fluorouracil, leucovorin, and irinotecan plus either sunitinib or placebo in metastatic colorectal cancer: a randomized, phase iii trial Fluorouracil, Leucovorin, and Irinotecan Plus Either Sunitinib or Placebo in Metastatic Colorectal Cancer: A Randomized, Phase III Trial

Fluorouracil, Leucovorin, and Irinotecan Plus Either Sunitinib or Placebo in Metastatic Colorectal Cancer: A Randomized, Phase III Trial

  1. Eric Van Cutsem
  1. Alfredo Carrato, Ramon y Cajal University Hospital, Madrid, Spain; Anna Swieboda-Sadlej and Marzanna Staszewska-Skurczynska, Samodzielny Publiczny Centralny Szpital Kliniczny, Warsaw, Poland; Robert Lim, National University Health System, National University of Singapore, Singapore; Laslo Roman, Leningrad Regional Oncology Centre, St. Petersburg, Russian Federation; Yaroslav Shparyk, Lviv State Oncologic Regional Treatment and Diagnostic Center, Lviv; Igor Bondarenko, City Multiple-Discipline Clinical Hospital #4, Dnipropetrovsk, Ukraine; Derek J. Jonker, The Ottawa Hospital Cancer Center, Ottawa, Ontario, Canada; Yan Sun, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Panjia Yuan, Bejing, China; Jhony A. De la Cruz, Grupo Oncológico Acapulco, Facultad de Medicina, Universidad Autónoma de Guerrero y Secretaría de Salud, Guerrero, Mexico; J. Andrew Williams, James G. Christensen, and Xun Lin, Pfizer Oncology, La Jolla, CA; Beata Korytowsky, Pfizer Oncology, New York, NY; Jennifer M. Tursi and Maria J. Lechuga, Pfizer Italia, Milan, Italy; and Eric Van Cutsem, University Hospital Gasthuisberg, Leuven, Belgium.
  1. Corresponding author: Alfredo Carrato, MD, PhD, Medical Oncology Department, Ramon y Cajal University Hospital, Carretera Colmenar Viejo Km 91, Madrid, Spain 28034; e-mail: acarrato{at}telefonica.net.
 
Next Section

Abstract

Purpose This double-blind, phase III study aimed to demonstrate that sunitinib plus FOLFIRI (fluorouracil, leucovorin, and irinotecan) was superior to placebo plus FOLFIRI in previously untreated metastatic colorectal cancer (mCRC).

Patients and Methods Patients were randomly assigned to receive FOLFIRI and either sunitinib (37.5 mg per day) or placebo (4 weeks on treatment, followed by 2 weeks off [schedule 4/2]) until disease progression. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, safety, and patient-reported outcomes. The correlation between genotype and clinical outcomes was also analyzed.

Results In all, 768 patients were randomly assigned to sunitinib plus FOLFIRI (n = 386) or placebo plus FOLFIRI (n = 382). Following a second prespecified interim analysis, the study was stopped because of potential futility of sunitinib plus FOLFIRI. Final results are reported. The PFS hazard ratio was 1.095 (95% CI, 0.892 to 1.344; one-sided stratified log-rank P = .807), indicating a lack of superiority for sunitinib plus FOLFIRI. Median PFS for the sunitinib arm was 7.8 months (95% CI, 7.1 to 8.4 months) versus 8.4 months (95% CI, 7.6 to 9.2 months) for the placebo arm. Sunitinib plus FOLFIRI was associated with more grade ≥ 3 adverse events and laboratory abnormalities than placebo (especially diarrhea, stomatitis/oral syndromes, fatigue, hand-foot syndrome, neutropenia, thrombocytopenia, anemia, and febrile neutropenia). More deaths as a result of toxicity (12 v four) and significantly more dose delays, dose reductions, and treatment discontinuations occurred in the sunitinib arm.

Conclusion Sunitinib 37.5 mg per day (schedule 4/2) plus FOLFIRI is not superior to FOLFIRI alone and has a poorer safety profile. This combination regimen is not recommended for previously untreated mCRC.

Previous SectionNext Section

INTRODUCTION

Colorectal cancer (CRC) is one of the most common cancers worldwide, with increasing incidence, particularly in developing countries.1 In patients with metastatic CRC (mCRC), chemotherapy alone yields median survival durations of approximately 20 months.2–4 Although the combination of bevacizumab and chemotherapy has modestly improved outcomes in treatment-naïve patients,5 additional therapeutic options are needed.

