PHASE II STUDIES

A phase II study of S-1 plus irinotecan and oxaliplatinin heavily-treated patients with metastatic colorectal cancer

Sun Young Kim & Yong Sang Hong &

Byung Chang Kim & Ji Won Park & Hyo Seong Choi &Seung-Yong Jeong & Dae Yong Kim &

Chang Won Hong & Dae Kyung Sohn & Kyung Hae Jung

Received: 25 July 2008 /Accepted: 3 September 2008 /Published online: 25 September 2008# Springer Science + Business Media, LLC 2008

Summary Three-drug combination of fluoropyrimidine,irinotecan and oxaliplatin has shown survival benefits inpatients with metastatic colorectal cancer (mCRC). Recent-ly we performed a phase II study of a new 3-drug regimen,TIROX (S-1 plus irinotecan and oxaliplatin) to evaluateefficacy and safety in refractory mCRC patients. Patientswith refractory to all of 3 drugs, age ≥18 years, PS 0–2, ≥1measurable lesion(s) and adequate organ functions wereeligible. S-1 was given 40 mg/m2 twice a day on D1–14,oxaliplatin 85 mg/m2 and irinotecan 150 mg/m2 on D1every 3 weeks. The primary endpoint was overall responserate (ORR). Between Mar 2007 and Nov 2007, 19 patients(of 18 planned) were enrolled; median age 50 years; M/F12/7; PS 0/1/2 5/13/1; colon/rectum 11/8. By intent-to-treatanalysis, ORR was 21.1% (95% CI, 8.7–43.7) and diseasecontrol rate was 52.6% (95% CI 31.5–72.8) with four PRsand six SDs. Median duration of disease control was4.3 months (95% CI 1.7–6.9). Median PFS was 2.6 months(95% CI 2.2–2.9) and median OS was 9.8 months (95% CI5.3–14.4) after median F/U of 15.4 months. G3/4 toxicitiesper pt included neutropenia (five, 26.3%), febrile neutropenia(two, 10.5%), thrombocytopenia (one, 5.3%), diarrhea (two,10.5%) and fatigue (two, 10.5%). TIROX seemed to befeasible and efficacious for refractory mCRC patients, andcould be an alternative for patients with good PS but no furthertreatment options.

Keywords S-1 . Irinotecan . Oxaliplatxin . Colorectal cancer

AbbreviationsmCRC metastatic colorectal cancerPS performance statusORR overall response ratePFS progression-free survivalOS overall survivalPR partial responseSD stable disease

Introduction

With advances in systemic therapy for metastatic colorectalcancer (mCRC), the survival of the patients has beenprolonged from 6 months, if untreated, to more than20 months with combination chemotherapy including bio-logics [1]. However, a considerable portion of patients withmCRC may still survive with good performance status (PS)despite progression on all available cytotoxic agents—fluoropyrimidine, irinotecan and oxaliplatin. In Korea, Na-tional Healthcare Insurance does not pay the cost ofbiologics used for mCRC, so these refractory patients havelittle treatment option.

Irinotecan, oxaliplatin and 5-fluorouracil (5-FU) havedifferent mechanisms of actions and non-overlapping toxic-ity profile. In several preclinical studies, there was therapeu-tic synergism or additive effect between irinotecan and 5-FU,oxaliplatin and 5-FU, and irinotecan and oxaliplatin [2–6].Furthermore, the triple-combination regimen of 5-FU/irinotecan/oxaliplatin showed survival benefits with favor-able toxicity profiles in untreated population and wasexplored in some trials including irinotecan- or oxalipla-tin-pretreated patients [7, 8]. For heavily treated but still

Invest New Drugs (2009) 27:269–274DOI 10.1007/s10637-008-9177-5

S. Y. Kim :Y. S. Hong (*) :B. C. Kim : J. W. Park :H. S. Choi :S.-Y. Jeong :D. Y. Kim :C. W. Hong :D. K. Sohn :K. H. JungCenter for Colorectal Cancer, Research Institute and Hospital,National Cancer Center,111 Jungbalsan-ro, Ilsandong-gu, Goyang-si,Gyeonggi-do 410-769, Republic of Koreae-mail: yshong@ncc.re.kr

medically fit patients, overcoming chemoresistance withcombination of previously failed drugs may bring clinicalbenefits.

In our institute, the TIROX regimen (S-1 plus irinotecanand oxaliplatin) was studied in a dose-finding phase I studyincluding both colorectal and gastric cancer patients [9],and also a phase II trial for untreated mCRC patients isongoing. In the preliminary results of phase I study, favorableresponses and acceptable toxicity profiles were observedeven in patients with heavily pretreated mCRC.

