Original Study

A Phase I Study of Irinotecan, Capecitabine

(Xeloda), and Oxaliplatin in Patients With
Advanced Colorectal Cancer
Jean Maroun,1 Horia Marginean,2 Derek Jonker,3 Christine Cripps,3 Rakesh Goel,3
Timothy Asmis,3 Rachel Goodwin,3 Gabriela Chiritescu4
Abstract
This was a phase 1 trial to determine the recommended phase 2 dose, safety and efficacy of oxaliplatin fol-
lowed by irinotecan and capecitabine given every 3 weeks as a triple combination (IXO regimen) in patients
with unresectable mCRC. IXO administered every 3 weeks as first-line therapy for mCRC is active by improving
response rate and survival.
Background: The objective of the present phase I study was to define the dose-limiting toxicities (DLTs) and maximum
tolerated dose (MTD) of irinotecan, capecitabine, and oxaliplatin given in combination (IXO regimen) to patients with
previously untreated, unresectable advanced or metastatic colorectal cancer (CRC). Patients and Methods: Patients
received oxaliplatin followed by irinotecan as intravenous infusions on day 1, with oral capecitabine taken twice daily
(BID) on days 2 to 15 of a 3-week cycle. The dose ranges were explored as follows: oxaliplatin, 75 to 120 mg/m2;
irinotecan, 160 to 230 mg/m2; capecitabine, 750 to 1000 mg/m2 BID. Dose escalation was performed individually
for each drug at each dose level according to the type and severity of toxicity encountered in the previous cohort.
Results: A total of 39 patients were enrolled at 7 dose levels and the MTD. The recommended doses for phase II
evaluation were oxaliplatin 100 mg/m2, irinotecan 160 mg/m2, and capecitabine 950 mg/m2 BID. Diarrhea and febrile
neutropenia were DLTs. Of the 39 enrolled patients, 26 (67%) had confirmed objective responses. The median
progression-free survival was 11 months, and the median overall survival was 25 months. The survival rate at 5 years
was 23%. Conclusion: The IXO regimen has a manageable toxicity profile with promising antitumor activity as first-line
treatment of advanced and metastatic CRC.

Clinical Colorectal Cancer, Vol. 17, No. 2, e257-68 ª 2017 The Authors. Published by Elsevier Inc. This is an open access
article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Advanced CRC, IXO regimen, Metastatic colorectal cancer, Phase 1, Triple combination

Introduction strategies need to be explored. Improved outcomes have been

Although the prognosis is poor for patients with unresectable
metastatic colorectal cancer (mCRC),1 no new cytotoxic drugs have
been developed or approved since the early 2000s. New treatment
1
Department of Medicine, University of Ottawa
2
Clinical Research
3
Division of Medical Oncology, Department of Medicine, University of Ottawa, The
Ottawa Hospital Regional Cancer Centre, Ottawa, ON, Canada
4
Digestive Oncology Unit, Department of Gastroenterology, Universitair Ziekenhuis
Leuven, Leuven, Belgium
Submitted: Apr 5, 2017; Revised: Nov 13, 2017; Accepted: Dec 7, 2017; Epub:
Dec 15, 2017
Address for correspondence: Horia Marginean, MD, Clinical Research, The Ottawa
Hospital Regional Cancer Centre, Ottawa, ON K1H 8L6, Canada
E-mail contact: hmarginean@yahoo.com
obtained by combining and sequencing existing chemotherapeutic
agents. The Groupe Coopérateur Multidisciplinaire en Oncologie
(GERCOR) study2 demonstrated improved overall survival (OS) of
patients with mCRC by combining 2 cytotoxic agents. Furthermore,
a meta-analysis of phase III trials concluded that combination therapy
should be the standard of care for first-line treatment of patients with
advanced CRC.3,4 These findings have led to increased interest in
triple combinations with irinotecan, oxaliplatin, and fluoropyr-
imidines, supported by in vitro data that showed that previous in-
cubation of human colon cancer cell lines with oxaliplatin increased
irinotecan cytotoxicity.5 Two phase III studies comparing a triplet
combination regimen, FOLFOXIRI (irinotecan, oxaliplatin, 5-
fluorouracil [5-FU]/leucovorin), against a doublet, FOLFIRI (5-
FU, leucovorin, irinotecan), as first-line therapy for patients with

