Phase I Study of Trifluridine/Tipiracil Plus Irinotecan and Bevacizumab in Advanced Gastrointestinal Tumors

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 2020 American Association for Cancer Research. of unknown primary, likely to be of gastrointestinal origin) were

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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 initiating therapy), any unresolved grade 1 toxicities from to switch to another cancer therapy.

Pretreatment period Up to 28 days Dose escalation Expansion 14-day treatment cyclesa Cohort 6: 14-day treatment cyclesb Safety follow-up FTD/TPI 30 mg/m2 IRI 180 mg/m2 (n = 6) Up to 30 days

Cohort 5: FTD/TPI 25 mg/m2 IRI 180 mg/m2 (n = 6)

Cohort 4: FTD/TPI 20 mg/m2 MTD 2 DLTs IRI 180 mg/m2 (n = 4) FTD/TPI 25 mg/m2 IRI 180 mg/m2 Cohort 3: BEV 5 mg/kg FTD/TPI 25 mg/m2 (n = 24) IRI 150 mg/m2 (n = 3)

Cohort 2: FTD/TPI 20 mg/m2 IRI 150 mg/m2 (n = 4)

Cohort 1: FTD/TPI 20 mg/m2 IRI 120 mg/m2 (n = 3)

Baseline FTD/TPI and IRI treatment continued until a treatment Treatment continued until assessments discontinuation criterion was met a treatment discontinuation criterion was met

Figure 1. Study design of the dose-escalation and expansion phases. Dose escalation followed the 3þ3 design to determine the MTD of the FTD/TPI þ IRI combination (FTD/TPI 25 mg/m2 twice daily þ IRI 180 mg/m2) in patients with advanced gastrointestinal tumors. In the expansion phase, the FTD/TPI 25 mg/m2 twice daily þ IRI 180 mg/m2 þ BEV 5 mg/kg triplet combination was administered to patients with mCRC. aFTD/TPI was administered orally at the indicated dose twice daily on days 1–5, followed by a 9-day recovery period from days 6–14; IRI was administered intravenously at the indicated doses at the same time as FTD/TPI on day 1 of each cycle. bFTD/TPI and IRI were administered as in the dose-escalation phase; BEV 5 mg/kg preceded IRI on day 1 of each cycle. BEV, bevacizumab; IRI, irinotecan.