Based on these promising results, we also planned anotherphase II trial of S-1 plus irinotecan and oxaliplatin toevaluate the efficacy and toxicity for patients who had beenalready exposed and refractory to all three drugs.

Patients and methods

Patient selection

We enrolled patients who met the following eligibilitycriteria: adenocarcinoma of the colon or rectum, unresect-able or metastatic disease, age at least 18 years, EasternCooperative Oncology Group (ECOG) PS of 2 or lower,one or more measurable lesions as defined by ResponseEvaluation Criteria in Solid Tumors (RECIST) criteria,previous failure to all of fluoropyrimidine, oxaliplatin andirinotecan, adequate hematologic parameters (absolute neu-trophil count ≥1,500/mm3 and platelet count ≥100,000/mm3),serum bilirubin ≤2.0 mg/dl, AST and ALT ≤3 times ofnormal values (≤5 if liver metastases), and serum creatinine≤1.5 mg/dl. Previous failure to a certain chemotherapeuticagent was defined as progression during the treatment orwithin 6 months from the last dose of the drug. Exclusioncriteria were active uncontrolled infection, pregnant orbreast-feeding women, and symptomatic cardiac disease.Patients were also excluded if they had any unresolvedtoxicity, including peripheral neuropathy, which was morethan grade 2 from previous treatment. Brain metastases werepermitted if neurologic symptom was controlled with radio-therapy and systemic corticosteroid.

The study was conducted in accordance to Helsinkideclaration and to Good Clinical Practice guideline, andpatients were provided their informed consent before regis-tration onto the study. The protocol was approved by theInstitutional Review Board of National Cancer Center, Korea(protocol number NCCNCS-08-118).

Study treatment

Patients were planned to be treated with irinotecan 150 mg/m2 followed by oxaliplatin 85 mg/m2 on day 1 and S-180 mg/m2/day from day 1 to 14 every 3 weeks. Reduced

starting doses of irinotecan (130 mg/m2), oxaliplatin(60 mg/m2) and S-1 (60–70 mg/m2/day) were applied tothose with prior abdomino-pelvic or spinal irradiation, historyof grade 4 neutropenia or any grade febrile neutropenia duringprevious chemotherapy, or ECOG PS of 2. Antiemeticpremedication with serotonin antagonists and dexamethasonewas given before chemotherapy, and subcutaneous atropinewas routinely used to prevent cholinergic syndrome byirinotecan. Patients were instructed to manage late diarrheaby loperamide; 2 mg of loperamide every 2 h until morethan 12 h have passed after the last loose stool. Colonystimulating factors were not planned to be used routinely,unless febrile neutropenia or documented infection withneutropenia occurs.

Treatment continued until disease progression or unac-ceptable toxicity. In the presence of grade 2 or more events,treatment was withheld until absolute neutrophil count≥1.5×109/l, platelets ≥75×109/l, and recovery from non-hematologic toxicity to baseline or grade 1. In case of grade3 or 4 toxicities, treatment was resumed with reduced doseafter resolution of toxicity.

Evaluation criteria

Responses were evaluated every two cycles according toRECIST criteria. All enrolled patients were included in theintention-to-treat analysis for efficacy and all responsesrequired confirmation at 4 weeks or later. Adverse eventswere evaluated according to National Cancer InstituteCommon Toxicity Criteria version 3.0.

Statistical analyses

The sample size was calculated according to Simon’sMinimax two-stage sequential design. A targeted objectiveresponse rate was 25%, and an objective response rate ofno interest was a 5%. Type 1 error rate of 5% and a powerof 80% were chosen. Assuming 10% of follow up loss, atleast of 18 patients were planned to be accrued for thisstudy.

All patients who received at least one course of therapywere considered assessable for toxicity, and all eligiblepatients who received at least one cycle of therapy wereincluded for survival estimation. Efficacy analysis wasperformed on the intention-to-treat (ITT) population, andprogression-free survival (PFS) and overall survival (OS)were estimated by the Kaplan–Meier method. OS wasmeasured from the start of TIROX until death, censoringpatients who had not died at the date of last follow up.PFS was defined as time from the date of treatmentbeginning to the date of progressive disease, censoringpatients without progression at the date of last diseaseassessment.