Sunitinib malate (SUTENT; Pfizer, New York, NY) is an oral, multitargeted inhibitor of vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors, as well as other receptor tyrosine kinases.6–10 Sunitinib is currently a multinationally approved drug for the treatment of advanced renal cell carcinoma, imatinib-resistant or imatinib-intolerant gastrointestinal stromal tumor, and unresectable or metastatic well-differentiated pancreatic neuroendocrine tumors.11

In preclinical CRC models, sunitinib demonstrated single-agent antitumor activity at well-tolerated doses.6 When sunitinib was combined with irinotecan, the combination was superior compared with either single agent alone (Pfizer, data on file). A phase II study of single-agent sunitinib after failure of standard mCRC therapy found median overall survival (OS) to be 10.2 and 7.1 months in patients with bevacizumab-untreated and bevacizumab-pretreated tumors, respectively (sunitinib treatment: 50 mg per day for 4 weeks on therapy, followed by 2 weeks off [schedule 4/2]).12 The investigators concluded that the mechanism of action and acceptable safety profile of sunitinib warranted further exploration in combination with standard mCRC regimens.

A subsequent phase I study investigated sunitinib combined with fluorouracil, leucovorin, and irinotecan (FOLFIRI) in treatment-naïve patients with mCRC and determined that the maximum-tolerated dose of sunitinib was 37.5 mg per day administered on schedule 4/2.13 This regimen showed promising antitumor activity and was further evaluated in a double-blind, randomized phase III study. This trial was initiated in July 2007 to determine whether sunitinib plus FOLFIRI was superior to placebo plus FOLFIRI in prolonging progression-free survival (PFS) in the first-line treatment of patients with mCRC. The study was stopped in June 2009 at the recommendation of an independent data monitoring committee following a second prespecified interim analysis because of potential futility of the combination regimen. Final results are reported here.

Previous SectionNext Section

PATIENTS AND METHODS

Study Population

Patients were age ≥ 18 years, had Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 and adequate organ function, and had histologically or cytologically confirmed colorectal adenocarcinoma with metastatic disease documented by diagnostic imaging. All patients had previously untreated metastatic disease not amenable to surgery (although adjuvant therapy for primary CRC was permitted provided that ≥ 6 months had elapsed from the conclusion of adjuvant therapy to the documentation of recurrent disease), were candidates for FOLFIRI therapy, and had one or more measurable lesions based on Response Evaluation Criteria in Solid Tumors, version 1.0 (RECIST).14

Patients were excluded if they had prior treatment with a tyrosine kinase inhibitor, CNS involvement, or previous radiation treatment to more than 30% of bone marrow or to all measurable areas of metastatic disease. Additional exclusion criteria are listed in Materials and Methods in the Appendix (online only).

Study Design and Treatment

This randomized, double-blind, placebo-controlled phase III study was conducted in multiple centers worldwide to investigate the efficacy and safety/tolerability of sunitinib combined with FOLFIRI. The study was approved by the institutional review board or independent ethics committee of each participating center and complied with the International Conference on Harmonization Good Clinical Practice guidelines and applicable local regulatory requirements. All patients provided written informed consent.

Patients were enrolled by clinical-site staff who used a Web-based system provided by the study sponsor and were then randomly assigned 1:1 to receive FOLFIRI plus either sunitinib or placebo (Fig 1). Patients were stratified on the basis of ECOG PS (0 or 1), number of organs with metastases (one or more than one), primary tumor site (colon or rectum), and prior adjuvant treatment (yes or no).

Fig 1.
View larger version:
Fig 1.

CONSORT diagram. FOLFIRI, fluorouracil, leucovorin, and irinotecan.

Intravenous FOLFIRI was administered in the standard fashion every 2 weeks: irinotecan 180 mg/m2, levo-leucovorin 200 mg/m2 immediately followed by fluorouracil 400 mg/m2 bolus, and then fluorouracil 2,400 mg/m2 as a 46-hour infusion. Oral sunitinib (37.5 mg per day) or placebo was administered on schedule 4/2.

Dose delays or reductions were permitted to manage treatment-related adverse events (AEs). For sunitinib/placebo or FOLFIRI, dose interruptions of more than 4 weeks were not permitted. Sunitinib/placebo doses could be reduced to 25 mg per day; FOLFIRI doses could be reduced according to institutional practices. The use of hematopoietic growth factors was permitted.

Treatment cycles were 6 weeks in duration (each 6-week sunitinib/placebo cycle included 3 cycles of FOLFIRI). Treatment was planned to continue until disease progression (unless unacceptable toxicity occurred or consent was withdrawn) for a maximum of 30 months. Crossover between treatment arms was not permitted.

Assessments

The primary study end point was PFS defined as time from the date of random assignment to the date of first documentation of objective tumor progression or death as a result of any cause, whichever occurred first. Secondary end points included OS, objective response rate (ORR) based on RECIST, version 1.0,14 safety, and patient-reported outcomes. In addition, genotype analysis of biologic samples was performed, after informed consent, to investigate potential associations with efficacy or toxicity. Additional information on the patient-reported outcomes and genotype analysis components of this study can be found in the Appendix.