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The dose-escalation phase followed a traditional 3þ3 design (Fig. 1), Statistical methods and analyses in which patients in sequential dose-level cohorts received escalating Descriptive statistics were used to summarize patient characteris- doses of FTD/TPI (20, 25, 30, or 35 mg/m2/dose, administered twice tics, efficacy, and safety measurements. Pharmacokinetic analyses used daily) and irinotecan (120, 150, or 180 mg/m2/dose). At least three standard noncompartmental models and calculations. Progression- evaluable patients were treated in each cohort, and at least six patients free survival (PFS) was analyzed using Kaplan–Meier methodology; were treated at the MTD. Escalation to subsequent dose levels occurred CIs for median PFS were generated using the Brookmeyer and Crowley only after the previous dose level was determined to be safe per method. All data summaries and listings were produced using SAS protocol. Intrapatient dose escalation was not allowed. The MTD was version 9.1.3 (SAS Institute). defined as the highest dose level at which less than 33% of evaluable patients treated had a dose-limiting toxicity (DLT) during cycles 1 or 2 of study drug administration. Results TheexpansionphasewasinitiatedoncetheMTDwasestab- Study population lished, and only patients with mCRC received bevacizumab. The A total of 50 patients were enrolled between September 24, 2013, first six patients were enrolled in parallel and administered the and September 8, 2016. Of these, 26 patients [21 (81%) with colorectal MTD of FTD/TPI plus irinotecan plus bevacizumab 5 mg/kg. The cancer, two (8%) with gastric/gastroesophageal junction cancer, two expansion phase included an interim safety assessment (ISA) to (8%) with pancreatic/biliary cancer, and one (4%) with gastrointestinal assess safety in the first six patients after two treatment cycles or cancer of unknown primary] were enrolled into six dose-escalation treatment discontinuation, whichever came first. Additional enroll- cohorts, with three to six patients per cohort, and 24 patients (all ment of patients into the expansion cohort for treatment with the with colorectal cancer), into the expansion cohort (Fig. 1). All triplet combination (up to a total of 36 patients) was contingent 50 patients received at least one dose of the study drug. At data cutoff upon the completion of the ISA and the absence of unexpected (March 9, 2017), 42 patients (84%) had discontinued treatment, safety concerns. In the event of unexpected AEs, another safety most frequently as a result of disease progression (n ¼ 35; 70%). The evaluation was planned for the next six patients enrolled, and eight patients (16%) for whom treatment was ongoing at the end of accordingly, treatment was planned to be continued with dose the study were in the expansion cohort (Supplementary Table S1). adjustments for bevacizumab or the doublet combination only. In the overall patient population (N ¼ 50), the median age was 55.5 years (range, 19–85 years), and the majority (74%) of patients had Safety and efficacy assessments an ECOG PS of 1 (Table 1). Overall, 60% of all patients had received The safety population included all patients who received one or more four or more prior regimens for advanced disease, and 84% had doses of the study drug. Safety assessments were performed from the previously received irinotecan. first dose until 30 days after the last dose of the study drug. AEs were graded according to the NCI Common Terminology Criteria for Determination of the MTD Adverse Events version 4.03. A DLT was defined as a cycle 1 or 2 AE In the dose-escalation cohorts, a total of two DLTs were observed that met one of the following criteria: grade 4 neutropenia lasting at the highest dose level assessed (dose level 6; FTD/TPI 30 mg/m2 >7 days; febrile neutropenia, grade 4 thrombocytopenia, or grade 3 twice daily and irinotecan 180 mg/m2): one patient developed grade thrombocytopenia with bleeding; grade 3 nonhematologic toxicity; 3 fatigue in cycle 1, and another developed grade 2 neutropenia in grade 3 nausea, diarrhea, or vomiting lasting >48 hours; any study cycle 2, which resulted in a >2-weekdelayininitiatingcycle3.No drug-related toxicity resulting in a >2-week delay in initiation of cycle 3; DLTs were observed at dose levels 1 through 5. On this basis, the or any study drug-related toxicity preventing the administration of MTD for the expansion phase was established as FTD/TPI 25 mg/ 80% of the planned cumulative dose for cycles 1 or 2. Dosing and dose m2 twice daily plus irinotecan 180 mg/m2 (dose level 5). Bevaci- reductions can be found in Supplementary Materials and Methods. zumab was added to this combination at the standard mCRC dose Response was evaluated using investigator-assessed RECIST of 5 mg/kg (15). version 1.1, with tumor assessments at baseline and every four cycles (8 weeks) for the first 24 cycles or as clinically necessary. Safety Patients who had completed one or more cycles of study medication The median duration of treatment was 4.5 months (range, 0.2– and had radiologic/clinical progression assessments were evaluable 14.0) in the overall patient population (N ¼ 50) and 6.6 months for efficacy. (range, 1.5–14.0)intheexpansioncohort.Intheexpansioncohort, 23 of 24 patients (96%) received 80% of the planned target dose of Pharmacokinetic assessments and analyses FTD/TPI. Pharmacokinetic assessments were performed in the first six In the combined dose-escalation cohorts (n ¼ 26), all patients patients and in at least 12 patients, following the ISA in the expansion experienced one or more AEs of any-cause and 69% of patients phase. Samples for pharmacokinetic analyses were collected on days 1– experienced grade 3 AEs (determined to be treatment-related in 3 of cycle 1 predose (30 minutes prior to the administration of the first 46% of patients); 27% experienced serious AEs (Table 2; Supplemen- study drug) and postdose (at 30 minutes and 1, 1.5, 2, 4, 6, 8, 10, 24, and tary Table S2; Supplementary Results). One death because of acute 48 hours after irinotecan infusion). renal failure (not considered treatment-related) occurred in cohort 5 Assessed pharmacokinetic parameters included maximum (FTD/TPI 25 mg/m2 twice daily plus irinotecan 180 mg/m2), and C 2 observed plasma concentrations ( max), area under the plasma another patient in cohort 6 (FTD/TPI 30 mg/m twice daily plus concentration–time curve (AUC) from time 0 to the last measur- irinotecan 180 mg/m2) died because of clinical disease progression. fi n ¼ able plasma concentration (AUC0–last) or from time 0 to in nity In the expansion cohort ( 24), all patients experienced one or C T (AUC0–inf), time to max ( max), apparent terminal phase elimi- more all-cause AEs, and 83% experienced grade 3 AEs (Table 2); t nation half-life ( 1/2), oral clearance (CL/F), and apparent volume serious AEs were observed in 38% of patients. Treatment-related AEs V of distribution ( d/F). of any grade occurred in 96% of patients and grade 3 treatment-

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Table 1. Patient baseline characteristics and prior therapy.

