Randomized phase II study of PEP02, irinotecan, or docetaxel as a second-line therapy in gastric or gastroesophageal junction adenocarcinoma

[[abstract]]Background: PEP02 is a novel nanoparticle liposome formulation of irinotecan (CPT-11). In phase I studies, PEP02 has improved pharmacokinetics (PK) of CPT-11 and its active metabolite-SN38 with encouraging safety and tumor response in several cancer types including gastric cancer. This study evaluated the efficacy and safety of PEP02 (P), irinotecan (I) or docetaxel (D) as a single agent in gastric or gastroesophageal junction (GEJ) adenocarcinoma. Methods: A randomized, 3 arms (1:1:1), Simon's 2-stage (2/21, 5/41 based on tumor response) study was conducted in Europe and Asia. Patients (pts) with locally advanced or metastatic disease, failed to one prior chemotherapy, ECOG PS ? 2, at least 1 measurable lesion, no prior CPT-11 or taxane, were treated with P - 120 mg/m2, I - 300 mg/m2, or D - 75 mg/m2 every 3 weeks. PK and pharmacogenetics (PGx) samples were collected for pts in P and I arms. Results: A total of 135 pts were randomized with 132 (44 per arm) treated between Jan 2008 and Jun 2010. Pts demographics (P/I/D): median age: 56/62/58, male (%): 79.5/77.3/77.3, Pts from Europe (%): 54.6/52.3/56.8, metastatic (%): 97.7/90.9/97.7, gastric adenocarcinoma (%): 84.1/79.6/68.2, and ECOG 0 + 1 (%): 93.2/93.2/90.9. The confirmed responders of P/I/D were 6 (13.6%)/3 (6.8%)/7 (15.9%) and disease control were 27 (61.4%)/27 (61.4%)/24 (54.6%). These three arms have similar progression free survival and overall survival. If stratified by region, Asian pts had longer survival than European pts. Toxicities of P/I/D were: grade 3/4 neutropenia (%): 9.1/13.6/15.9. grade 3/4 diarrhea (%): 27.3/18.2/2.3, hand-foot syndromes (%): 0.0/6.8/18.2. It was notable that symptoms related to acute cholinergic syndrome were less reported in P arm than in I arm. The PK data showed the mean T1/2, Cmax and AUC0→∞ of SN-38 in P/I arms were 88.8/22.8 hr, 8.79/44.1 ng/mL and 879/440 hr x ng/mL. Conclusions: This randomized phase II study suggests that PEP02 improves the PK profile and tumor response over irinotecan, and it is as efficacious as docetaxel in the 2nd-line treatment for gastric or GEJ adenocarcinoma. PEP02 is worthy of further evaluation as either 1st- or 2nd-line setting in future gastric cancer studies