Tumors were imaged at baseline, every 6 weeks, or whenever disease progression was suspected to confirm an objective response (partial response or complete response) ≥ 4 weeks after initial documentation of response, at study withdrawal (if not done in the previous 6 weeks), and after study drug discontinuation. Tumor assessments were subjected to blinded central review.

Safety was evaluated by using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0 and through assessment of laboratory results, physical examinations, clinical history, PS, vital signs, and ECGs. An independent data monitoring committee reviewed safety data periodically from January 2008.

Statistical Methods

Study sample size was determined based on the assumptions of a median PFS of 8.0 months for patients receiving placebo plus FOLFIRI4 and 10.8 months for patients receiving sunitinib plus FOLFIRI (a 35% improvement). In total, 568 PFS events were required for a one-sided stratified log-rank test with a significance level of 0.025% and 85% power to detect a statistically significant difference between the treatment arms (superiority design). The number of events was determined by a group-sequential design with two interim analyses and one final analysis. The interim analyses were planned at 25% and 60% of the 568 PFS events, and the stopping boundary for futility at the second interim analysis was a hazard ratio (HR) of ≥ 0.876 based on an O'Brien-Fleming stopping boundary.15 The planned sample size was 720 patients (360 per arm).

The efficacy analysis population included all randomly assigned patients. The safety analysis population included all patients who received at least one dose of study medication. Time-to-event end points were analyzed by using Kaplan-Meier methods. Cox regression models were used to explore potential influences of baseline and on-treatment characteristics on PFS.

Previous SectionNext Section

RESULTS

Study Conduct, Patients, and Treatment Administration

Enrollment began in July 2007. At the second interim analysis in June 2009, after enrollment was complete and 367 PFS events had occurred, the PFS HR was 1.095 in favor of the placebo arm (95% CI, 0.892 to 1.344; one-sided stratified log-rank P = .807). The data monitoring committee noted that the futility boundary had been crossed and that there were increased toxic events (including neutropenia and diarrhea) in patients who received sunitinib plus FOLFIRI compared with placebo plus FOLFIRI. At this point, patients on treatment were notified and treatment was unblinded. Sunitinib discontinuation was recommended or left to investigator discretion in cases of clinical benefit. The last patient visit occurred in March 2010.

In total, 768 patients were randomly assigned to the sunitinib plus FOLFIRI arm (n = 386) or the placebo plus FOLFIRI arm (n = 382) at 128 centers worldwide (Europe, 58%; Asia-Pacific, 31%; Africa, 5%; South America 5%; Canada 1%). The efficacy analysis population comprised all 768 patients (Fig 1). Five patients did not receive study medication; the remaining 763 patients received at least one dose of study medication and comprised the safety analysis population (sunitinib plus FOLFIRI, n = 384; placebo plus FOLFIRI, n = 379). The data cutoff was April 16, 2010.

The treatment arms were well balanced for demographic, disease, and prior adjuvant treatment characteristics (Table 1). Overall, 38% (n = 146) and 23% (n = 89) of patients had sunitinib and placebo dose delays, respectively; 22% (n = 83) and 7% (n = 28) had a dose reduction, respectively. The resulting median relative dose-intensity was 86% (range, 7% to 120%) for sunitinib and 93% (range, 7% to 115%) for placebo. The median relative dose-intensity for irinotecan and fluorouracil was 75% to 76% (range, 21 to 112) and 91% to 92% (range, 25 to 113) in the sunitinib and placebo arms, respectively. Most patients discontinued treatment as a result of study termination (46% in the sunitinib plus FOLFIRI arm; 50% in the placebo plus FOLFIRI arm) or death (42% and 39%, respectively; Fig 1).

View this table:
Table 1.

Baseline Patient Characteristics

Efficacy

Median PFS was 7.8 months (95% CI, 7.1 to 8.4 months) in the sunitinib plus FOLFIRI arm and 8.4 months (95% CI, 7.6 to 9.2 months) in the placebo plus FOLFIRI arm (HR, 1.095; 95% CI, 0.892 to 1.344; one-sided stratified log-rank P = .807; (Fig 2A). At data cutoff, death or disease progression had occurred in 52% and 51% of patients in the sunitinib and placebo arms, respectively. In a post hoc Cox proportional hazards model, the following were not predictors of PFS: baseline characteristics (including serum lactate dehydrogenase levels, sex, and race), the presence of grade ≥ 3 sunitinib-related neutropenia or diarrhea, and exposure/duration of chemotherapy or blinded treatment (Table 2).

