Background: FOLFIRINOX improves survival compared with gemcitabine in advanced pancreatic cancer (PC), but at the cost of significant toxicity (Conroy, NEJM2011). UGT1A1 clears SN-38, the active metabolite of irinotecan (IRI); UGT1A1 gene polymorphisms that reduce enzymatic activity predispose to severe IRI toxicity. We hypothesized that dosing mFOLFIRINOX based on UGT1A1*28 genotype could prevent toxicity. Thus, the primary objective of this study (NCT01643499) was to determine whether genotype-guided dosing of IRI in mFOLFIRINOX is tolerable. A secondary objective was to describe objective response rates (ORR; by RECIST 1.1) in PC, biliary tract cancers (BTC), and gastric cancer (GC). Methods: mFOLFIRINOX was given every 14 days. CT scans were obtained every 8 weeks. UGT1A1 *1/*1, *1/*28, and *28/*28 pts received initial IRI doses of 180, 135, and 90 mg/m², respectively. 5-FU dose was 2400 mg/m² over 46 hours (no bolus); leucovorin 400 mg/m²; oxaliplatin 85 mg/m². Prophylactic pegfilgrastim was not allowed in cycle 1 (28 days), unless clinically indicated. DLT during cycle 1 was defined as Grade (Gr) 3/4 neutropenia with fever; Gr 4 neutropenia lasting ≥ 5 days; Gr 4 thrombocytopenia, or Gr 3/4 non-hematologic toxicity despite optimal medical management. Doses were tolerable if the DLT rate during cycle 1 was ≤ 33% with 70-80% statistical confidence, which required ≤ 2 DLTs in 15 pts. Results: 40 pts were evaluable for tolerability: 19 PC, 14 BTC, 7 GC. DLTs were observed in 2 of 15 *1/*1 pts (both neutropenic fevers); 2 of 16 *1/*28 pts (Gr 3 fatigue, diarrhea; Gr 3 fatigue); and 3 of 9 *28/*28 pts (2 neutropenic fevers; Gr 3 abdominal pain). Neutropenic fever was the most common DLT (4/7; 57%). To date, 35 pts are evaluable for response. ORR: 10/18 (56%) PC; 4/13 (31%) BTC; 3/4 (75%) GC. Conclusions: mFOLFIRINOX is tolerable in UGT1A1*1/*1 pts at the standard IRI dose of 180 mg/m² and in *1/*28 pts at a reduced dose of 135 mg/m². *28/*28 pts cannot tolerate a reduced dose of 90 mg/m². Accrual is ongoing for expansion cohorts in PC and BTC with prophylactic pegfilgrastim. Clinical trial information: NCT01643499.