Background: High grade (G3) GEPNENs are a rare and heterogeneous disease entity for which there is little prospective treatment data. EP chemotherapy is the treatment standard but this may not be appropriate for all G3 GEPNEN pts. CAPTEM has demonstrated activity in G3 GEPNENs and may be a promising alternative. EA2142 aimed to determine if CAPTEM was superior to EP in pts with G3 GEPNENs. Methods: This was a multicenter, randomized (1:1) phase II trial for pts with a locally advanced and unresectable or metastatic well differentiated G3 neuroendocrine tumor (NET) or a poorly differentiated, non-small cell G3 neuroendocrine carcinoma (NEC) of suspected gastrointestinal origin and an ECOG PS of 0-2. Pathology must have demonstrated a Ki-67 of 20-100% or at least 10 mitoses/10 high powered field. Pts were randomized to receive capecitabine 750 mg/m2 orally every 12 hours on days 1-14 and temozolomide 200 mg/m2 orally once daily on days 10-14 of a 28-day treatment cycle (Arm A) or etoposide 100 mg/m2 daily on days 1-3 with either cisplatin 25 mg/m2 daily on days 1-3 or carboplatin AUC 5 on day 1 of a 21-day treatment cycle (Arm B). Restaging scans were performed every 8 weeks and toxicity monitored per CTCAEv4. Final statistical plan was to accrue 80 pts to detect a 67% improvement in progression free survival (PFS) (primary endpoint) with CAPTEM as compared to EP, 80% power and one-sided significance level of 0.10. A planned interim analysis for efficacy and futility was conducted. Results: A total of 67 pts were enrolled (Arm A, n=32; Arm B, n=35). Male 58%, African American 4%, Asian 3%. Mean age 61. Among 63 eligible pts, primary tumor site pancreatic 56%, non-pancreatic 43%. Poorly differentiated 57%, well differentiated 33%, unknown 10%. Mean Ki-67 48% (Arm A), 60% (Arm B). The study was closed prior to full accrual due to futility at 57.7% information time. In the interim analysis, among 62 eligible pts, PFS, overall survival and response rate with CAPTEM were 2.43 months (mos) (95% CI 2.04, 7.72), 12.6 mos, 9% respectively vs 5.36 mos (95% CI 2.14, 7.23), 13.6 mos and 10% with EP. Toxicity was evaluable in 57 pts with Grade (G) 3/4 events occurring in 29% of pts on Arm A, 66% of pts on Arm B. G3/4 events occurring in more than 5% of pts on Arm A—febrile neutropenia (n=2); abdominal pain (n=2); diarrhea (n=2); nausea (n=2); neutropenia (n=2); dehydration (n=2) and on Arm B—anemia (n=8); febrile neutropenia (n=2); fatigue (n=2); lymphopenia (n=2); neutropenia (n=12); thrombocytopenia (n=4); leukopenia (n=6). There was one G5 event on Arm A due to sepsis. Conclusions: CAPTEM does not appear to be superior to EP chemotherapy as front-line treatment for pts with G3 NENs but does demonstrate a more favorable toxicity profile. Studies assessing G3 NET independently of G3 NEC are needed. Clinical trial information: NCT02595424.