Dose-escalation cohorts 1–6: Expansion cohort: FTD/TPI þ IRIa FTD/TPI þ IRI þ BEVb All patients Variable (n ¼ 26) (n ¼ 24) (N ¼ 50)

Age, median (range) 55.5 (30–85) 55.5 (19–73) 55.5 (19–85) Sex, male 14 (54) 8 (33) 22 (44) Racec White 24 (92) 19 (79) 43 (86) Black 1 (4) 2 (8) 3 (6) Asian 0 1 (4) 1 (2) Missing 1 (4) 1 (4) 2 (4) Other 0 1 (4) 1 (2) ECOG PS 0 6 (23) 7 (29) 13 (26) 1 20 (77) 17 (71) 37 (74) Primary cancer type Colon 14 (54) 18 (75) 32 (64) Rectal 8 (31) 6 (25) 14 (28)d Stomach/GEJ 2 (8) 0 2 (4) Biliary tract 1 (4) 0 1 (2) Pancreas 1 (4) 0 1 (2) Number of prior regimens 1 1 (4) 3 (12) 4 (8) 2 4 (15) 3 (12) 7 (14) 3 3 (12) 6 (25) 9 (18) 4 18 (69) 12 (50) 30 (60) Prior systemic therapy for metastatic disease Irinotecan 23 (88) 19 (79) 42 (84) Fluoropyrimidine 22 (85) 22 (92) 44 (88) Oxaliplatin 18 (69) 17 (71) 35 (70) Bevacizumab/aﬂibercept/ramucirumab 17 (65) 19 (79) 36 (72) Cetuximab/panitumumab 10 (38) 6 (25) 16 (32) Regorafenib 4 (15) 3 (12) 7 (14) Other 24 (92) 21 (88) 45 (90) Time from initial diagnosis to ﬁrst dose, months 33.0 (7.6–113.5) 39.2 (8.9–113.3) 33.5 (7.6–113.5) Number of metastatic sites 1–2 6 (23) 6 (25) 12 (24) 3 20 (77) 18 (75) 38 (76) Hepatic function Normal 17 (65) 21 (88) 38 (76) Mild impairment 9 (35) 3 (12) 12 (24)

Note: Data are presented as n (%) or median (range), unless otherwise indicated. Abbreviations: BEV, bevacizumab; GEJ, gastroesophageal junction; IRI, irinotecan. aFTD/TPI 20–30 mg/m2 twice daily (days 1–5 every 14 days) þ IRI 120–180 mg/m2 (day 1 every 14 days). bFTD/TPI 25 mg/m2 twice daily (days 1–5 every 14 days) þ IRI 180 mg/m2 (day 1 every 14 days) þ BEV 5 mg/kg (day 1 every 14 days). cNot collected for three patients. dIncludes two patients (one in the dose-escalation and one in the dose-expansion cohort) with colorectal adenocarcinoma.

related AEs occurred in 67% of patients (Supplementary Table S2). Pharmacokinetics AEs were predominantly hematologic or gastrointestinal-related, with Pharmacokinetic parameters were evaluated in 18 patients in the the most frequent all-cause any-grade AEs being neutropenia (in 79% of expansion cohort following the ﬁrst dose of FTD/TPI in combination patients), fatigue (58%), nausea (58%), vomiting (54%), and diarrhea with irinotecan and bevacizumab. After a single dose, FTD and TPI (50%). The most frequently occurring grade 3 AEs were neutropenia reached maximum plasma concentrations at a mean of 1.22 and t (42%), leukopenia (25%), and diarrhea (12%). Most AEs were managed 2.73 hours, respectively, and declined with a 1/2 of 2.32 and 1.85 hours using dosing adjustments: seven patients (29%) had dosing interrup- (Table 3). The pharmacokinetic exposure for FTD and TPI in the ﬁ tions and four (17%) had dosing modi cations because of AEs of any- triplet combination regimen (AUC0–inf, 5,625 and 372 ng hour/mL, cause. One patient discontinued study treatment as a result of an AE respectively) was consistent with data from previous single-agent C (rectal hemorrhage) that was not treatment-related. At the time of data studies (16). The max for irinotecan was reached at a mean of t cutoff, no deaths were reported in the expansion cohort. Overall, no 0.54 hours after dose administration and declined with a 1/2 of grade 5 AEs related to treatment were reported in this study. 8.72 hours; AUC0–inf was 13,054 ng hour/mL.

