose determination in Ph 1/ Ph 1b dose escalation studies, emphasizing the importance of controlling PK variability in dose-finding oncology studies through optimal drug formulations and inclusion/ exclusion criteria that are customized to the predicted ADME (Absorption, Distribution, Metabolism, Excretion) properties of the development candidate. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A217. Citation Format: Xiaofei Zhou, Yi Liu, Karthik Venkatakrishnan. Impact of pharmacokinetic (PK) variability on dose finding in phase 1 oncology studies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A217. [1]: pending:yes

Abstract C122: Phase 1b relative bioavailability (BA) study of enteric coated tablet (ECT) in reference to powder in capsule (PIC) formulation of the investigational drug alisertib (MLN8237), an Aurora A Kinase (AAK) inhibitor, in patients with advanced nonhematologic malignancies.

Background: The investigational drug alisertib (MLN8237) is an orally available, selective AAK inhibitor. Early clinical studies used a PIC formulation; an ECT formulation was recently developed. Here we present relative BA results of ECT referenced to PIC designed to bridge transition to ECT in MLN8237 clinical development. Methods: Eligible patients were age ≥18 years with advanced solid tumors and ECOG PS 0–1. Dose-escalation cohorts received alisertib 10 mg BID (N=1), and 20 mg BID (N=1), before formal relative BA evaluation at 40 mg BID, in a 7-day schedule followed by 14 days9 rest (21-day cycles). Patients received MLN8237 40 mg BID as either ECT or PIC in a 2-cycle, 2-way cross-over design. Pharmacokinetic (PK) sampling was performed on Day 7 of cycles 1 and 2 to characterize steady-state PK of alisertib formulated as ECT or PIC for relative BA analysis. PK was also evaluated on Day 1 of ECT dosing. Results: 22 patients were included (N=1 each at 10 and 20 mg BID; N=20 at 40 mg BID); 55% were male, 90% were white, and median age was 56 years. 14 patients were evaluable for relative BA analysis. Following BID oral dosing, absorption was fast (median T max ∼2.5 hours for ECT; ∼2 hours for PIC). Relative BA of ECT referenced to PIC was 90% (90% CI: 74.4, 108.8). Steady-state C max following ECT was 82% of that from PIC (90% CI: 69.9, 95.5). Mean accumulation ratio of ECT BID was ∼2.8-fold; mean peak-to-trough ratio was ∼2.5. The range of dose-normalized exposures following ECT was within the corresponding range observed with PIC, which has previously been associated with favorable pharmacodynamic effects (Dees et al. Abstract 3010; Cervantes et al. Abstract 3031, J Clin Oncol 2010;28:15s). Conclusions: Systemic exposures following administration of ECT and PIC formulations of alisertib are generally similar, supporting transition from PIC to ECT in clinical development. Taken together with PK, pharmacodynamics, and antitumor activity from other trials, these data indicate that the ECT formulation of alisertib can provide exposures needed for clinically relevant bioactivity. 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 C122.

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 solid tumors.

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.

Alisertib in Combination With Weekly Paclitaxel in Patients With Advanced Breast Cancer or Recurrent Ovarian Cancer: A Randomized Clinical Trial

Importance There is an unmet medical need for the treatment of recurrent ovarian cancer, and new approaches are needed to improve progression-free survival (PFS) and overall survival. Objective This phase 1/2 study evaluated the activity of alisertib in combination with weekly paclitaxel in patients with breast (phase 1) and ovarian cancer (phase 1 and phase 2). Design, Setting, and Participants An open-label phase 1 and randomized phase 2 clinical trial conducted from April 16, 2010, for phase 1 and March 28, 2012, to August 12, 2013, for phase 2 was conducted at 33 sites (United States, France, and Poland). Data are reported from a cutoff date of August 12, 2014, with a median duration of follow-up of 7.2 months in the alisertib plus paclitaxel arm and 4.6 months in the paclitaxel arm. A total of 191 women with advanced breast (phase 1 only) or recurrent ovarian cancer were enrolled, including 142 patients randomized to alisertib plus paclitaxel (n = 73) or paclitaxel alone (n = 69) in the phase 2 study. Interventions Patients were randomized 1:1 stratified by platinum-free interval (refractory, 0-6 months, 6-12 months) and prior weekly taxane treatment (yes, no) to receive alisertib 40 mg twice per day orally and 3 days on and 4 days off for 3 weeks, plus paclitaxel (60 mg/m2 intravenously, days 1, 8, and 15), or weekly paclitaxel 80 mg/m2 intravenously in 28-day cycles. Main Outcomes and Measures Primary endpoint was PFS; primary efficacy analysis and safety analysis used modified intention to treat (mITT) population (all randomized patients who received ≥1 dose of study drug). Results The median age for the 191 patients enrolled in phase 1 was 59 (range, 29-75) years. The median age for the 142 patients enrolled in phase 2 was 63 (range, 30-81) years for patients receiving alisertib plus paclitaxel and 61 (range, 41-81) years for patients receiving paclitaxel. At data cutoff, 107 (75%) patients had a documented PFS event; 52 (71%) in the alisertib plus paclitaxel arm, and 55 (80%) in the paclitaxel arm. Median PFS was 6.7 months with alisertib plus paclitaxel vs 4.7 months with paclitaxel (HR, 0.75; 80% CI, 0.58-0.96; P = .14; 2-sided P value cutoff = .20 to be considered worthy of further investigation). Drug-related grade 3 or higher adverse events were reported in 63 (86%) vs 14 (20%) patients in the alisertib plus paclitaxel and paclitaxel arms, including 56 (77%) vs 7 (10%) neutropenia, 18 (25%) vs 0 stomatitis, and 10 (14%) vs 2 (3%) anemia; 54 (74%) vs 17 (25%) had adverse events leading to dose reductions. Two patients died during the study (1 in each arm); neither death was considered related to study drug. Conclusions and Relevance The primary endpoint, PFS, significantly favored alisertib plus paclitaxel over paclitaxel alone. Further investigation is warranted. Trial Registration ClinicalTrials.gov identifier: NCT01091428