270 Invest New Drugs (2009) 27:269–274

Results

Patient characteristics

Between March 2007 and November 2007, a total of 19patients were enrolled in the study. The median follow upduration was 15.4 months (range 9.5–17.4). The baselinecharacteristics of the patients were described in Table 1.The study patients were relatively young (median age of

50 years) and extensively treated population whose mediansurvival from initial diagnosis of mCRC to TIROX was20.9 months. Their maximum responses to previous irinote-can and oxaliplatin were shown in Table 2. Patients who werepreviously treated with cetuximab and/or bevacizumab (9/19,47.4%) were also included. TIROX was their third linetreatment in three (15.8%), fourth in 13 (57.9%) and ≥5th inthree patients (15.8%). Most patients maintained ECOG PS 0or 1, despite of previous treatment and long disease course.Baseline peripheral neuropathy was noted in 15 out of 19patients (78.9%) and all were grade 1.

Efficacy assessment

By August 2008, all patients had progressive disease onTIROX and 14 patients were deceased. One patient was lostto follow up after the first cycle followed by grade 3infectious diarrhea, so tumor response was evaluable inremaining 18 patients. The objective response and PFS ofeach patient are summarized in Table 2. There was nocomplete response, and partial responses (PR) were ob-served in four patients with the median duration of responseof 4.8 months (95% CI 2.7–6.9). Another six patientsachieved stable disease (SD), with the median duration ofdisease control of 4.3 months (95% CI 1.7–6.9). Accordingto intention-to-treat analysis, the objective response ratewas 21.1% (95% CI 8.7–43.7) and disease control rate(PR+SD) was 52.6% (95% CI 31.5–72.8). The responseto TIROX was not associated with previous responses toirinotecan or oxaliplatin. Only one patient responded toTIROX among six responders to irinotecan, and none ofnine responders to oxaliplatin showed response to TIROX(Table 2). The median PFS was 2.6 months (95% CI 2.2–2.9) and the median OS was 9.8 months (95% CI 5.3–14.4) with 6-month survival of 73.7% (Fig. 1).

Safety assessment

All 19 patients were assessable for toxicity. A total of 57courses were administered with a median number of twocourses (range 2–7). Forty-three of 57 cycles (75%) wereadministered with reduce dose, and 18 cycles (32%) weredelayed due to toxicity. Six out of 19 patients were initiallytreated with reduced starting doses because of history ofprior radiotherapy or previous chemotherapy-inducedgrade 3/4/febrile neutropenia. These upfront reductionswere the most part (20 out of 43 cycles, 47%) of dosereductions. The most common cause for delay wasneutropenia (11 out of 18 cycles, 61%). Actual delivereddose in median was 267 mg/m2/week (relative doseintensity (RDI) 71.5%) for S-1, 40 mg/m2/week (RDI80.8%) for irinotecan and 21 mg/m2/week (RDI 75.0%)for oxaliplatin, respectively.

Table 1 Patient characteristics (N=19)

Characteristic No. of patients (%)

Age—yearMedian (range) 50 (31–63)SexFemale 7 (36.8)Male 12 (63.2)ECOG performance Status0 5 (26.3)1 13 (68.4)2 1 (5.3)Site of primary cancerRectum 8 (42.1)Colon 11 (57.9)HistologyWell differentiated 2 (10.5)Moderately differentiated 16 (84.2)Mucinous 1 (5.3)No. of chemotherapy regimens3 3 (15.8)4 11 (57.9)≥5 3 (15.8)Irinotecan+fluoropyrimidine 19 (100.0)Oxaliplatin+fluoropyrimidine 19 (100.0)Capecitabine 16 (84.2)Bevacizumab 4 (21.1)Cetuximab 7 (36.8)Survival since metastatic disease—monthsMedian (range) 20.9 (5.1–51.4)Site of metastasisLiver 13 (68.4)Lung 14 (73.7)Lymph nodes 3 (15.8)Brain 1 (5.3)No. of metastatic sites1 2 (10.5)2 7 (36.8)3 5 (26.3)≥4 5 (26.3)Baseline neuropathyNo 4 (21.1)Yes (all grade 1) 15 (78.9)Baseline CEA—ng/mlMedian (range) 87.8 (3.6–3247.7)

ECOG Eastern Cooperative Oncology Group, CEA carcinoembryonicantigen

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The toxicity profile is presented in Table 3. Twelvepatients (63.2%) experienced grade 3 to 4 toxicity, but fourof them had only asymptomatic hematologic toxicities. Themost common grade 3 or 4 toxicity was neutropenia (5,26.3%) and infection (5, 26.3%). Grade 3 or 4 infectionincluded neutropenic infection (typhlitis) in one patient andnon-neutropenic infections in 4 patients (cholangitis, pneu-monia, cystitis and infectious diarrhea), which were associ-ated with underlying disease or had uncertain relationshipwith chemotherapeutic agents. There was no treatment-related death, and the 60-days mortality rate was 0%.

