Published OnlineFirst January 10, 2020; DOI: 10.1158/1078-0432.CCR-19-2743 CLINICAL CANCER RESEARCH | CLINICAL TRIALS: TARGETED THERAPY Phase I Study of Trifluridine/Tipiracil Plus Irinotecan and Bevacizumab in Advanced Gastrointestinal Tumors A C Anna M. Varghese1, Dana B. Cardin2, Jonathan Hersch1, Al B. Benson3, Howard S. Hochster4, Lukas Makris5, Kensuke Hamada6, Jordan D. Berlin2, and Leonard B. Saltz1 ABSTRACT ◥ Purpose: This two-part phase Ib trial determined the maximum toxicities (fatigue and neutropenia) were observed in the dose- tolerated dose (MTD) of the combination of trifluridine/tipiracil escalation phase, and MTD was defined as FTD/TPI 25 mg/m2 (FTD/TPI) and irinotecan in patients with advanced gastrointes- twice daily plus irinotecan 180 mg/m2.Intheexpansionphase, tinal tumors, and evaluated the safety, pharmacokinetics, and 83% (20/24) experienced any-cause grade 3 adverse events antitumor activity of the FTD/TPI, irinotecan, and bevacizumab (AEs) with the triplet combination, most frequently neutropenia triplet combination in previously treated metastatic colorectal (42%), leukopenia (25%), and diarrhea (12%). AEs of any-cause cancer (mCRC). led to dosing interruptions, modifications, and discontinuations Patients and Methods: Dose escalation (3þ3 design) in advanced in 29%, 17%, and 4% of patients, respectively. No treatment- gastrointestinal tumors was followed by expansion in mCRC. related deaths occurred. Three patients (12%) experienced partial During dose escalation, patients received FTD/TPI (20–35 mg/m2 responses and 16 (67%) patients had stable disease lasting twice daily; days 1–5 of a 14-day cycle) and irinotecan (120– >4 months. The median progression-free survival was 7.9 months 180 mg/m2; day 1). During expansion, the MTD of FTD/TPI and (95% confidence interval, 5.1–13.4 months). irinotecan plus bevacizumab (5 mg/kg; day 1) was administered. Conclusions: Tolerability and activity observed in this phase I Results: Fifty patients (26 across six dose-escalation cohorts trial support further investigation of the FTD/TPI–irinotecan– and 24 in the expansion phase) were enrolled. Two dose-limiting bevacizumab combination in previously treated mCRC. Introduction 0.68; 95% confidence interval (CI), 0.58–0.81; P < 0.001; median OS, 7.1 vs 5.3 months, respectively] and manageable toxicity (9). On the Fluoropyrimidines [5-fluorouracil (5-FU) or capecitabine] form the basis of these results, FTD/TPI was approved at 35 mg/m2/dose for backbone of active combination regimens for metastatic colorectal patients with previously treated mCRC. FTD/TPI also recently received cancer (mCRC) and are often combined with oxaliplatin, irinotecan, or approval for the treatment of metastatic gastric or gastroesophageal both (1, 2). The further addition of targeted agents, such as the anti- junction cancer after two previous lines of chemotherapy (10). VEGF antibody bevacizumab to these regimens has been shown to In preclinical studies involving human colorectal cancer xeno- improve overall survival (OS) in the first- and second-line settings graft models, the antitumor activity of FTD/TPI combined with (3–5). Despite these advances, many patients develop treatment- irinotecan or bevacizumab was significantly greater than that of refractory mCRC, for which there are few treatment options. each agent alone (11, 12). Consistent with these preclinical data, Trifluridine and tipiracil [FTD/TPI (TAS-102)] is an orally admin- preliminary antitumor activity was observed with the combination istered cytotoxic agent consisting of trifluridine (FTD), a thymidine of FTD/TPI and irinotecan in patients with previously treated analog, and tipiracil (TPI), a thymidine phosphorylase inhibitor (6). mCRC in an initial phase I study; however, a high rate of grade FTD/TPI has a unique mechanism of action that distinguishes it from 3 hematologic toxicities was observed, indicating that further fluoropyrimidines: FTD is incorporated into DNA, causing DNA investigation was needed to optimize the FTD/TPI–irinotecan dysfunction, and TPI increases FTD bioavailability (7, 8). In a phase regimen (13). On the other hand, it was expected that bevacizumab III trial evaluating FTD/TPI versus placebo in patients with mCRC and FTD/TPI would have nonoverlapping toxicities based on prior refractory to standard therapies, FTD/TPI achieved a statistically experience with fluoropyrimidines (3–5, 14). significant improvement in OS versus placebo [hazard ratio (HR), These findings formed the basis for exploring the combination of FTD/TPI with irinotecan and bevacizumab in patients with advanced gastrointestinal tumors, including mCRC, in a two-part, 1 2 Memorial Sloan Kettering Cancer Center, New York, New York. Vanderbilt- phase Ib dose-escalation/expansion study (ClinicalTrials.gov identifier 3 Ingram Cancer Center, Nashville, Tennessee. Northwestern Medicine, Chicago, NCT01916447). The dose-escalation phase examined the safety of the Illinois. 4Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. 5Stathmi, Inc., New Hope, Pennsylvania. 6Taiho Oncology, Inc., Princeton, New combination of FTD/TPI and irinotecan and characterized the MTD, Jersey. and the expansion phase further evaluated the safety, preliminary activity, and pharmacokinetics of the combination of FTD/TPI, Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). irinotecan, and bevacizumab. Corresponding Author: Leonard B. Saltz, Memorial Sloan Kettering Cancer Center, 300 E 66th Street, Room 1049, New York, NY 10065. Phone: 646- Patients and Methods 888-4181; Fax: 646-888-4258; E-mail: [email protected] Eligibility criteria Clin Cancer Res 2020;XX:XX–XX Patients with histologically confirmed advanced gastrointestinal doi: 10.1158/1078-0432.CCR-19-2743 tumors (malignancy of gastrointestinal origin or an adenocarcinoma Ó2020 American Association for Cancer Research. of unknown primary, likely to be of gastrointestinal origin) were AACRJournals.org | OF1 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst January 10, 2020; DOI: 10.1158/1078-0432.CCR-19-2743 Varghese et al. prior therapies, partial or total gastrectomy, a serious illness or Translational Relevance medical condition that precluded safe participation, or active Trifluridine/tipiracil (FTD/TPI), an oral cytotoxic agent, has central nervous system metastases. To assess the contribution of shown clinical benefit in patients with pretreated, refractory the toxicity of FTD/TPI to the FTD/TPI–irinotecan combination, mCRC. This article describes the phase I clinical evaluation of the patients with prior exposure to irinotecan were eligible only if they combination of FTD/TPI, irinotecan, and bevacizumab in patients had required no dose reductions or delays in irinotecan during their with advanced previously treated gastrointestinal tumors, includ- previous therapy. ing mCRC. The triplet combination was tolerable in patients with The study followed the Declaration of Helsinki and good clinical mCRC and demonstrated a safety profile consistent with that of the practice guidelines, and approval was obtained from each institution's individual agents. No unexpected safety concerns were noted. The review board or an independent ethics committee. All patients pro- triplet combination demonstrated promising antitumor activity, vided written, informed consent prior to enrollment. including partial responses, and a majority of patients achieved stable disease. This evidence of efficacy and tolerability in these Study design heavily pretreated patients, half of whom had received four or more This was a multicenter, open-label, nonrandomized, two-part previous regimens, supports further investigation of this regimen phase Ib study comprising a dose-escalation phase to evaluate the in mCRC. These results are also consistent with phase I results of safety and to determine the MTD of the combination of FTD/TPI other FTD/TPI-containing combination regimens in mCRC. and irinotecan in gastrointestinal cancers, followed by an expansion phase to further investigate the safety, pharmacokinetics, and preliminary activity of FTD/TPI and irinotecan at the MTD in colorectal cancer with or without bevacizumab. Patients received eligible for enrollment in the dose-escalation phase. Eligibility for the oral FTD/TPI twice daily on days 1–5 of a 14-day treatment cycle, triplet combination in the expansion phase was restricted to those intravenous irinotecan on day 1 of every cycle at the same time as with histologically confirmed mCRC. Patients aged 18 years with FTD/TPI, and in the expansion phase, intravenous bevacizumab on an Eastern Cooperative Oncology Group performance status day 1 of every cycle before irinotecan. Treatment was administered (ECOG PS) of 0 or 1 at baseline who were refractory to at least until RECIST-defined disease progression or clinical disease pro- one line of chemotherapy for metastatic disease and had no curative gression, unacceptable toxicity [adverse events (AEs) leading to treatment options were enrolled. Key exclusion criteria included more than three dose reductions of FTD/TPI or irinotecan or a dose recent major surgery or extended-field radiotherapy (within 4 weeks delay >14 days from the scheduled start of the next cycle], patient prior to starting therapy), recent anticancer therapy (within 3 weeks request to withdraw treatment, pregnancy, or physician's decision prior to