Phase 1 study of nanoliposomal irinotecan in combination with trifluridine/tipiracil in refractory solid tumors.
Authors: Bai Li-Yuan , Chiang Nai-Jung , Hsu Chih-Hung , Liang Yi-Hsin , Chiu Chang-Fang , Lin Ching-Chan , Chang Kwang-Yu , Chen Shang-Hung , Tsai Hui-Jen , Lin Yu-Ping , Chen Li-Tzong , Lin Chia-Chi 
Published: January 2022

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Background: Nal-IRI is irinotecan (as known as CPT-11) encapsulated in a nanoliposome drug delivery system (nanoliposomal irinotecan; nal-IRI). Nal-IRI + 5-FU/LV has been approved in patients with metastatic pancreatic cancer after gemcitabine-based therapy through the NAPOLI-1 study. TAS-102 is a combination drug of trifluridine (FTD), an antineoplastic thymidine analog, and tipiracil hydrochloride (TPI), a thymidine phosphorylase inhibitor. TAS-102 has been approved in metastatic colorectal cancer and gastric or gastroesophageal junction adenocarcinoma. Given both drugs show antitumor activity in various cancers, this study is to identify the MTD (maximum tolerated dose) and recommended phase II dose (RP2D), and to explore the preliminary efficacy of nal-IRI and TAS-102 combination in solid tumors. Methods: This multi-center phase I study consists of a classical 3 + 3 dose finding portion and an expansion portion. Eligible patients have pathologically confirmed solid malignancies with no standard treatment available. Patients will be treated with nal-IRI at dose of 60, 70, 80 mg/m2 over 90 minutes on day 1, and oral TAS-102 25, 30, 35 mg/m2 twice daily on day 1-5, every 14 days. Patients who have homozygous for the UGT1A1*28 allele ( TA7/TA7) or UGT1A1*6 allele ( A/A), or double heterozygous for both UGT1A1*28 allele ( TA6/TA7) and UGT1A1*6 allele ( G/A) will be excluded from the dose finding portion. This trial is registered with ClinicalTrials.gov, NCT 03810742. Results: From February 2019 to May 2021, a total of 43 (male/female: 27/16; median age 56, range 25-69) patients (pts) were treated, including 28 in the dose finding portion in which 3, 3, 3, 3, 7, 3 and 6 pts were at levels 1, 2A, 2B, 3, 4A, 4B and 5, respectively, and 15 pts in the expansion portion. The results here are reported from the dose finding portion. The most common cancer types were cholangiocarcinoma (N = 6), neuroendocrine tumor (N = 3), and ampulla of Vater (N = 3). DLTs were noted at one patient who had G4 sepsis and G3 diarrhea at level 4A (80/30), and two subjects who had G3 diarrhea and G3 dehydration at level 5 (80/35). The dosage of the level 4A is determined to be the MTD and it is also the RP2D for the expansion phase. Most common treatment related toxicities during the DLT observation period (the first 2 cycles) are neutropenia, thrombocytopenia, diarrhea, fatigue, and vomiting. In this dose finding portion, 4 pts had partial response and 17 pts had stable disease as the best response. Conclusions: The MTD of Nal-IRI in combination with TAS-102 every 2 weeks is 80/30 mg/m2, which is also the RP2D for expansion study. The clinical benefit was observed in pts at different dose levels. The expansion portion of the study is still ongoing and pts will be followed until disease progression or consent withdrawal. Clinical trial information: NCT03810742.