- e257
1533-0028/ª 2017 The Authors. Published by Elsevier Inc. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
https://doi.org/10.1016/j.clcc.2017.12.003 Clinical Colorectal Cancer June 2018
 Phase I Study of IXO for Advanced CRC
mCRC have reported conflicting results.6,7 The GONO (Gruppo
Oncologico Nord Ovest) trial reported improvements in the response
rate, progression-free survival (PFS), OS, and secondary resection rate
with the FOLFOXIRI regimen.6 However, the Hellenic Oncology
Research Group study,7 using lower doses of irinotecan (150 vs. 164
mg/m2) and oxaliplatin (56 vs. 85 mg/m2), and a different 5-FU
schedule did not observe the same results.
The main objective of the present study was to determine the
safety of oxaliplatin, followed by irinotecan and capecitabine
(Xeloda), given every 3 weeks as a triple combination (IXO regimen)
in patients with unresectable mCRC. The secondary objective
included assessment of the efficacy of this particular regimen.
Patients and Methods
Study Design
A phase I, single-arm, open-label study was conducted at The
Ottawa Hospital Cancer Centre (available at: www.
canadiancancertrials.ca; protocol identification no. OCT1162). The
Ottawa Hospital research ethics board approved the present study,
which was performed in accordance with the provisions of the
Declaration of Helsinki, International Conference on Harmo-
nisation, and Good Clinical Practice guidelines. The patients were
informed of the study and provided written informed consent before
enrollment. The CONSORT checklist is provided as supporting
information in Supplemental Figure 1 (in the online version).
Patients
Eligible patients were aged
18 years and had an Eastern
Cooperative Oncology Group performance status of  2, measur-
able disease using the Response Evaluation Criteria in Solid Tu-
mors, version 1.0,8 and histologically documented locally advanced
CRC or mCRC, which had been evaluated as unresectable. The
surgical unresectability was established through a multidisciplinary
evaluation, performed by medical and radiation oncologists and
colorectal and hepatobiliary surgeons. No previous chemotherapy
for advanced disease was allowed. Previous adjuvant therapy with
fluoropyrimidines, but not irinotecan or oxaliplatin, was permitted.
Adequate hematologic, renal, and hepatic function was required.
Treatment and Dose-escalation Protocol
We performed a phase I trial with a standard 3- to 6-patient
cohort design.9 All patients received the IXO regimen. The
3-week IXO cycle was based on the recommended capecitabine
monotherapy oral administration of 2 tablets twice daily (BID) for 2
weeks, followed by a 1-week rest period. Each cycle consisted of
oxaliplatin given as a 2-hour intravenous infusion, followed by a 60-
to 90-minute intravenous infusion of irinotecan on day 1, with oral
capecitabine BID given on days 2 to 15, every 3 weeks.
The starting dose was oxaliplatin 75 mg/m2, with increases in
5-mg/m2 increments; irinotecan 160 mg/m2, with increases in
10-mg/m2 increments; and capecitabine 750 mg/m2 BID, increased
to 850, 950, and 1000 mg/m2 BID. The sequence and magnitude
of the dosage increments during dose escalation were considered
independently for each drug, according to the type and severity of
toxicity encountered in the previous cohort.
Dose escalation was allowed between patient cohorts but not
within individual patients. The maximum tolerated dose (MTD)
e258 - Clinical Colorectal Cancer June 2018
was defined as the highest dose level (DL) at which  33% of
patients experienced a dose-limiting toxicity (DLT); the MTD was
recommended for further phase II evaluation.10
With the occurrence of IXO-related toxicities, dose reductions
were recommended before treatment delays. The dose adjustments
were consistent with the individual package labels. Treatment
continuation required recovery to toxicity grade  1. Once a drug
dose had been reduced for a patient, no dose re-escalation was
permitted. Treatment was discontinued in the case of serious or
unmanageable toxicity, by patient request, or by physician decision.
Otherwise, therapy was continued until the development of
progressive disease using the Response Evaluation Criteria in Solid
Tumors, version 1.8
Toxicity, DLT, and Tumor Response Evaluations
Screening included clinical history, physical examination, full
blood count, biochemistry panel, urinalysis, and creatinine clearance
(calculated using serum creatinine). Toxicity and laboratory test