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Table 2. AEs occurring in 10% of patients in any group.

Dose-escalation cohorts 1–6: Expansion cohort: FTD/TPI þ IRIa FTD/TPI þ IRI þ BEVb All patients (n ¼ 26) (n ¼ 24) (N ¼ 50) Any grade Grade 3 Any grade Grade 3 Any grade Grade 3

Any AE of any-cause 26 (100) 18 (69) 24 (100) 20 (83) 50 (100) 38 (76) Any serious AE of any-cause 7 (27) 7 (27) 9 (38) 8 (33) 16 (32) 15 (30) AEs of any-cause reported in 10% of patients Hematologic AEs Neutropeniac 10 (38) 6 (23) 19 (79) 10 (42) 29 (58) 16 (32) Anemiad 7 (27) 4 (15) 5 (21) 2 (8) 12 (24) 6 (12) Leukopeniae 7 (27) 4 (15) 10 (42) 6 (25) 17 (34) 10 (20) Gastrointestinal AEs Nausea 18 (69) 3 (12) 14 (58) 1 (4) 32 (64) 4 (8) Vomiting 14 (54) 3 (12) 13 (54) 2 (8) 27 (54) 5 (10) Constipation 11 (42) 0 8 (33) 0 19 (38) 0 Abdominal pain 9 (35) 1 (4) 7 (29) 1 (4) 16 (32) 2 (4) Diarrhea 7 (27) 0 12 (50) 3 (12) 19 (38) 3 (6) Dyspepsia 2 (8) 0 5 (21) 0 7 (14) 0 Stomatitis 1 (4) 0 3 (12) 0 4 (8) 0 Other AEs Fatigue 9 (35) 4 (15) 14 (58) 2 (8) 23 (46) 6 (12) Pyrexia 7 (27) 0 4 (17) 0 11 (22) 0 Dyspnea 6 (23) 0 1 (4) 0 7 (14) 0 Back pain 5 (19) 0 5 (21) 1 (4) 10 (20) 1 (2) Cough 5 (19) 0 4 (17) 0 9 (18) 0 Decreased appetite 5 (19) 0 9 (38) 0 14 (28) 0 Alopecia 4 (15) 0 10 (42) 0 14 (28) 0 Hypokalemia 4 (15) 1 (4) 2 (8) 1 (4) 6 (12) 2 (40) Dehydration 3 (12) 1 (4) 3 (12) 0 6 (12) 1 (2) Dysgeusia 3 (12) 0 1 (4) 0 4 (8) 0 Headache 3 (12) 0 4 (17) 0 7 (14) 0 Peripheral edema 3 (12) 0 2 (8) 0 5 (10) 0 Tachycardia 3 (12) 0 0 0 3 (6) 0 Pain 2 (8) 0 3 (12) 0 5 (10) 0 Infusion-related reaction 1 (4) 0 6 (25) 1 (4) 7 (14) 1 (2) Weight decreased 1 (4) 0 4 (17) 0 5 (10) 0 Chills 0 0 3 (12) 0 3 (6) 0 Epistaxis 0 0 3 (12) 0 3 (6) 0 Hypertension 0 0 3 (12) 3 (12) 3 (6) 3 (6) Inﬂuenza-like illness 0 0 3 (12) 0 3 (6) 0 Muscle spasms 0 0 3 (12) 0 3 (6) 0 Proteinuria 0 0 4 (17) 0 4 (8) 0

Note: Data are presented as n (%). Abbreviations: BEV, bevacizumab; IRI, irinotecan. aFTD/TPI 20–30 mg/m2 twice daily (days 1–5 every 14 days) þ IRI 120–180 mg/m2 (day 1 every 14 days). bFTD/TPI 25 mg/m2 twice daily (days 1–5 every 14 days) þ IRI 180 mg/m2 (day 1 every 14 days) þ BEV 5 mg/kg (day 1 every 14 days). cIncludes decreased neutrophil count. dIncludes decreased hemoglobin. eIncludes decreased leucocyte count.

