Background: 5FU, Ox, Iri, and Tax are each active in upper GI cancers. Triplet cytotoxic therapies (txs) improved survival compared to doublets/singlets. However, combination of all 4 agents (FOLFOXIRITAX) has not been studied. UGT1A1 polymorphisms reduce UGT enzymatic activity predisposing to Iri toxicity. We sought to determine the maximum tolerated dose (MTD) in the 1st month of tx among each of the low (L), intermediate (I) and high (H) risk UGT1A1 genotype (UGT) groups. Methods: Previously untx’d advanced upper GI cancer patients (pts) with ECOG PS 0/1 received gFOLFOXIRITAX (+ trastuzumab if HER2+) with pegfilgrastim. 5FU 2400mg/m2 over 46 hrs, LV 400mg/m2, Ox 85mg/m2, and Tax 25mg/m2 were given IV Q14 days. UGT-L, I, and Hriskgroups received starting Iri dose levels (DL1) of 120, 105 and 45mg/m2, respectively; Iri doses were escalated in each UGT group by 15mg/m2 increments and Tax to DL2 of 37.5mg/m2 using a I3+3 novel design (Liu & Ji. J Biopharm Stat 2020). Other endpoints included overall safety (thru up to 8 cycles before maintenance 5FU +/- Iri/tras), ORR (RECIST1.1), & ctDNA response (> 50% decrease in highest MAF) by G360 (Guardant Health). Results: From 6/30/2020-8/6/2021 20 pts (8F, 12M) enrolled: median age 50 (range 21-76); 8 ECOG PS 1, UGT-L:I:H with 3:14:3 pts; 10 esophageal, 6 gastric, 2 pancreatic, 1 unknown GI primary and 1 bile duct cancer; 2 pts HER2+; 18 metastatic, 2 locally advanced unresectable. The median (range) of albumin and neutrophil-to-lymphocyte ratio (NLR) were 3.9 mg/dL (3.3-4.6) and 4.28 (1.89-27.6), respectively; 80% (16/20) of pts had a NLR > 2.88, a poor prognostic marker. Dose limiting toxicities (DLTs) were seen in 4 pts: one G3 diarrhea (UGT-H, DL1/DL1 Iri/Tax), two G3 sepsis not neutropenic (one UGT-I, DL2/DL2 Iri/Tax; and one UGT-I, DL3/DL1 Iri/Tax) and one G3 fatigue (UGT-I DL2/DL2 Iri/Tax). MTD has not been reached in any UGT TAX DL1 cohorts to date; currently enrolling UGT-H Iri/Tax DL1/DL1, UGT-I DL4/DL1, & UGT-L DL3/DL1. Any Gr tx related toxicities in ³ 10% pts thru up to 8 cycles: nausea (70%), fatigue (70%, 5% G3), diarrhea (65%, 5% G3), anorexia (50%), peripheral neuropathy (30%, 5% G3), anemia (30%), thrombocytopenia (25%), elevated LFTs (25%), hyponatremia (25%), vomiting (20%), mucositis (20%, 5% G3), hyperglycemia (20%), edema (15%), alopecia (15%), hypocalcemia (15%) and dysgeusia (10%). Of evaluable pts across all cohorts, PR/CR was seen in 13/16 (81%) patients, with 2 (12.5%) SD and 1 (6.25%) PD for a disease control rate of 94%. Of evaluable pts, best ctDNA response was seen in 12/13 (92%). Conclusions: gFOLFOXIRITAX demonstrated tolerability at initial dose levels of Iri/Tax, with dose escalation continuing. Efficacy is promising and could be an aggressive approach in upper GI cancers having high relapse risk in curative-intent settings. Clinical trial information: NCT04361708.