results were assessed on day 1 of every treatment cycle. Hematology
was assessed weekly. Adverse events were evaluated continuously
from the start of study treatment until 30 days after the final dose of
study treatment. Toxicities were graded using the National Cancer
Institute Common Toxicity Criteria, version 2.0.11
The DLT evaluation period was limited to the first cycle (3 weeks)
of treatment. Hematologic DLTs were defined as an absolute
neutrophil count <0.5  109/L for
7 days, febrile neutropenia
(absolute neutrophil count < 1.0  109/L, fever
38.5 C), platelet
count < 50  109/L, and grade 3 thrombocytopenic bleeding.
Nonhematologic DLTs were defined as any grade 3/4 event
(excluding alopecia, nausea, vomiting, and transient transaminase
elevations), creatinine clearance < 40 mL/min, and grade
2
neurotoxicity for > 5 days.
The tumor response was evaluated using computed tomography
at baseline and every 6 weeks (every 2 IXO cycles) thereafter until
disease progression. Evaluable patients should have received
1
cycle of chemotherapy and had their disease reevaluated after study
treatment. After discontinuation of IXO, patients were assessed
every 3 months until disease progression.
Clinical antitumor activity was measured using the investigator-
assessed objective response rate (ORR), PFS, and OS. Responses
were confirmed
6 weeks after the initial computed tomography
scan had documented the reduction. The duration of response was
measured from the first documentation of a complete or partial
response until the first documentation of progressive disease or
death, whichever occurred first. PFS was defined as the interval from
enrollment until disease progression or death from any cause. OS
was defined as the interval from the day of enrollment until death.
Statistical Analysis
The present clinical trial was not powered for inferential statistical
analyses. Continuous variables were summarized using the median
and range. Categorical variables were summarized with numbers
and percentages. Waterfall plots were used to illustrate the tumor
response. ORRs are reported with 95% confidence intervals (CIs).
The median PFS and OS were obtained from the 50th percentile of
the estimated Kaplan-Meier survival rates and are presented with the
95% CIs.
 Jean Maroun et al
after a median of 4 cycles (range, 1-17 cycles) because of toxicity
Table 1 Baseline Patient and Disease Characteristics
(n [ 39) (neutropenia and diarrhea) and patient request. For 18 patients
(46%), the IXO schedule was changed from a 3- to a 4-week
Characteristic n (%) schedule after a median of 7 cycles (range, 1-18 cycles), mostly
Sex because of delays for neutropenia and diarrhea. The patients who
Male 31 (79) had undergone liver resection (n ¼ 10; 26%) had received a median
Female 8 (21) of 13 preoperative cycles (range, 4-31 cycles) and 3 postoperative
Age at enrollment, y cycles (range, 1-4 cycles). In addition, 23 patients (59%) received
Median 58 further lines of antineoplastic treatment.
Range 25-74
Dose Escalation
ECOG performance status
The dose-escalation steps, DLTs, and serious adverse events are
0 19 (49)
summarized in Table 2. The first patient at DL1 experienced a DLT
1 18 (46)
(febrile neutropenia with bowel perforation at the site of an unre-
2 2 (5)
sected primary tumor). We assessed DL1 as not tolerated, and all
Primary site drug doses were reduced by 10%. At DL2 (the new starting point
Colon 31 (79) for the dose escalations), 1 DLT of grade 3 diarrhea occurred. At
Rectum 8 (21) DL3, febrile neutropenia was documented in 1 patient. At DL4, 1
Adjuvant treatment patient experienced febrile neutropenia in cycles 2 and 3; the doses
No 28 (72) were not reduced for cycle 3, and the patient died of septic shock
Yes 11 (28) and aspiration. One patient died of a sudden stroke, which was
Disease site considered unrelated to treatment. No DLT occurred at DL5 or
Liver, limited 17 (44) DL6. At DL7, 1 patient experienced grade 3 dehydration. At DL8,
Liver, not limited 32 (82) the acceptable toxicity was exceeded, with 2 patients experiencing
Lung 12 (31) the same DLT of grade 3 diarrhea.
Lymph nodes 13 (33) In summary, the DLTs were grade 3 diarrhea (n ¼ 3), febrile
neutropenia (n ¼ 3), and grade 3 dehydration (n ¼ 1). The MTD
Other 14 (36)
and recommended phase II dose (RP2D) were oxaliplatin 100 mg/
Metastatic sites, n
m2, irinotecan 160 mg/m2, and capecitabine 950 mg/m2 BID. At
1 19 (49)
the RP2D, diarrhea and neutropenia were the main toxicities
2 11 (28)
(grade
2).
>2 9 (23)