Fig 2.
View larger version:
Fig 2.

Kaplan-Meier estimates of (A) progression-free survival (PFS; independent central review) and (B) overall survival. A hazard ratio (HR) > 1 was in favor of the placebo plus FOLFIRI (fluorouracil, leucovorin, and irinotecan) arm. (*) P value from one-sided stratified log-rank test for superiority. N/R, not reached as a result of early study closure.

View this table:
Table 2.

Influence of Characteristics at Baseline and During Treatment on PFS (Cox model)

Median OS was 20.3 months (95% CI, 17.4 months to not reached [as a result of early study closure]) in the sunitinib plus FOLFIRI arm and 19.8 months (95% CI, 18.7 months to not reached) in the placebo plus FOLFIRI arm (HR, 1.171; 95% CI, 0.936 to 1.466; one-sided stratified log-rank P = .916; Fig 2B). At data cutoff, 42% of sunitinib-treated patients and 39% of placebo-treated patients had died. The ORR was 32% (124 of 386) for sunitinib plus FOLFIRI and 34% (128 of 382) for placebo plus FOLFIRI (Table 3).

View this table:
Table 3.

Best Objective Response Based on RECIST (independent central review)

Safety

The most commonly reported all-grade, nonhematologic AEs were diarrhea (66% and 50%; P < .001), nausea (50% and 48%; P = .585), and vomiting (39% and 35%; P = .290) for the sunitinib and placebo arms, respectively. AEs reported ≥ 10% more frequently with sunitinib than with placebo were diarrhea, stomatitis, hand-foot syndrome, and hypertension.

The most frequently reported nonhematologic grade ≥ 3 all-causality AEs were diarrhea (16%; P = .002 v placebo), fatigue (8%; P < .001 v placebo), and hand-foot syndrome (7%; P < .001 v placebo) for sunitinib plus FOLFIRI, and diarrhea (8%), vomiting (5%), and fatigue (3%) for placebo plus FOLFIRI (Table 4). In addition, sunitinib was associated with more grade ≥ 3 pooled stomatitis and related oral syndromes (9% v 2%; P < .001; Table 4). Grade ≥ 3 hypertension was observed in 3% of patients in the sunitinib arm compared with less than 1% in the placebo arm (P = .053). The most common grade ≥ 3 hematologic laboratory abnormalities were neutropenia (68% and 30%; P < .001) and thrombocytopenia (11% and 1%; P < .001) for the sunitinib and placebo arms, respectively (Table 4). Febrile neutropenia was reported in 7% and 3% (P = .011) of patients, respectively.

View this table:
Table 4.

Grade ≥ 3 Adverse Events and Hematologic Abnormalities Reported in ≥ 5% of Patients or of Clinical Interest, Regardless of Causality

Sixteen patients died on study as a result of treatment-related grade 5 AEs. Twelve of these patients were in the sunitinib arm: sepsis/septic shock (four patients); febrile neutropenia/neutropenia (two); colonic obstruction (one); death from an unknown cause (one); peritonitis (one); respiratory failure (one); myocardial infarction with pulmonary embolism (one); or combined leukopenia, mucosal inflammation, and febrile neutropenia (one). Four patients had treatment-related grade 5 toxicities in the placebo arm: death from an unknown cause (one), hepatic failure (one), neutropenic sepsis (one), or pneumonia (one).

For sunitinib and placebo treatment, respectively, 24% (n = 91) and 11% (n = 43) of patients permanently discontinued treatment (P < .001), 61% (n = 233) and 35% (n = 131) experienced dose delays (P < .001), and 19% (n = 74) and 5% (n = 18) had dose reductions (P < .001). FOLFIRI dose reductions due to AEs occurred in 42% (n = 163) and 20% (n = 77) of patients in the sunitinib and placebo arms, respectively (P < .001). The most common AEs resulting in sunitinib versus placebo dose delays/modifications were neutropenia (36% v 12%; P < .001), diarrhea (11% v 5%; P = .003), and leukopenia (9% v 3%; P < .001).

Previous SectionNext Section

DISCUSSION

After many phase III trials, no benefit has been shown for combining conventional chemotherapy with VEGFR inhibitors in first-line mCRC treatment (despite preclinical data indicating that the combination of sunitinib and irinotecan was superior to either agent alone [P < .05; Fig 3; Pfizer, data on file]).16,17 In this study, sunitinib plus FOLFIRI failed to demonstrate superior efficacy compared with placebo plus FOLFIRI in patients with mCRC. The PFS curves overlapped (Fig 2A), and median PFS was 7.8 months (95% CI, 7.1 to 8.4 months) in the sunitinib plus FOLFIRI arm and 8.4 months (95% CI, 7.6 to 9.2 months) in the placebo plus FOLFIRI arm. Although the placebo plus FOLFIRI results are comparable with historical data,4 the median PFS of 7.8 months (95% CI, 7.1 to 8.4 months) in the sunitinib plus FOLFIRI arm is in contrast to results from studies of other targeted agents in combination with FOLFIRI in treatment-naïve patients with mCRC. Bevacizumab plus FOLFIRI, for example, yielded a median PFS of 11.1 months in a phase IV study,18 11.2 months in a randomized phase III study,19 and 12.8 months in a single-arm phase II study.20

Fig 3.
View larger version:
Fig 3.

