Abstract
Updated results of the phase 1 I-FLOAT trial: Safety and efficacy of combining genotype-guided irinotecan with 5FU, leucovorin, oxaliplatin and docetaxel (gFOLFOXIRITAX) in advanced upper GI cancers.
Author
Koosha Paydary
University of Chicago Medical Center, Chicago, IL
info_outline
Koosha Paydary, Colton Loew, Aurelie Desgardin, Ardaman Shergill, Natalie Marie Reizine, Chanelle Robinzine, Christine Racette, Elena Ignatiev, Anu Radha Neerukonda, Yuan Ji, Blase N. Polite, Chih-Yi Liao
Full text
Authors
Koosha Paydary
University of Chicago Medical Center, Chicago, IL
info_outline
Koosha Paydary, Colton Loew, Aurelie Desgardin, Ardaman Shergill, Natalie Marie Reizine, Chanelle Robinzine, Christine Racette, Elena Ignatiev, Anu Radha Neerukonda, Yuan Ji, Blase N. Polite, Chih-Yi Liao
Organizations
University of Chicago Medical Center, Chicago, IL, University of Chicago, Chicago, IL, Department of Medicine, Section of Hematology & Oncology, University of Chicago Medical Center, Chicago, IL, University of Illinois Chicago, Chicago, IL, University of Chicago Medical Center, Tinley Park, IL, University of Chicago Department of Family Medicine, Chicago, IL, North Shore University Health System/University of Chicago, Evanston, IL
Abstract Disclosures
Research Funding
Institutional Funding
University of Chicago Comprehensive Cancer Center
Background:
5FU, Oxaliplatin (ox), irinotecan (iri) and docetaxel (tax) are each active in upper GI cancers; however, combination of all 4 agents (FOLFOXIRITAX) has not been studied. UGT1A1 polymorphisms may predispose to Iri toxicity. We sought to determine the maximum tolerated dose (MTD) in the 1st month of therapy (tx) among each of the low (L), intermediate (I) and high (H) risk UGT1A1 genotype (UGT) groups. We report the updated results of the I-FLOAT trial.
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 H
risk
groups 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 6/30/2020-1/1/2023, 27 pts (11F, 16M) enrolled: median age 51 (range 21-76); 9 ECOG PS 1,
UGT-
L:I:H with 6:18:3 pts; 12 esophageal, 6 gastric, 8 pancreatic, and 1 bile duct cancer; 3 pts HER2+; 22 metastatic, 5 locally advanced unresectable. The median (range) of albumin and neutrophil-to-lymphocyte ratio (NLR) were 3.9 mg/dL (3.2-4.7) and 4.06 (1.89-27.6), respectively; 81% (22/27) of pts had a NLR > 2.88, a poor prognostic marker. Dose limiting toxicities (DLTs) were seen in 5 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), one G3 fatigue (UGT-I DL2/DL2 Iri/Tax) and one G3 diarrhea and neutropenic fever (UGT-L DL4/DL1 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 DL4/DL1. The most frequent any Gr tx related toxicities: diarrhea (78%), fatigue (74%), nausea (70%), neuropathy (67%), anorexia (52%), elevated LFT (48%), anemia (37%), vomiting (37%). Of evaluable pts across all cohorts, PR/CR was seen in 18/22 (82%) patients, with 2 (9%) SD and 2 (9%) PD for a disease control rate of 91%. Of evaluable pts, best ctDNA response was seen in 12/13 (92%).
Conclusions:
gFOLFOXIRITAX continues to demonstrate tolerability at initial DLs of Iri/Tax. Efficacy is promising and could be an aggressive approach in upper GI cancers with high relapse risk in curative-intent settings. Clinical trial information: NCT04361708.
Clinical status
Clinical
1 clinical trial
7 organizations
6 drugs
6 targets
Clinical trial
A Phase 1 Dose Finding Study of the gFOLFOXIRITAX Regimen Using UGT1A1 Genotype-directed Irinotecan With Fluorouracil, Leucovorin, Oxaliplatin and Taxotere in Patients With Untreated Advanced Upper Gastrointestinal Adenocarcinomas: The I-FLOAT StudyStatus: Recruiting, Estimated PCD: 2025-06-01
Organization
University of ChicagoOrganization
Section of Hematology & OncologyOrganization
University of Illinois ChicagoDrug
5-FUDrug
mFOLFOX6Drug
mFOLFOXIRIDrug
docetaxelDrug
TrastuzumabDrug
FilgrastimTarget
docetaxelTarget
thymidylate synthaseTarget
HER2 (ERBB2)Target
DNATarget
topoisomerase I