Discussion

The present study showed that the TIROX regimen, anactive three-drug combination, showed promising activityeven in patients who were refractory to all three drugs

(fluoropyrimidine, irinotecan, and oxaliplatin). Responserate of 21.1% for refractory patients are strikingly high,considering the study population consisted of extremelyheavily treated patients, of whom more than 80% had beentreated with four or more regimens of chemotherapy.

Currently, we can say that the standard chemotherapeuticregimen for patients who are refractory to all three drugs isthe combination of cetuximab plus irinotecan, whichproduce objective response in 22.9% in irinotecan-pretreatedpatients. Response rate in irinotecan and oxaliplatin-pretreated subgroup was 22.2%, which was similar with thatof the whole population [10]. In this study, the response rateof the three-drug regimen was comparable with that ofcetuximab plus irinotecan, so TIROX was shown to be alsoan active chemotherapeutic regimen in heavily-treatedmCRC patients.

The rationale for combination of previously failed drugis based on the synergism between the drugs. Resistance to

Table 2 Best response to pre-vious treatment and TIROX(present regimen)

M male, F female, PR partialresponse, SD stable disease,PD progressive disease, NA notassessable

PatientID

Age Sex Lines of treatment formetastatic disease

Best response toprevious treatment

Best responseto TIROX

PFS(months)

Irinotecan Oxaliplatin

1 F 31 5 SD PR PD 1.92 F 54 4 PR PD SD 4.63 M 50 5 SD PD PD 0.94 F 62 4 PD PR SD 4.35 F 37 4 PD SD PR 5.76 M 42 3 PR SD SD 2.77 M 49 4 NA PD PD 2.48 M 43 4 PR PR PD 2.49 F 57 4 PR SD PR 4.810 M 51 4 NA SD SD 2.611 F 44 3 SD PR NA 2.512 M 48 5 SD PR SD 2.913 M 50 4 PR PR PD 1.414 M 50 6 NA PR SD 5.715 M 63 4 SD PD PR 5.116 M 61 4 NA PR PD 1.217 F 53 6 NA PD PR 3.018 M 59 3 PD PD PD 1.319 M 51 4 PR PR PD 2.4

Fig. 1 Progression-free survivaland overall survival of allpatients (n=19)

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fluoropyrimidine is thought to be caused by induction ofthymidylate synthase (TS), the target enzyme of 5-FU.Fluoropyrimidine resistance might be overcome by addingoxaliplatin, which showed reversal of TS induction inpreclinical studies [5]. Irinotecan is known to exert its actionwith 5-FU in cell cycle-dependent manner: irinotecaninduces G2/M phase arrest and increases S phase fractionof tumor cells, which is the target of DNA incorporation by5-FU [3]. Synergism between irinotecan and oxaliplatin alsowas demonstrated: topoisomerase I inhibition by SN-38, theactive metabolite of irinotecan, resulted in delayed reversionof oxaliplatin-induced DNA inter-strand cross-links, andcytotoxicity analysis elicited synergy between the two drugsin human colon cancer HT29 cell line [6].

Based on these preclinical data, several trials whichaimed to attenuate chemoresistance using all active drugstogether in mCRC were conducted, however, the results wereunfavorable. Garufi et al. showed 20% response rate withcombination of irinotecan, oxaliplatin, 5-FU and leucovorinamong 35 mCRC patients, but none of the 15 patientspreviously treated both irinotecan and oxaliplatin achievedobjective response [11]. Levi et al. conducted a pilot trial ofirinotecan/oxaliplatin/5-FU/leucovorin in 32 pretreatedpatients (all pretreated with oxaliplatin; 91% pretreated withirinotecan), and partial response was observed in 5.6%(chronomodulated infusion) to 7.1% (standard infusion)[12]. Although the 3-drug regimen (irinotecan, oxaliplatinand fluoropyrimidine) was highly active in untreated mCRCpatients [13–15], its efficacy has been uncertain in extremelypretreated patients.