Growth inhibition of established LS174t human colon carcinoma xenografts in nude mice following treatment with sunitinib and irinotecan. LS174t human colon tumors were established in nude mice. When tumors reached an average size of 105 to 107 mm3, animals were treated with either oral sunitinib 40 mg/kg daily until the end of the experiment, irinotecan 100 mg/kg administered intraperitoneally every 7 days for 3 weeks, both drugs in combination, or vehicle control (vehicle 1: carboxymethylcellulose used to deliver sunitinib; vehicle 2: 5% dextrose in water used to deliver irinotecan). Tumor volume was measured by using Vernier calipers on the indicated days, with the median tumor volume shown for groups of eight animals. (*) P < .05 versus sunitinib 40 mg/kg and irinotecan 100 mg/kg groups (one-way analysis of variance).

Similarly, median OS in this study was approximately 20 months in both arms, showing no statistical evidence of superiority for sunitinib. However, at the time of the analysis, the survival data were not mature. After the data monitoring committee made its recommendation, the majority of patients remaining in survival follow-up were removed from the study (approximately 40% of patients had died in both arms), and as a result, these findings should be interpreted with caution. In addition, the ORR in the sunitinib plus FOLFIRI arm failed to be significantly better than the ORR in the placebo plus FOLFIRI arm (32% v 34%; P = .683).

In line with previous observations,11,12 AEs reported in the sunitinib arm of this study included gastrointestinal symptoms (diarrhea, nausea, and vomiting), fatigue, skin toxicities (hand-foot syndrome), hematologic toxicities, and hypertension. Sunitinib in combination with chemotherapy was also associated with higher frequencies of grade ≥ 3 AEs and laboratory abnormalities compared with placebo (including diarrhea, stomatitis and related oral syndromes, fatigue, hand-foot syndrome, neutropenia, febrile neutropenia, anemia, and thrombocytopenia) and more treatment-related deaths (12 v four). Grade ≥ 3 hypertension was observed in 3% of sunitinib-treated patients. In addition, more patients had dose delays, dose reductions, or permanent discontinuations of sunitinib treatment due to AEs compared with placebo (all P < .001). An increase in rates of grade ≥ 3 AEs negatively influenced treatment administration in the experimental arm.

A post hoc analysis was performed with regard to potential clinical or biologic factors predictive of clinical benefit with sunitinib treatment. Subgroup analyses evaluated baseline characteristics (including race, sex, and lactate dehydrogenase levels), as well as the presence of grade ≥ 3 sunitinib-related AEs (neutropenia or diarrhea) and exposure to or duration of chemotherapy or blinded treatment. Toxicity was explored only within the sunitinib arm to identify differences between patients who responded with an HR below 1 and those with an HR above 1. No clear predictors of PFS were identified. In contrast to the CONFIRM 2 trial [Colorectal Oral Novel Therapy for the Inhibition of Angiogenesis and Retarding of Metastases], in which the VEGFR inhibitor vatalanib (PTK787) was combined with chemotherapy,21 lactate dehydrogenase levels were not predictive of PFS in this study.

Other factors potentially contributing to the observed outcome include the relatively low median dose-intensity of both FOLFIRI (75% to 76%) and sunitinib (86%) in the sunitinib arm, compared with FOLFIRI (91% to 92%) and placebo (93%) in the placebo arm. The lower dose-intensity of FOLFIRI might have resulted from increased toxicity (eg, diarrhea and neutropenia) with the addition of sunitinib, which could have reduced the chemotherapy effect in the experimental arm. Similarly, low sunitinib dose-intensity in this study may have limited the ability to demonstrate a benefit, a possibility supported by a meta-analysis indicating that increased exposure to sunitinib is associated with improved clinical outcome.22 An increased exposure might be achieved when sunitinib monotherapy is scheduled rather than combination treatment. In addition, mCRC cells may not be particularly dependent on the signaling pathways inhibited by sunitinib. If the inhibited kinases are not relevant to the cancer being treated, it may be detrimental to block multiple targets. Conversely, additional proangiogenic factors, independent of VEGF, may be implicated in tumor progression.20

In summary, sunitinib 37.5 mg per day on schedule 4/2 combined with FOLFIRI is not recommended for patients with treatment-naïve mCRC, because the addition of sunitinib increased toxicity and did not improve PFS, OS, or ORR compared with placebo.