Abbreviation: ECOG ¼ Eastern Cooperative Oncology Group. Safety and Tolerability

Results
Patient Characteristics
The baseline characteristics of the 39 patients enrolled are presented
in Table 1. The CONSORT flow diagram is provided as supporting
information in Supplemental Figure 2 (in the online version). One
patient, who had been enrolled in error while the study was on hold for
resolution of drug source issues, was notified and then agreed to
continue in the study. Patients discontinued study treatment for the
following reasons: disease progression (n ¼ 16); toxicity (neutropenia,
n ¼ 2; recurring grade 2/3 toxicity, n ¼ 1); death (n ¼ 2; 1 unrelated to
treatment); complete response (n ¼ 3); patient’s best interest (liver
resection, n ¼ 10; patient request after prolonged treatment, n ¼ 3;
clinical deterioration, n ¼ 1; and scheduled heart surgery, n ¼ 1).
Treatment Exposure
Overall, patients received 466 cycles. The median was 11 cycles
per patient (range, 1-34). Six patients (15%) received > 20 cycles.
The mean dose intensity was 85% for oxaliplatin, 90% for irino-
tecan, and 85% for capecitabine.
Of the 39 patients, 24 (61%) required
1 dose reduction after a
median of 3 cycles (range, 1-13 cycles) because of toxicity (diarrhea
and neutropenia). Also, 25 patients (64%) required
1 dose delay
Treatment-related toxicities and the proportion of patients
experiencing grade 1/2 and grade 3/4 events are shown in Table 3
and Figure 1, respectively. Of the 39 patients, 24 (61%)
experienced
1 grade 3/4 toxic event.
During dose escalation, the most commonly occurring hemato-
logic adverse events were neutropenia (n ¼ 37; 95%), anemia
(n ¼ 34; 87%), and thrombocytopenia (n ¼ 30; 77%; Table 3).
Although thrombocytopenia and anemia were generally grade 1 or 2
in severity, neutropenia tended to be of grade 2 or 3, with grade 4
events documented in 8 patients (21%).
The most common nonhematologic events were nausea or
vomiting (n ¼ 36; 92%), followed by neurosensory events (n ¼ 34;
87%), diarrhea (n ¼ 33; 85%), and fatigue (n ¼ 30; 77%; Table 3).
Most events were of grade 1 or 2 in severity (Figure 1). Grade 4
events were observed in only 2 patients (5%) and was febrile neu-
tropenia in both cases. Grade 2/3 diarrhea appeared to be related to
the irinotecan and capecitabine doses. Most neurosensory events
were grade 1 severity with only 3 grade 2 events (8%) and 1 grade 3
event (3%), despite the high number of oxaliplatin cycles admin-
istered. At the RP2D, 5 of 6 patients experienced grade 3 toxicities;
however, no grade 4 toxicities were observed. Of the 14 serious
adverse events reported in 12 patients (31%), most (57%) were
experienced by the 6 patients enrolled at the dose level that exceeded
the recommended dose (Table 2). Two patients died while receiving

Clinical Colorectal Cancer June 2018 - e259

 Phase I Study of IXO for Advanced CRC
the study medication; 1 death was considered treatment related
(febrile neutropenia in cycle 3).

SAEs, n
1
0
0
3
0
2
4
4
Efficacy
Thirty-eight patients were evaluable for response. One patient
had died of a stroke before the first response evaluation. The ORR
was 77% (95% CI, 63%-91%), with 6 complete responses (2
unconfirmed) and 24 partial responses (2 unconfirmed). A waterfall
Outcome

Deceased
Resolved
Resolved
Resolved

Resolved
Resolved
plot of the best tumor response is shown in Figure 2A.

NA
NA
The responses were achieved rapidly and observed after only 2
cycles of treatment, with confirmation or stabilization after 4 to 6
cycles (Figure 2B-D). The median time to the first response was 5.1
weeks. The median duration of response was 10.5 months (95% CI,
DLTs

Grade 3 dehydration (1) 9-12 months). The disease control rate (overall response and stable
Febrile neutropenia (1)a
Grade 3 diarrhea (1)a,b
Febrile neutropenia (1)

Febrile neutropenia (1)

Grade 3 diarrhea (2) disease) was 90% (95% CI, 80%-100%). Ten patients (26%)
underwent curative-intent surgery for metastases. The median PFS
Type (n)

None
None

was 11 months (95% CI, 9-15 months; Figure 3A). After a median
follow-up of 71 months (range, 1-81 months), 30 patients had died
and 9 were alive. The median OS was 25 months (95% CI, 18-36
months; Figure 3B). The 3- and 5-year survival rates were 33% and
23%, respectively.

Discussion
Administered
Total Cycles

The current treatment of patients with mCRC is the combination of

91
70
85
38
23
92
66
1

2 cytotoxic drugs.12,13 However, exposure to the 3 available cytotoxic

agents, fluoropyrimidines, oxaliplatin, and irinotecan, has provided
even better outcomes. The FOLFOXIRI triple combination, associ-
ated in a phase III study with greater survival rates, improved PFS,
Capecitabine BID

One patient experienced during grade 3 fatigue on day 1 of 30 minutes’ duration that was evaluated by study committee as not a DLT.

better responses, and a greater magnitude of responses,6 has been

recommended in National Comprehensive Cancer Network guide-
850
750
750
750
750
850
950
950

lines as level 2B evidence for the treatment of mCRC.

