Background: FOLFIRINOX improves survival compared with gemcitabine in advanced pancreatic cancer (PC), but with significant toxicity (Conroy, NEJM 2011). UGT1A1 clears SN-38, the active metabolite of irinotecan (IRI); UGT1A1*28 polymorphism reduces enzymatic activity and predisposes to severe IRI toxicity. We hypothesized that dosing mFOLFIRINOX based on UGT1A1 genotype would improve tolerability. 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) in PC and biliary tract cancers (BTC). 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. In cohort 1 (tolerability cohort by genotype), prophylactic pegfilgrastim was not allowed in cycle 1 (28 days) unless clinically indicated. In cohort 2 (expansion tolerability cohort in PC and BTC), prophylactic pegfilgrastim was given. 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. Results: In cohort 1, DLTs were observed in 2/15 (13%) *1/*1 pts; 2/16 (13%) *1/*28 pts; 3/9 (33%) *28/*28 pts. In cohort 2, DLTs were observed in 6/19 (32%) PC pts and 4/19 (21%) BTC pts. DLTs in cohort 1 (some pts with multiple): neutropenic fever (5); Gr 3 fatigue (4); Gr 3 diarrhea (2). DLTs in cohort 2: Gr 3 fatigue (3); Gr 3 diarrhea (3); Gr 3 nausea/vomiting (2); Gr 5 sepsis without neutropenia (1); Gr 5 multi-organ failure (1); neutropenic fever (1); Gr 3 anorexia (1). To date, ORR is 13/39 (33%) in PC and 6/28 (21%) in BTC. Conclusions: mFOLFIRINOX is not tolerable in PC and BTC, even with UGT1A1 genotype-guided dosing of IRI and prophylactic pegfilgrastim. More needs to be done to improve the tolerability of this regimen. Clinical trial information: NCT01643499