In our study, a new triple-combination regimen, irinotecan/oxaliplatin/S-1 (TIROX) was used, and the response rate washigher as compared with those of other studies on similarthree-drug combination in refractory patients. Of course the

results of the present study might be largely affected byselection bias; our study involved highly selected patients,who had good PS even after previous long duration ofchemotherapy. They were already long term survivors beforethe study entry; the median duration from diagnosis ofmetastatic disease to the study entry was more than20 months. The study patients might have tumors withmore indolent and favorable biology compared to generalpopulation with mCRC. However, the favorable efficacy ofTIROX may be ascribed to incorporation of S-1, which is anew oral fluoropyrimidine including potent dihydropyrimi-dine dehydrogenase (DPD) inhibitor. S-1 consists of tegafur,the prodrug of 5-FU with two biomodulators, 5-chloro-2, 4-dihydroxypyridine (CDHP) and potassium oxonate. CDHP, apotent inhibitor of 5-FU degradating enzyme (DPD) mighthave a role for maintaining high 5-FU concentration andenhances antitumor effect [16]. Some preclinical studieshave demonstrated more potent activity of S-1 comparedto other fluoropyrimidine: S-1 inhibited cellular growthand TS expression in 5-FU-resistant cell lines [17], and anti-tumor effect was even higher than UFT in an orthotopichuman colon cancer model [18]. Clinical studies alsoshowed activity of S-1 in untreated colorectal cancer [19,20], as well as in refractory cases. In phase I trials of S-1,including our phase I TIROX trial, heavily treated casesoften respond to S-1 or S-1 containing regimen [9, 21].Monotherapy with S-1 was highly active for even irinotecan-and oxaliplatin-pretreated patients with mCRC in a phase IItrial [22]. The precise mechanism of clinical potency of S-1is uncertain. Although S-1 might overcome 5-FU resistancecaused by TS overexpression, there are no preclinical studiesdescribing activity of S-1 in irinotecan- or oxaliplatin-pretreated tumor. However, DPD inhibition by CDHP mightprovide stable pharmacokinetic profile and restore synergis-tic effect with irinotecan or oxaliplatin compared to otherfluoropyrimidines. Thus the triple combination with S-1could be remarkably active compared to previously explored5-FU containing three-drug regimens.

Despite of the high response rate, the median PFS of2.6 months with TIROX was somewhat insufficient,compared to 4.1 months of cetuximab plus irinotecan and3.5 months of bevacizumab plus 5-FU/leucovorin in refrac-tory mCRC patients [10, 23]. Maybe suboptimal doseintensity due to frequent dose reduction or delay may beresponsible for decreased durability of response. Neverthe-less, at least TIROX seems to achieve more durable responsethan cetuximab alone, of which the median PFS rangedfrom 1.5 to 1.9 months [10, 24].

Toxicity of TIROX was generally tolerable and manage-able. Grade 3 or 4 toxicities occurred in more than 60%of patients as a total, but the majority of them wereasymptomatic hematologic toxicities or non-neutropenicinfectious episodes, which were unlikely to be related

Table 3 Maximum toxicity per patient (N=19)

Event Any grade Grade 3/4No. of patients (%) No. of patients (%)

Leukopenia 10 (52.6) 3 (15.8)Neutropenia 11 (57.9) 5 (26.3)Anemia 15 (78.9) 2 (10.5)Thrombocytopenia 5 (26.3) 1 (5.3)Febrile neutropenia 1 (5.3) 1 (5.3)Hyperbilirubinemia 7 (36.8) 2 (10.5)Neuropathy 18 (94.7) 0 (0.0)Fatigue 18 (94.7) 2 (10.5)Anorexia 17 (89.5) 1 (5.3)Nausea 15 (78.9) 1 (5.3)Vomiting 13 (68.4) 1 (5.3)Stomatitis 8 (42.1) 0 (0.0)Abdominal pain 7 (36.8) 0 (0.0)Infection 6 (31.6) 5 (26.3)Diarrhea 6 (31.6) 2 (10.5)

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with study treatment. However, in current study, smallamount of treatment exposure (median two cycles wereadministered) and lower RDI should be considered, andfor all intents, use of triple-combination chemotherapyin heavily treated patients could be a threat to theirquality of life. Cautious selection of patients with goodPS and little comorbidity would minimize the toxicityof TIROX.

In conclusion, TIROX for heavily treated mCRC patientswas feasible, and demonstrated high response rate andmodest PFS. Toxicity of the regimen was generally tolerable.Though all study patients had failed to both irinotecan andoxaliplatin, the synergism between the drugs and integrationof a newer oral fluoropyrimidine, S-1, might have augment-ed antitumor effect of TIROX. Refractory patients but withfine general conditions could be candidates for TIROXregimen.

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