Efficacy than 4 months. These 17 patients had received a median of four pre- No objective responses occurred in the dose-escalation phase. As the vious systemic regimens, with 16 having received previous irinotecan; dose-escalation phase included a heterogeneous population with one patient was irinotecan-na€ve. The median PFS was 7.9 months (95% respect to tumor types and dose levels and bevacizumab was not CI, 5.1–13.4 months; Fig. 2), and PFS rates at 6 and 12 months were included in the dosing, efficacy was not reported in further detail for 66% (95% CI, 42–82) and 37% (95% CI, 12–63), respectively. these cohorts. All 24 patients in the expansion cohort were evaluable for efficacy. Three patients (12%) had confirmed partial responses, two of whom Discussion had received previous irinotecan and one of whom was irinotecan na€ve. The results of this phase I trial demonstrated that FTD/TPI com- Seventeen patients (71%) had stable disease for a median duration of bined with irinotecan and bevacizumab was tolerable and showed 8.1 months, and 16 (67%) patients had stable disease lasting longer preliminary efficacy in patients with heavily pretreated mCRC. In the

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Table 3. Pharmacokinetics of triﬂuridine, tipiracil, and irinotecan.

Expansion cohort: FTD/TPI þ IRI þ BEVa Pharmacokinetic (n ¼ 18)b parameters Triﬂuridine Tipiracil Irinotecan

Cmax, ng/mL 3,362.78 1,702.89 93.41 36.11 3,159.44 699.33 AUC0–last,nghour/mL 5,321.19 1,782.95 362.96 139.80 12,861.12 3,779.76 AUC0–inf,nghour/mL 5,625.14 1,645.84 371.62 109.73 13,053.82 3,846.99 Tmax, hour 1.22 0.57 2.73 1.14 0.54 0.06 t1/2, hour 2.32 2.38 1.85 0.43 8.72 0.97 CL/F, L/hour 8.94 3.20 62.38 18.07 —

Vd/F, L 33.46 42.56 170.21 75.29 — CL, L/hour/m2 ——15.03 4.63 2 Vd, L/m ——187.75 54.81

Note: Data are presented as mean SD. Abbreviations: BEV, bevacizumab; CL, clearance; IRI, irinotecan. aFTD/TPI 25 mg/m2 twice daily (days 1–5 every 14 days) þ IRI 180 mg/m2 (day 1 every 14 days) þ BEV 5 mg/kg (day 1 every 14 days). bPharmacokinetic assessments were performed only in the ﬁrst 18 patients enrolled in the expansion cohort.

dose-escalation portion of the study, two DLTs were observed (grade 3 to treatment-related deaths. These results indicated an overall safety fatigue and grade 2 neutropenia), and the MTD for the doublet profile that was consistent with that of the individual agents, with no combination was defined as FTD/TPI 25 mg/m2 (administered twice unexpected safety concerns. daily on days 1–5 of a 14-day cycle) plus irinotecan 180 mg/m2 The pharmacokinetic assessment of the triplet combination regi- (administered on day 1 of a 14-day cycle) in patients with heavily men presented no notable changes from the pharmacokinetics of pretreated gastrointestinal tumors. single-agent FTD/TPI or irinotecan. The AUC0–inf values for FTD In the expansion phase, bevacizumab was added at 5 mg/kg (on day and TPI in the triplet combination regimen (5,625 and 372 nghour/ 1 of the 14-day cycle) to this regimen in patients with previously treated mL, respectively) were similar to those of single-agent FTD/TPI (at mCRC. The safety profile of the triplet combination, with respect to the 25 mg/m2/dose) in patients with solid tumors (4,297 and 222 nghour/ types and frequencies of AEs, was similar to that with the doublet mL, respectively; ref. 16). In addition, the mean clearance of irinotecan combination; any-grade serious AEs were reported in 38% of patients in the present study (15.03 L/hour/m2) was comparable with previ- in the expansion cohort and in 32% of patients in the overall popu- ously published data for single-agent irinotecan (19.3 L/hour/ lation. This finding indicated that the addition of bevacizumab did not m2; ref. 17). result in cumulative toxicity or in new safety concerns. The most Evidence of antitumor activity was noted with the triplet combi- common AEs of any-cause and grade were neutropenia, fatigue, nation in this heavily pretreated patient population, half of whom had nausea, and vomiting, and the most frequently occurring grade 3 received four or more previous systemic regimens. Preliminary efficacy AEs were hematologic (decreased neutrophil count and decreased results indicated partial responses in 12% of patients, stable disease in leucocyte count). However, AEs were managed using dosing mod- 71%, and a median PFS of 7.9 months in the expansion phase. For ifications, including dosing delays and interruptions, and there were no reference, in phase III second-line studies conducted in patients treatment-related AEs leading to the discontinuation of treatment or refractory to only one regimen for mCRC, FOLFIRI (leucovorin,

