Phase I study of the combination of alisertib (MLN8237) and gemcitabine in advanced solid tumors.

Abstract

3589 Background: Aurora Kinase A (AKA) is a key mitotic regulator overexpressed in multiple solid tumors. This open-label dose escalation and expansion phase I study evaluated the safety and tolerability of alisertib (MLN8237), an oral AKA inhibitor, in combination with gemcitabine. Methods: In dose escalation, patients (pts) > 18y with refractory solid tumors received 28-day cycles of gemcitabine on days 1, 8, 15 and alisertib twice daily on days 1-3, 8-10, and 15-17. Gemcitabine was given at 1000mg/m2. Four dose levels (DL) of alisertib (20-50mg) were given per 3+3 design to investigate dose limiting toxicities (DLT) in cycle 1, to determine maximum tolerated dose (MTD) and recommended phase II dose (RP2D). In dose expansion, advanced pancreatic adenocarcinoma pts received the MTD dose twice daily on a modified dosing schedule to allow for pharmacokinetic (PK) evaluation. Anti-tumor activity was assessed by response rate (RECIST 1.1) and progression-free survival (PFS). PK evaluation of plasma gemcitabine and alisertib was performed on all pts enrolled in the dose expansion. PK sampling was performed before treatment, immediately after gemcitabine infusion, and at other pre-specified post-infusion timepoints. Results: Twenty-six pts were treated in total: 21 pts in dose escalation and 5 pts in dose expansion. Overall, median age was 57y [42-82]; 50% male; 62% PS 1 (16 pts); 2 [0-7] median prior therapies. In the dose escalation phase, 9 tumor types were included and NSCLC was most common (7 pts). Maximum administered dose (DL4) achieved 900 mg alisertib per cycle and was tolerated (1 DLT in 6 pts). The dose expansion phase enrolled 5 pts with advanced pancreatic adenocarcinoma; median age 63y [48-82]; 60% male; 60% PS 1 (3 pts); 2 [1-2] median prior therapies. Grade ≥3 TRAEs were observed in 73% of all pts and were predominantly hematologic, including neutropenia (54%), leukopenia (50%), and lymphopenia (31%). Similar TRAEs were seen at DL4; all 14 pts experienced neutropenia with 64% experiencing grade ≥3 neutropenia. Fourteen of 23 evaluable pts (61%) had stable disease and 2 pts (9%) had partial response (PR) as best overall response. Median PFS was 2.9 months (95% CI 2.0-4.2). Analysis of PK data is ongoing and will be reported. Conclusions: Alisertib can be safely administered with gemcitabine. RP2D for alisertib is 50 mg PO BID in combination with full dose gemcitabine. Best response was at least stable disease in a majority of pts with PR observed in 9% of this heavily pretreated group of patients. Most grade ≥3 TRAEs were hematologic. Results of PK studies will also be reported. Clinical trial information: NCT01924260 .