A double-blind, randomized, placebo-controlled, phase II study of maintenance enzastaurin with 5-FU/leucovorin plus bevacizumab following first-line therapy for metastatic colorectal cancer (mCRC).

Abstract

3527 Background: Maintenance therapy is designed to maximize progression-free survival (PFS) and minimize toxicity in mCRC. Enzastaurin (ENZ) is an oral serine/threonine kinase inhibitor targeting PKCβ and AKT/PI3K pathways. Preclinical studies showed synergistic antitumor effects when ENZ was combined with bevacizumab (BV). In phase I studies, the combination was well tolerated. Our phase II study assessed ENZ with 5-FU/Leucovorin (5-FU/LV) plus BV as maintenance therapy for mCRC. Methods: Patients had locally advanced or mCRC, and completed 6 cycles of first-line chemotherapy ≤4 wks prior to randomization. Arm A received a loading dose of ENZ 1125 mg, then 500 mg/d subsequent doses. Arm B received placebo. Both groups received 5-FU/LV (LV 400 mg/m2 IV, 5-FU 400 mg/m2 bolus, 5-FU 2400 mg/m2 IV) plus BV 5 mg/kg IV, every 2 wks. Patients were treated with 5-FU/LV plus BV plus either ENZ or placebo until disease progression (PD) or 1 yr. Primary endpoint: PFS from randomization. Secondary endpoints were overall survival (OS) from randomization, and OS and PFS from start of first-line therapy. Analysis was done after 50 events (objective or clinical PD or death) to compare endpoints between the treatment arms. Results: 58 patients were randomized to Arm A (57 treated), 59 to Arm B (58 treated). 82 (70.1%) patients discontinued treatment (Arm A, 42 [72.4%]; Arm B, 40 [67.8%]), mostly due to PD. Median cycles were 9 in Arm A, 10 in Arm B. Median PFS (months) was 5.8 in Arm A and 8.1 in Arm B (hazard ratio [HR]=1.35, 95% CI: 0.84, 2.16; protocol specified one-sided test, p=0.896). Median OS was not calculable due to high censoring (77.6% in Arm A and 91.5% in Arm B). Median PFS (months) from start of first-line therapy was 8.9 in Arm A and 11.3 in Arm B (HR=1.39, 95% CI: 0.86, 2.23; one-sided, p=0.913). More patients developed thrombosis or embolism (TE), including pulmonary embolism, on Arm A (5 [8.8%] patients had grade 3 and 5 [8.8%] grade 4 TE); Arm B had (no grade 3 and 1 [1.7%] grade 4 TE). Conclusions: ENZ did not show an advantage in PFS compared to BV-based therapy alone. Development of maintenance therapy with ENZ is not recommended for mCRC.