Table 2 Dose-escalation Steps, Doses, Dose-limiting Toxicities, and SAEs (n [ 39)

Since our IXO study began in 2004, with the last closeout visits
Abbreviations: BID ¼ twice daily; DLTs ¼ dose-limiting toxicities; NA ¼ not applicable; SAEs ¼ serious adverse events.

occurring in 2007, the therapeutic options have improved with

addition of systemic biologic targeted agents, although no comple-
Dose, mg/m2

mentary or alternative treatments have yet been found to be effec-

Oxaliplatin

tive in colon cancer. Moreover, the dose intensity and dose schedule
100
100
100
100
85
75
85
95

of the triplet chemotherapy-based regimens have continued to be

investigated for the first-line treatment of patients with mCRC.14
We believe that our research contributes to the better understand-
ing of the possible therapeutic opportunities and the limitations and
optimization of triplet chemotherapy regimens for patients with
Irinotecan

mCRC.
180
160
160
160
160
160
160
175

To the best of our knowledge, our IXO study has explored for
the first time a 3-week schedule of the combination of irinotecan,
capecitabine, and oxaliplatin. Previously reported studies of this
triple combination had investigated either 2-week15-20 or 5-week21
schedules. Our study has outlined the safety profile of the IXO
Patients, n

regimen for patients with mCRC. The RP2D of the IXO regimen
1
7
6
7
3
3
6
6

One patient was not assessable for DLT.

was irinotecan 160 mg/m2 and oxaliplatin 100 mg/m2 on day 1

every 3 weeks and capecitabine 950 mg/m2 BID starting on day 2
for 14 days. Diarrhea and febrile neutropenia were the main DLTs,
Recommended phase II dose.

consistent with other triple combination studies of irinotecan,

oxaliplatin, and fluoropyrimidines, including capecitabine,15,19
Dose Level

5-FU,22,23 and S-1.24 We continued to observe DLT-like toxicity

after the first cycle, supporting the recommendation of Postel-Vinay
et al25 to continue monitoring diligently for late severe toxicities
7c
1
2
3
4
5
6

after the RP2D had been defined.

b
a

e260 - Clinical Colorectal Cancer June 2018

 Jean Maroun et al
Table 3 Treatment-related Adverse Events Stratified by Dose Level and Grade (n [ 39)a

Patients, n
DL1 DL2 DL3 DL4 DL5 DL6 DL7 DL8 Total
(n [ 1) (n [ 7) (n [ 6) (n [ 7) (n [ 3) (n [ 3) (n [ 6) (n [ 6) (n [ 39)
Adverse Event 1/2 3/4 1/2 3/4 1/2 3/4 1/2 3/4 1/2 3/4 1/2 3/4 1/2 3/4 1/2 3/4 1/2 3/4
Hematologic
Neutropenia 0 1 3 4 3 3 2 4b 3 0 1 1 1 5b 2 4b 15 22
Anemia 0 1 7 0 4 1 7 0 1 0 3 0 6 0 4 0 32 2
Thrombocytopenia 0 1 6 0 4 0 5 1 2 0 2 0 5 1 3 0 27 3
Nonhematologic
Nausea and vomiting 0 0 6 1 5 2 6 1 3 0 3 0 6 1 5 1 34 2
Late-onset diarrheac 0 0 5 2 3 1 4 0 3 0 3 0 5 1 4 2 27 6
Abdominal pain/ 0 0 1 0 2 0 2 0 2 0 0 0 1 1 3 1 11 2
cramping
Fatigue 0 0 6 1d 2 0 4 0 3 0 3 0 4 2 5 0 27 3
e
Febrile neutropenia 0 1 0 0 1 0 2 0 0 0 2 0 1 0 0 0 7
Neurosensory 0 0 6 0 5 0 5 0 3 0 3 0 5 1 6 0 33 1
Neuromotor 0 0 1 0 1 0 1 0 1 0 1 0 1 0 2 0 8 0
Hand-foot syndrome 0 0 1 0 1 0 0 0 0 0 1 0 3 0 1 0 7 0
Skin flushing/ 0 0 1 0 2 0 1 0 0 0 0 0 1 0 3 0 8 0
cholinergic
Stomatitis 0 0 2 0 0 0 1 0 2 0 2 0 1 0 2 0 10 0

Abbreviation: DLT ¼ dose-limiting toxicity.

a
Worst grade per patient reported during treatment period.
b
One patient developed short-term neutropenia that was not considered a DLT.
c
Late onset defined as toxicity beginning > 24 hours after administration of irinotecan.
d
One patient experienced grade 3 fatigue for 30 minutes on day 1 that was evaluated by the treating physician and the primary investigator, and subsequently by the study monitoring committee, with
the conclusion that it was not a DLT; however, at the treating physician’s discretion, doses were reduced for cycle 2 as a protocol deviation.
e
One of the cases of febrile neutropenia resulted in the death of the patient.