Previous SectionNext Section

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: J. Andrew Williams, Pfizer (C); Beata Korytowsky, Pfizer (C); James G. Christensen, Pfizer (C); Xun Lin, Pfizer (C); Jennifer M. Tursi, Pfizer (C); Maria J. Lechuga, Pfizer (C) Consultant or Advisory Role: Alfredo Carrato, Pfizer (C) Stock Ownership: J. Andrew Williams, Pfizer; Beata Korytowsky, Pfizer; James G. Christensen, Pfizer; Xun Lin, Pfizer; Jennifer M. Tursi, Pfizer; Maria J. Lechuga, Pfizer Honoraria: Alfredo Carrato, Pfizer Research Funding: Alfredo Carrato, Pfizer; Yaroslav Shparyk, Pfizer; Eric Van Cutsem, Pfizer Expert Testimony: None Other Remuneration: None

Previous SectionNext Section

AUTHOR CONTRIBUTIONS

Conception and design: Alfredo Carrato, Laslo Roman, Yan Sun, J. Andrew Williams, James G. Christensen, Xun Lin, Jennifer M. Tursi, Maria J. Lechuga

Provision of study materials or patients: Alfredo Carrato, Yaroslav Shparyk, Igor Bondarenko, Derek J. Jonker, Eric Van Cutsem

Collection and assembly of data: Anna Swieboda-Sadlej, Marzanna Staszewska-Skurczynska, Laslo Roman, Yaroslav Shparyk, Igor Bondarenko, Jhony A. De la Cruz, J. Andrew Williams, Beata Korytowsky, Xun Lin, Eric Van Cutsem

Data analysis and interpretation: Alfredo Carrato, Robert Lim, Laslo Roman, Igor Bondarenko, Derek J. Jonker, J. Andrew Williams, Beata Korytowsky, James G. Christensen, Xun Lin, Jennifer M. Tursi, Maria J. Lechuga, Eric Van Cutsem

Manuscript writing: All authors

Final approval of manuscript: All authors

Previous SectionNext Section

Acknowledgment

Presented in part at the 12th World Congress on Gastrointestinal Cancer, Barcelona, Spain, June 30-July 3, 2010; at the 102nd Annual Meeting of the American Association for Cancer Research, Orlando, FL, April 2-6, 2011; and at the 13th World Congress on Gastrointestinal Cancer, Barcelona, Spain, June 22-25, 2011.

We thank all of the participating patients and their families, as well as the global network of investigators, research nurses, study coordinators, and operations staff. Medical writing support was provided by Molly Heitz at ACUMED (Tytherington, United Kingdom) and was funded by Pfizer.

Previous SectionNext Section

Appendix

Previous SectionNext Section

Materials and Methods

Patient-reported outcomes.

Patient-reported outcomes (PROs) were assessed by using the MD Anderson Symptom Inventory-Gastrointestinal (MDASI-GI) questionnaire and the EuroQol EQ-5D questionnaire (EQ-5D) at the start of cycles 1 to 3, at every odd-numbered cycle thereafter, and at the end of treatment.

Outcomes were evaluated for the intent-to-treat population. Completion rates, summary statistics (absolute mean and median scores), and change from baseline were analyzed for each PRO measure. The mean change from baseline score was evaluated within each treatment arm at each cycle by using a paired t test when there were at least 10 patients per arm (cycles 2, 3, 5, 7, 9, 11, and at the end of treatment or at study withdrawal). On the basis of published standards, a clinically meaningful change in score was defined as at least 0.98 to 1.2 points for the MDASI-GI (Cleeland CS: MD Anderson Symptom Inventory Users' Guide, Version 1.0. Houston, TX, 2009), a conservative estimate of 0.06 to 0.08 points for the EQ-5D Health State Index (Pickard AS, et al: Health Qual Life Outcomes 5:70-78, 2007), and 7 to 10 points for the EQ-5D Visual Analog Scale score (Pickard AS, et al: Health Qual Life Outcomes 5:70-78, 2007). Because of the premature cessation of the study, PRO data collection was terminated earlier than originally planned and a between-treatment assessment was not performed.

Results

PROs.