100 Figure 2. 90 PFS in the expansion cohort. The Kaplan–Meier curve of PFS in patients 80 treated with the FTD/TPI–IRI–BEV triplet combination in the expan- 70 sion cohort. BEV, bevacizumab; IRI, 60 irinotecan. 50

40 30 Median PFS (95% CI), months 20 7.9 (5.1–13.4)

Progression-free survival (%) 10 FTD/TPI–IRI–BEV 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time (months) Number of 24 24 21 18 16 15 13 9 41222 20 patients at risk

OF6 Clin Cancer Res; 2020 CLINICAL CANCER RESEARCH

Triﬂuridine/Tipiracil, Irinotecan, and Bevacizumab in mCRC

fluorouracil, and irinotecan) plus ramucirumab resulted in an objec- prior exposure; although, it is likely that better responses may be tive response rate (ORR) of 13.4% and median PFS of 5.7 months, observed in patients without prior exposure to irinotecan. whereas FOLFIRI plus aflibercept resulted in an ORR of 19.8% and In conclusion, the results of this dose-escalation/expansion study median PFS of 6.9 months (18, 19). The results in this study also indicate that the triplet combination of FTD/TPI, irinotecan, and compare favorably with those from phase III studies of regorafenib bevacizumab is feasible in patients with mCRC refractory to standard versus placebo (CORRECT and CONCUR), which were conducted in therapies and that further evaluation of this regimen is warranted in similar patient populations (40%–50% with four or more prior treat- this patient population. Given the standard use of bevacizumab– ment regimens). In CORRECT, the median PFS with regorafenib was fluoropyrimidine–irinotecan chemotherapy combinations in first- 1.9 months, with an ORR of 1.0%, and in CONCUR, the median PFS line mCRC, these results may also support future exploration of the was 3.2 months, with an ORR of 4% (20, 21). FTD/TPI–bevacizumab–irinotecan combination in earlier lines of It should be noted that the MTD and dosing schedule of FTD/TPI in treatment (2, 3, 14). this study (25 mg/m2 twice daily on days 1–5 of a 14-day cycle) differ 2 from the approved monotherapy dose and schedule (35 mg/m twice Disclosure of Potential Conflicts of Interest – – daily on days 1 5 and 8 12 of a 28-day cycle; ref. 10). The dose and A.M. Varghese is an employee/paid consultant for Roche, and reports receiving schedule for the triplet combination was selected on the basis of earlier other commercial research support from Illumina, Lilly, Bristol-Myers Squibb, and preclinical studies and the results of an initial phase I Japanese study, Silenseed. A.B. Benson is an employee/paid consultant for Envision, Guardant, Dava which evaluated the FTD/TPI–irinotecan combination in 10 patients Onc, Bayer, LSK, Therabionic, Terumo, Lexicon, Incyte, ACCC, and Bristol-Myers – Squibb, and reports receiving commercial research grants from Acerta, Celegene, with mCRC refractory to 5-FU and oxaliplatin (11 13). In the Japanese fi – 2 Advanced Accelerator Applications, Novartis, In nity Pharmaceuticals, Merck Sharp study, patients were administered 40 70 mg/m twice daily FTD/TPI and Dohme, Taiho Pharmaceuticals, Bristol-Myers Squibb, Medimmune/AstraZe- – – fi (on days 1 5 and 8 12 of a 28-day cycle) and a xed dose of irinotecan neca, Xencor, PreECOG, Astellas, Amgen, ECOG-ACRIN, and SynCore. H.S. 2 (150 mg/m on days 1 and 15). However, the standard FTD/TPI dosing Hochster is an employee/paid consultant for Taiho, Bayer, and Genentech. L. Makris schedule resulted in delayed myelotoxicity in that study: although and K. Hamada are employees/paid consultants for Taiho Oncology. J.D. Berlin is preliminary activity was observed, all patients experienced grade 3 an employee/paid consultant for LSK biopharma and Bayer, and reports receiving fl hematologic AEs (13). On this basis, lower starting doses of FTD/TPI commercial research grants from Taiho and Bayer. No