Figure 1 Bar Graph Showing Proportion of Patients With Worst Toxicity. Grade (Gr.) 1/2 and 3/4 Adverse Events Were Scored Using the
Common Toxicity Criteria, Version 2.0, Attributed as “Possibly,” “Probably,” or “Definitely” Related to IXO (Irinotecan,
Capecitabine, Oxaliplatin) Treatment (n [ 39)

Neutropenia 38% 56%

18% Febrile Neutropenia
Anemia 5% 82%

Thrombocytopenia 8% 69%

Nausea/Vomiting 5% 87%

Diarrhea 15% 69%

Abdominal pain 5% 28%

Fatigue 8% 69%

Neurosensory 3% 84%

Neuromotor 0% 21% Gr. 3/4 Gr. 1/2

0 20 40 60 80 100
Proportion with adverse event %

Clinical Colorectal Cancer June 2018 - e261

 Phase I Study of IXO for Advanced CRC
Figure 2 Waterfall Plot of Patients With Advanced Colorectal Cancer Measuring the Maximum Percentage of Change From Baseline in
the Sum of the Longest Diameter for Target Lesions; D20% Marked by Red Line and L30% Marked by Green Line. (A)
Overall Maximum Percentage of Change for 38 Evaluable Patients (1 Patient Was Not Evaluable for Response). (B-D)
Percentage of Change in Target Lesions After Cycles 2, 4, and 6, Respectively

Grade 3/4 toxicities were observed in 61% of patients; most of
them occurred at the dose level above the RP2D. The most
common grade 3/4 toxicity was neutropenia, which was
encountered within the first 3 cycles. Neutropenia was the only
grade 4 event reported in our study, and 1 patient died as a result
of treatment-related febrile neutropenia identified after the third
cycle. Diarrhea, the most common dose-limiting nonhematologic
event, was of grade 2/3 severity. All other toxicities associated
with the IXO regimen were of mild to moderate severity. Despite
the large number of cycles received, a lower than expected fre-
quency of grade 3/4 oxaliplatin-associated neurotoxicity had
occurred, which could be accounted for by the reduced dose in-
tensity associated with a 3-week schedule and/or a switch from a
3- to 4-week schedule. The febrile neutropenic event in the first
patient enrolled in the study at DL1 and the pattern of the rate of
increase of grade 3/4 diarrhea and neutropenia, suggest that in our
triple combination, the escalation of irinotecan increased these
toxicities. The safety of IXO in our phase I study was manageable,
comparable to that of XELOXIRI (capecitabine, oxaliplatin, iri-
notecan),15 COI (capecitabine, oxaliplatin, irinotecan),18 FOL-
FOXIRI,6 or TIROX (S-1, irinotecan, oxaliplatin),24 achieved
through the use of ongoing monitoring and initiation of appro-
priate therapeutic and/or supportive care measures. Consistent
with other triple combinations in different tumors,26-28 careful
selection of patients with good performance status and ongoing
patient monitoring is warranted.
In the present IXO trial, the confirmed response rate was 67% (the
unconfirmed response rate was 77%), with disease control achieved in
nearly all patients (90%). The response to the IXO regimen was rapid,
attained after 2 cycles of treatment. Significant tumor downsizing was
observed during the first 6 cycles, after which the responses appeared
to be maintained. The median PFS was 11 months. Our results are
within the range of values reported by other phase I/II studies of
2-week IXO in terms of ORR and PFS.15,16,19,21
Despite the limitations, our data from a phase I trial are also
consistent with the results from first-line randomized controlled
studies of FOLFOXIRI. Of the 39 patients with unresectable
advanced CRC enrolled in our study, treatment with the IXO
regimen led to a median PFS of 11 months and median OS of 25
months. FOLFOXIRI in phase III trials6,7 led to a median PFS of 8
to 10 months and median OS of 22 to 23 months. IXO was also
associated with a high response rate of 67%; phase III trials of
FOLFOXIRI have reported a 43% to 66% response rate. Thus,
IXO use resulted in a 28% resectability rate and a favorable R0
resection rate of 18%; the R0 resection rate with FOLFOXIRI in
phase III trials was 15%.6,7 This is an important outcome from our
study, because the long-term follow-up data have shown that
patients who undergo radical resection will have prolonged survival,
with a 5- and 8-year survival rate of 42% and 33%, respectively.26
However, 1 limitation of our study was the small number of
patients with favorable predictive characteristics (ie, 95% patients
had an Eastern Cooperative Oncology Group performance status of

e262 - Clinical Colorectal Cancer June 2018

 Jean Maroun et al
Figure 3 (A) Progression-free Survival and (B) Overall Survival (n [ 39). Solid Line Represents Survival, Gray Lines Represent Upper
and Lower Boundaries of 95% Confidence Interval (CI) for Each Kaplan-Meier Curve, and Dotted Line Represents Median
Survival