PRO completion rates in this study were robust at more than 90% for almost all cycles through cycle 11 (Appendix Table A2). No statistically significant and clinically meaningful change from baseline was observed in the MDASI-GI Total Symptom Intensity scale through cycle 11, except at the end of treatment when scores were significantly higher than at baseline for both treatment arms (Appendix Table A3). However, completion rates for both treatment arms were ≤ 73% at the end of treatment (Appendix Table A2). Two individual symptoms (fatigue and distress) demonstrated a statistically significant and clinically meaningful change at a single cycle in the placebo plus FOLFIRI group (cycle 11: fatigue, P = .050, difference of −1.0; distress, P = .027, difference of −1.0). The Total Symptom Interference scale did not demonstrate a statistically significant change from baseline in either treatment arm except at cycle 3 (when the score was lower than at baseline in the placebo plus FOLFIRI group [P = .028, difference of −1.7]) and at the end of treatment, when scores were significantly higher than at baseline in both arms (Appendix Table A3). In addition, no clinically meaningful changes were observed in either treatment arm for the gastrointestinal-specific items of the MDASI-GI.

For the EQ-5D Health State Index and Visual Analog Scale scores, no statistically significant and clinically meaningful differences from baseline within each arm were reported, except at cycle 11 when the placebo plus FOLFIRI arm showed clinical improvement (Health State Index, P < .001, difference of 0.09, data not shown; Visual Analog Scale, P = .008, difference of 9.0; Appendix Table A4).

Discussion

In contrast to the toxicity difference observed, PROs appeared to follow a similar trend for both treatment arms. This may be because of patients' personal interpretations of their clinical situations. The recommendation is that when both measurements are performed, they should be evaluated together (Basch E, et al: Lancet Oncol 7: 903-909, 2006).

For the genotype analysis, the relationship between the SNP rs717620 in the ABCC2 gene (encoding the drug transporter MRP2) and grade 3 to 4 diarrhea in the placebo plus FOLFIRI arm (n = 4) appeared to be related to a previous ABCC2 haplotype association with severe diarrhea in patients receiving single-agent irinotecan who did not carry a UGT1A1*28 allele (de Jong FA, et al: Clin Pharmacol Ther 81:42-49, 2007). The previous association was observed when the rs717620 polymorphism was part of the ABCC2*2 haplotype and may be due to reduced hepatobiliary secretion of irinotecan metabolites. The relationship between ABCC2*2 haplotype and irinotecan-related diarrhea supports the apparent association between genotype and phenotype observed in four patients in our study. However, further investigation is required to confirm this result.

⇓⇓⇓⇓

View this table:
Table A1.

Polymorphisms for Genotyping, Based on Previously Reported Associations With the Efficacy and Safety of FOLFIRI Alone or Sunitinib Alone

View this table:
Table A2.

MDASI-GI Completion Rates by Treatment and Cycle

View this table:
Table A3.

MDASI-GI Mean Change From Baseline

View this table:
Table A4.

MDASI-GI Visual Analogue Scale, Mean Change From Baseline

Previous SectionNext Section

Footnotes

  • Written on behalf of the SUN 1122 investigators.

  • Supported by Pfizer.

  • Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

  • Clinical trial information: NCT00457691.