potential con icts of interest were disclosed by the other authors. were used in this study, and the FTD/TPI dosing schedule was adjusted to accommodate irinotecan dosing using a biweekly schedule, which ’ maintains the same dose intensity as the standard regimen (28-day Authors Contributions cycle). At the recommended dose in the expansion cohort, lower Conception and design: A.M. Varghese, A.B. Benson, L. Makris, K. Hamada, L.B. Saltz frequencies of grade 3 hematologic AEs were observed, supporting Development of methodology: A.M. Varghese, L. Makris, K. Hamada, L.B. Saltz the current dose and dosing schedule. Acquisition of data (provided animals, acquired and managed patients, provided The results of this study were also consistent with recent phase I facilities, etc.): A.M. Varghese, D.B. Cardin, J. Hersch, A.B. Benson, H.S. Hochster, reports of other FTD/TPI combinations in mCRC, although FTD/ J.D. Berlin, L.B. Saltz TPI was dosed at a lower level in the triplet combination than in Analysis and interpretation of data (e.g., statistical analysis, biostatistics, the other combination regimens (22–25). In a phase I/II study computational analysis): A.M. Varghese, H.S. Hochster, L. Makris, K. Hamada, J.D. Berlin, L.B. Saltz of FTD/TPI plus bevacizumab in refractory mCRC, the recom- 2 Writing, review, and/or revision of the manuscript: A.M. Varghese, mended phase II dose was FTD/TPI 35 mg/m (twice daily on D.B.Cardin,J.Hersch,A.B.Benson,H.S.Hochster,L.Makris,K.Hamada, days 1–5and8–12 of a 28-day cycle) and bevacizumab 5 mg/kg J.D.Berlin,L.B.Saltz every 2 weeks (24). Three dose-escalation studies of FTD/TPI Administrative, technical, or material support (i.e., reporting or organizing data, and oxaliplatin in patients with previously treated mCRC arrived constructing databases): J. Hersch, L. Makris, K. Hamada, J.D. Berlin at a MTD of FTD/TPI 35 mg/m2 (twice daily on days 1–5ofa14- Study supervision: A.M. Varghese, J.D. Berlin, L.B. Saltz day cycle) plus oxaliplatin 85 mg/m2 (on day 1 of a 14-day cycle; refs. 22, 23, 25). These studies showed manageable safety Acknowledgments and preliminary antitumor activity of the FTD/TPI-containing This study was sponsored by Taiho Oncology, Inc. and Taiho Pharmaceutical Co., regimens in patients with previously treated mCRC (22–25). Ltd. Medical writing and editorial assistance were provided by Vasupradha Vethan- tham, PhD and Lilly Ostrovsky of Scientific Connexions and funded by Taiho The main limitation of this study was the nature of the analysis: this Oncology, Inc. was a nonrandomized study with a small sample size. As only 24 patients were enrolled in the dose-expansion phase, no formal statis- The costs of publication of this article were defrayed in part by the payment of page tical analysis was performed to assess efficacy. In addition, as part of the charges. This article must therefore be hereby marked advertisement in accordance study design, nearly all patients enrolled in the study had been with 18 U.S.C. Section 1734 solely to indicate this fact. previously treated with and had tolerated irinotecan. It is unclear whether similar efficacy/tolerability would be observed in a patient Received October 3, 2019; revised November 22, 2019; accepted January 7, 2020; population with a higher incidence of irinotecan resistance or without published first January 10, 2020.

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OF8 Clin Cancer Res; 2020 CLINICAL CANCER RESEARCH

Phase I Study of Trifluridine/Tipiracil Plus Irinotecan and Bevacizumab in Advanced Gastrointestinal Tumors

Anna M. Varghese, Dana B. Cardin, Jonathan Hersch, et al.

Clin Cancer Res Published OnlineFirst January 10, 2020.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-19-2743

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