Clinical Colorectal Cancer June 2018 - e263

 Phase I Study of IXO for Advanced CRC
0 or 1), which might explain why our outcomes are marginally
better than those observed in phase III trials.
In this context, the IXO regimen can be distinguished from
5-FUebased triple combination regimens (eg, FOLFOXIRI) by its
relative simplicity. The IXO regimen eliminates the need for venous
access and continuous 5-FU infusion, which could be more desirable
for many eligible patients, and reduces the administration costs.
Moreover, in contrast to the regimens delivered biweekly, such as
FOLFOXIRI, IXO given every 3 weeks appeared to be associated with
a lower frequency of oxaliplatin-associated neurotoxicity.
The realization has been increasing that the triple combination
will benefit patients with gastrointestinal tumors. Further evalua-
tions have been conducted in patients with mCRC in combinations
with bevacizumab,29,30 neoadjuvant rectal cancer (unpublished
data), or metastatic gastric cancer.31,32
Conclusion
IXO administered every 3 weeks as first-line therapy for mCRC is
highly active by improving the response rate and survival. However, this
results in increased toxicity, including neurotoxicity and neutropenia.
However, the toxicity was manageable through dose adjustments.
Switching from a 3- to 4-week schedule also improved the regimen’s
tolerability. Therefore, IXO can be recommended for physically fit
patients with a preference and support system for aggressive triplet
chemotherapy, including patients without access or with difficult access
to the chemotherapy port and infusion pump management services,
and for whom oral administration of capecitabine is a convenient
substitute for infused 5-FU. The speed and magnitude of downsizing of
metastatic lesions would deem IXO of interest for converting border-
line unresectable metastatic disease to resectable status. Good results in
tumor shrinkage could support the use of IXO in the neoadjuvant
treatment of primary rectal cancer. Additional prospective clinical trials
are warranted to better examine the role of scheduling in the activity and
tolerability of the triplet combination and to identify the potential of
IXO within this population.
Clinical Practice Points
 We have described a phase I study that investigated the safety
and efficacy of the IXO regimen, a 3-week triple combination of
capecitabine, oxaliplatin, and irinotecan, as first-line treatment of
patients with advanced CRC.
 To the best of our knowledge, this is the first study to investigate
a 3-week schedule; previous studies of this triple combination
tested 2- or 5-week schedules.
 We have described the safety of the IXO regimen and the DLTs,
MTDs, and the recommended doses for phase II study.
 We have reported the full details of the toxicities that occurred at
each dose level and our experience in mitigating these toxicities.
 We have described the efficacy findings, in terms of the response
rates, PFS, and OS.
 We propose continuing the investigation of the IXO regimen for
maintenance therapy for advanced CRC, conversion of borderline
unresectable mCRC, and neoadjuvant downsizing of rectal cancer.
 Our findings suggest that IXO can improve survival beyond that
of first-line treatment doublet regimens in fit patients with
mCRC and increase the resectability rate for patients with
borderline unresectable disease.
e264 - Clinical Colorectal Cancer June 2018
Acknowledgments
The authors wish to thank the patients and families who agreed
to participation in this clinical trial and the study staff from the
Ottawa Hospital Cancer Centre. The present study was supported
by F. Hoffmann-La Roche, Pfizer, Sanofi Canada, and the Ottawa
Regional Cancer Foundation.
Disclosure
D.J. is currently conducting research sponsored by F. Hoffmann-
La Roche and Sanofi. The remaining authors declare that they have
no competing interests.
Supplemental Data
The supplemental figures accompanying this article can be found
in the online version at https://doi.org/10.1016/j.clcc.2017.12.003.
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Clinical Colorectal Cancer June 2018 - e265
 Phase I Study of IXO for Advanced CRC
Supplemental Figure 1 Consolidated Standards of Reporting Trials (CONSORT) Checklist

CONSORT checklist *

A phase 1 study of irinotecan, capecitabine, and oxaliplatin in patients with advanced colorectal cancer

Item
Section/Topic No Checklist item Reported in section
Title and abstract
1a Identification as a randomised trial in the title Not Applicable
1b Structured summary of trial design, methods, results, and conclusions (for specific guidance see Abstract
CONSORT for abstracts)

Introduction
Background and 2a Scientific background and explanation of rationale Introduction
objectives 2b Specific objectives or hypotheses Introduction