Previous Section
 

REFERENCES

  1. 1.↵
    1. Center MM,
    2. Jemal A,
    3. Ward E
    (2009) International trends in colorectal cancer incidence rates. Cancer Epidemiol Biomarkers Prev 18:1688–1694.
    Abstract/FREE Full Text
  2. 2.↵
    1. Douillard JY,
    2. Sobrero A,
    3. Carnaghi C,
    4. et al.
    (2003) Metastatic colorectal cancer: Integrating irinotecan into combination and sequential chemotherapy. Ann Oncol 14:ii7–ii12.
    Abstract
  3. 3.
    1. Goldberg RM,
    2. Sargent DJ,
    3. Morton RF,
    4. et al.
    (2006) Randomized controlled trial of reduced-dose bolus fluorouracil plus leucovorin and irinotecan or infused fluorouracil plus leucovorin and oxaliplatin in patients with previously untreated metastatic colorectal cancer: A North American Intergroup Trial. J Clin Oncol 24:3347–3353.
    Abstract/FREE Full Text
  4. 4.↵
    1. Tournigand C,
    2. André T,
    3. Achille E,
    4. et al.
    (2004) FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol 22:229–237.
    Abstract/FREE Full Text
  5. 5.↵
    1. Saltz LB,
    2. Clarke S,
    3. Díaz-Rubio E,
    4. et al.
    (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: A randomized phase III study. J Clin Oncol 20:2013–2019.
    Search Google Scholar
  6. 6.↵
    1. Mendel DB,
    2. Laird AD,
    3. Xin X,
    4. et al.
    (2003) In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: Determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 9:327–337.
    Abstract/FREE Full Text
  7. 7.
    1. Murray LJ,
    2. Abrams TJ,
    3. Long KR,
    4. et al.
    (2003) SU11248 inhibits tumor growth and CSF-1R-dependent osteolysis in an experimental breast cancer bone metastasis model. Clin Exp Metastasis 20:757–766.
    CrossRefMedline
  8. 8.
    1. Kim DW,
    2. Jo YS,
    3. Jung HS,
    4. et al.
    (2006) An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases. J Clin Endocrinol Metab 91:4070–4076.
    Abstract/FREE Full Text
  9. 9.
    1. Abrams TJ,
    2. Lee LB,
    3. Murray LJ,
    4. et al.
    (2003) SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther 2:471–478.
    Abstract/FREE Full Text
  10. 10.↵
    1. O'Farrell AM,
    2. Abrams TJ,
    3. Yuen HA,
    4. et al.
    (2003) SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 101:3597–3605.
    Abstract/FREE Full Text
  11. 11.↵
    (2010) Pfizer: SUTENT (sunitinib malate) prescribing information.
  12. 12.↵
    1. Saltz LB,
    2. Rosen LS,
    3. Marshall JL,
    4. et al.
    (2007) Phase II trial of sunitinib in patients with metastatic colorectal cancer after failure of standard therapy. J Clin Oncol 25:4793–4799.
    Abstract/FREE Full Text
  13. 13.↵
    1. Starling N,
    2. Vázquez-Mazón F,
    3. Cunningham D,
    4. et al.
    (2012) A phase I study of sunitinib in combination with FOLFIRI in patients with untreated metastatic colorectal cancer. Ann Oncol 23:119–127.
    Abstract/FREE Full Text
  14. 14.↵
    1. Therasse P,
    2. Arbuck SG,
    3. Eisenhauer EA,
    4. et al.
    (2000) New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216.
    Abstract/FREE Full Text
  15. 15.↵
    1. O'Brien PC,
    2. Fleming TR
    (1979) A multiple testing procedure for clinical trials. Biometrics 35:549–556.
    CrossRefMedline
  16. 16.↵
    1. Wilson D,
    2. Hoff PM,
    3. Schmoll H,
    4. et al.
    (2011) Application of adaptive study designs: Phase II and III results from the cediranib (CED) HORIZON (HZ) II and III studies. J Clin Oncol 29(suppl; abstr 3633^):254s.
    Search Google Scholar
  17. 17.↵
    1. Hecht JR,
    2. Trarbach T,
    3. Hainsworth JD,
    4. et al.
    (2011) Randomized, placebo-controlled, phase III study of first-line oxaliplatin-based chemotherapy plus PTK787/ZK 222584, an oral vascular endothelial growth factor receptor inhibitor, in patients with metastatic colorectal adenocarcinoma. J Clin Oncol 29:1997–2003.
    Abstract/FREE Full Text
  18. 18.↵
    1. Sobrero A,
    2. Ackland S,
    3. Clarke S,
    4. et al.
    (2009) Phase IV study of bevacizumab in combination with infusional fluorouracil, leucovorin and irinotecan (FOLFIRI) in first-line metastatic colorectal cancer. Oncology 77:113–119.
    Medline
  19. 19.↵
    1. Fuchs CS,
    2. Marshall J,
    3. Mitchell E,
    4. et al.
    (2007) Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: Results from the BICC-C Study. J Clin Oncol 25:4779–4786.
    Abstract/FREE Full Text
  20. 20.↵
    1. Kopetz S,
    2. Hoff PM,
    3. Morris JS,
    4. et al.
    (2010) Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: Efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol 28:453–459.
    Abstract/FREE Full Text
  21. 21.↵
    1. Van Cutsem E,
    2. Bajetta E,
    3. Valle J,
    4. et al.
    (2011) Randomized, placebo-controlled, phase III study of oxaliplatin, fluorouracil, and leucovorin with or without PTK787/ZK 222584 in patients with previously treated metastatic colorectal adenocarcinoma. J Clin Oncol 29:2004–2010.
    Abstract/FREE Full Text
  22. 22.↵
    1. Houk BE,
    2. Bello CL,
    3. Poland B,
    4. et al.
    (2010) Relationship between exposure to sunitinib and efficacy and tolerability end points in patients with cancer: Results of a pharmacokinetic/pharmacodynamic meta-analysis. Cancer Chemother Pharmacol 66:357–371.
    CrossRefMedline
| Table of Contents

This Article

  1. Published online before print January 28, 2013, doi: 10.1200/JCO.2012.45.1930 JCO vol. 31 no. 10 1341-1347
  1. Abstract
  2. » Full Text
  3. PDF
  4. Protocol

Classifications

Navigate This Article

Current Issue

  1. July 20, 2013, 31 (21)
  1. Alert me to new issues of JCO
    • Advertisement
    • Advertisement
    • Advertisement