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.
Authors: Falchook Gerald S. , Sarantopoulos John , Kurzrock Razelle , Mita Alain C. , Fu Siqing , Mita Monica M. , Zhou Xiaofei , Milch Catherine , Jung JungAh , Venkatakrishnan Karthik , Rosen Lee S. 
Published: June 2012

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 days' rest (23-day cycles). From cycle 3 onwards, patients received alisertib PIC 40 or 50 mg BID for 7 days followed by 14 days' 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.