Methods
Trial design 3a Description of trial design (such as parallel, factorial) including allocation ratio Study design in Patients and
Methods
3b Important changes to methods after trial commencement (such as eligibility criteria), with Patients in Patients and
reasons Methods
Participants 4a Eligibility criteria for participants Patients in Patients and
Methods
4b Settings and locations where the data were collected Study design in Patients and
Methods
Interventions 5 The interventions for each group with sufficient details to allow replication, including how and Treatment and dose-escalation
when they were actually administered protocol in Patients and
Methods
Outcomes 6a Completely defined pre-specified primary and secondary outcome measures, including how and Toxicity, DLT, and tumour
when they were assessed response evaluations in
Patients and Methods
6b Any changes to trial outcomes after the trial commenced, with reasons Not Applicable
Sample size 7a How sample size was determined Statistical analysis
7b When applicable, explanation of any interim analyses and stopping guidelines Not Applicable
Randomisation:
Sequence 8a Method used to generate the random allocation sequence Not Applicable
generation 8b Type of randomisation; details of any restriction (such as blocking and block size) Not Applicable
Allocation 9 Mechanism used to implement the random allocation sequence (such as sequentially numbered Not Applicable
concealment containers), describing any steps taken to conceal the sequence until interventions were
mechanism assigned
Implementation 10 Who generated the random allocation sequence, who enrolled participants, and who assigned Not Applicable
participants to interventions
Blinding 11a If done, who was blinded after assignment to interventions (for example, participants, care Not Applicable
providers, those assessing outcomes) and how
11b If relevant, description of the similarity of interventions Not Applicable
Statistical methods 12a Statistical methods used to compare groups for primary and secondary outcomes Not Applicable
12b Methods for additional analyses, such as subgroup analyses and adjusted analyses Statistical analysis in Patients
and Methods

e266 - Clinical Colorectal Cancer June 2018

 Jean Maroun et al
Supplemental Figure 1 continued

Results
Participant flow (a 13a For each group, the numbers of participants who were randomly assigned, received intended Patient characteristics
diagram is strongly treatment, and were analysed for the primary outcome
recommended) 13b For each group, losses and exclusions after randomisation, together with reasons CONSORT figure
Recruitment 14a Dates defining the periods of recruitment and follow-up Patient characteristics
14b Why the trial ended or was stopped Patient characteristics
Baseline data 15 A table showing baseline demographic and clinical characteristics for each group Table 1
Numbers analysed 16 For each group, number of participants (denominator) included in each analysis and whether the Safety and tolerability &
analysis was by original assigned groups Efficacy
Outcomes and 17a For each primary and secondary outcome, results for each group, and the estimated effect size Safety and tolerability &
estimation and its precision (such as 95% confidence interval) Efficacy
17b For binary outcomes, presentation of both absolute and relative effect sizes is recommended Safety and tolerability &
Efficacy
Ancillary analyses 18 Results of any other analyses performed, including subgroup analyses and adjusted analyses, Not Applicable
distinguishing pre-specified from exploratory
Harms 19 All important harms or unintended effects in each group (for specific guidance see CONSORT for harms) Dose escalation & Safety and
tolerability
Discussion

Limitations 20 Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of Discussion
analyses
Generalisability 21 Generalisability (external validity, applicability) of the trial findings Discussion
Interpretation 22 Interpretation consistent with results, balancing benefits and harms, and considering other Discussion
relevant evidence
Other information
Registration 23 Registration number and name of trial registry Study design in Patients and
Methods
Protocol 24 Where the full trial protocol can be accessed, if available Corresponding author
Funding 25 Sources of funding and other support (such as supply of drugs), role of funders Funding

*We strongly recommend reading this statement in conjunction with the CONSORT 2010 Explanation and Elaboration for important clarifications on all the items. If relevant, we also
recommend reading CONSORT extensions for cluster randomised trials, non-inferiority and equivalence trials, non-pharmacological treatments, herbal interventions, and pragmatic trials.
Additional extensions are forthcoming: for those and for up to date references relevant to this checklist, see www.consort-statement.org.

Clinical Colorectal Cancer June 2018 - e267

 Phase I Study of IXO for Advanced CRC
Supplemental Figure 2 Consolidated Standards of Reporting Trials (CONSORT) Flow Diagram

Enrollment Assessed for eligibility (n=39)

Excluded (n=0)

Allocated to intervention (n=39)

irinotecan + capecitabine + oxaliplatin
2 2
♦ Dose Level 1 (n=1 ) 180 mg/m + 850 mg/m + 85 mg/m2
♦ Dose Level 2 (n=7 ) 160 mg/m2 + 750 mg/m2 + 75 mg/m2
2 2
♦ Dose Level 3 (n=6 ) 160 mg/m + 750 mg/m + 85 mg/m2
♦ Dose Level 4 (n=7 ) 160 mg/m2 + 750 mg/m2 + 95 mg/m2
♦ Dose Level 5 (n=3 ) 160 mg/m2 + 750 mg/m2 + 100 mg/m2
2 2
♦ Dose Level 6 (n=3 ) 160 mg/m + 850 mg/m + 100 mg/m2
♦ Dose Level 7 (n=6 )* 160 mg/m2 + 950 mg/m2 + 100 mg/m2
♦ Dose Level 8 (n=6 ) 175 mg/m2 + 950 mg/m2 + 100 mg/m2

Follow-Up Toxicity evaluation (n=39)

Efficacy evaluation (n=38)

- one patient died of a stroke before the first

response evaluation

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