Background: FTD/TPI combines a thymidine-based nucleoside analog, FTD, and a thymidine phosphorylase inhibitor, TPI, and is approved for previously treated patients with metastatic colorectal cancer (mCRC). Preclinical results with FTD/TPI indicated additive antitumor activity with IRI. The primary objectives of this Phase I study were to determine the safety, maximum tolerated dose (MTD), and dose-limiting toxicity (DLT) of combined FTD/TPI and IRI treatment in patients with advanced GI tumors.

Methods: Patients aged ≥18 years with advanced GI tumors who were refractory to ≥1 line of chemotherapy were included. Patients were excluded if they had received any prior IRI dose reductions, dose delay, or growth factor support in the first 8 weeks of treatment with IRI. Escalating doses of FTD/TPI (20, 25, 30, or 35 mg/m2/dose BID p.o.) and IRI (30-minute i.v. infusion of 120, 150, or 180 mg/m2/dose) were administered using a standard 3+3 design. FTD/TPI was given on days 1-5 of 14-day cycles; IRI on day 1 of each cycle. DLT was assessed during the first 28 days.

Results: 26 patients were enrolled and assigned to 6 treatment cohorts consisting of 3-6 patients per cohort. The most common cancer types were colon (54%) and rectal (27%). All patients initiated treatment but 3 patients were not evaluable for DLT (2 patients had disease-related complications and 1 was ineligible). The majority (65%) of patients had received ≥4 lines of prior systemic therapies and 25/26 patients initiated cycle 3. Two patients in the dose-escalation phase were IRI-naïve. Mean relative dose intensities (ratio to planned) for FTD/TPI and IRI during the first 2 cycles were 92% and 93%, respectively. Two DLTs (grade 3 fatigue and grade 2 neutropenia resulting in a >2-week delay to cycle 3) were observed in the FTD/TPI 30 mg/m2 and IRI 180 mg/m2 cohort. Thus, the MTD was FTD/TPI 25 mg/m2 and IRI 180 mg/m2. Based on a data cut-off point for the dose-escalation phase (March 22, 2016), grade ≥3 adverse events were reported in 15 patients (58%); the most common were fatigue (15%), nausea (11%), and vomiting (11%). Of 25 patients (data missing for 1 patient due to early discontinuation), the most common laboratory abnormalities that worsened from baseline were leukocytes (28%), neutrophils (24%), lymphocytes (20%), hemoglobin (16%), and hypokalemia (12%).

Conclusions: In patients with advanced GI tumors, the safety findings of FTD/TPI in combination with IRI were consistent with the existing safety profiles of these drugs. The MTD was declared as FTD/TPI 25 mg/m2 and IRI 180 mg/m2. Further safety, pharmacokinetic, and efficacy (with bevacizumab) analyses in patients with mCRC are complete and will be presented at a later date.

Citation Format: Anna M. Varghese, Dana B. Cardin, Jon Hersch, Al B. Benson, Howard S. Hochster, Robert Winkler, Fabio Benedetti, Kensuke Hamada, Jordan D. Berlin, Leonard Saltz. A phase I dose escalation study of trifluridine and tipiracil (FTD/TPI) in combination with irinotecan (IRI) in patients with advanced gastrointestinal (GI) tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT062.