P-121 Phase Ib trial of oxaliplatin, UGT1A1 genotype-directed dosing of irinotecan and chronomodulated capecitabine (OXIRI) chemotherapy in patients with advanced pancreatic cancer

Abstract

Introduction: The FOLFIRINOX regimen is highly active in advanced pancreatic cancer (APC), but its use is limited by toxicity. Irinotecan toxicity is correlated with UGT1A1 genotype status and chronomodulated delivery of fluoropyrimidines may reduce toxicity and increase efficacy. In this study, safety, tolerability and preliminary activity of oxaliplatin (OXP), irinotecan (IRI) and chromomodulated capecitabine in patients ( pts) with APC were evaluated and maximum tolerated dose (MTD) established in pts without homozygous UGT1A1∗6/∗6 or UGT1A1∗28/∗28 genotype. Methods: Pts with APC and ECOG performance status (PS) 0‐2, adequate organ function were enrolled. Previous OXP or IRI exposure was disallowed. During dose‐escalation, patients who were homozygous for UGT1A1∗6/∗6 or UGT1A1∗28/∗28 were excluded. Pts received iv OXP 50mg/m2 and IRI 75mg/m2 on D1, 8 and capecitabine po once daily at midnight on D1‐14 in a 21D cycle (C) till disease progression. Capecitabine was dose‐escalated from 2000mg, 2650mg to 3500mg. Prophylactic GCSF was not permitted. During dose‐expansion, IRI dose will be determined by UGT1A1 status. Results: Data from seventeen pts enrolled in the dose‐escalation cohort are reported, 14 had metastatic and 3 had locally advanced APC. Sex M/F 12/5, the median (range) age and ECOG PS was 65yrs (50‐75) and 0 (0‐1) respectively. Prior lines of chemo were 0,1 and 2 in 4 pts (24%), 8 pts (47%) and 5 pts (29%) respectively. This included gemcitabine and nab‐paclitaxel doublet in six pts (35%), capecitabine or TS‐1 in five pts (29%), gemcitabine‐platinum doublet in two patients (12%) and gemcitabine monotherapy in three patients (18%). Sixteen pts were evaluable for determination of the MTD. C1 dose‐limiting toxicities (DLTs) occurred in four patients (Table 1). There were no Grade 4 adverse events (AEs) in all seventeen patients. Grade 3 AEs observed were neutropenia (47%), anemia (35%), diarrhea (18%), weight loss (18%), fatigue (6%) and infection (6%) but no neutropenic sepsis. Dose‐reductions were performed in 10/17 pts (59%) and 13/17 pts (76%) required dose delay predominantly due to low ANC not meeting retreatment criteria. As of data cut‐off (Mar 1, 2016), three patients remain on treatment. The median duration on study and overall survival was 13wks and 22wks respectively. Fourteen patients were evaluable for response, with 2 (14%) partial response (PR) and 8 (57%) stable disease (SD) seen. Disease control rate (PR + SD) for ≥ 12wks was 8/14 (57%). CA19‐9 decrease of ≥ 20% was seen in 6/14 pts (42%). Conclusion: The MTD of the OXIRI regimen in patients that are non‐homozygous for UGT1A1∗6/∗6 or UGT1A1∗28/∗28 was OXP 50mg/m2 and IRI 75mg/m2 on D1, 8 and capecitabine 2650mg daily at midnight from D1‐14 in a 21D cycle. The DLTs were diarrhea and fatigue. There were no Grade 4 AEs and neutropenic sepsis. Toxicities were manageable with dose interruption and reduction. Response was seen in both treatment naïve and previously treated patients with overall disease control for ≥ 12wks in 57% of patients. OXIRI is an active regimen in APC with comparable activity to other agents reported in the 2nd and 3rd line setting. Pharmacokinetic analysis and dose‐expansion in previously treated APC is ongoing.