Original Article
A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Study of Maintenance Enzastaurin With 5-Fluorouracil/Leucovorin Plus Bevacizumab After First-Line Therapy for Metastatic Colorectal Cancer Robert A. Wolff, MD1; Martin Fuchs, MD2; Maria Di Bartolomeo, MD3; Anwar M. Hossain, MS4; Clemens Stoffregen, MD5; Steven Nicol, MD4; and Volker Heinemann, MD6
BACKGROUND: Enzastaurin and bevacizumab have demonstrated synergistic antitumor effects and, in phase 1 studies, the combination was well tolerated. This phase 2 study assessed enzastaurin with 5-fluorouracil/leucovorin plus bevacizumab as maintenance therapy for metastatic colorectal cancer (MCRC). METHODS: Patients with locally advanced or MCRC and stable or responding disease after completing 6 cycles of first-line chemotherapy randomly received a loading dose of enzastaurin 1125 mg, followed by 500 mg/d subsequent doses or placebo. Both arms received 5-fluorouracil/leucovorin (leucovorin 400 mg/m2 intravenously [IV], 5-fluorouracil 400-mg/m2 bolus, 5-fluorouracil 2400 mg/m2 IV) plus bevacizumab 5 mg/kg IV, every 2 weeks. The primary endpoint was progression-free survival (PFS), from randomization. Overall survival (OS) and PFS were also assessed from start of first-line therapy. Enrollment was stopped, and the final analysis was conducted after 73 PFS events. RESULTS: Fifty-eight patients were randomized to enzastaurin and 59 to placebo. For the enzastaurin and placebo arms, respectively, the median cycles received were 9 and 10, and the median PFS was 5.8 and 8.1 months (hazard ratio [HR], 1.35; 95% confidence interval [CI], 0.84-2.16; P ¼ .896). Median OS was not calculable because of high censoring (77.6% enzastaurin; 91.5% placebo). The median PFS from start of first-line therapy was 8.9 months for enzastaurin and 11.3 months for placebo (HR, 1.39; 95% CI, 0.86-2.23; P ¼ .913). More enzastaurin patients developed thrombosis or embolism compared with placebo (15.8% and 1.7%; P ¼ .008). One possibly enzastaurin-related death occurred because of arrhythmia. CONCLUSIONS: Enzastaurin combined with bevacizumab-based therapy is tolerable, but does not improve PFS during maintenance therapy in patients with MCRC compared with bevacizumab-based therapy alone. Cancer C 2011 American Cancer Society. 2012;118:4132-8. V KEYWORDS: 5-fluorouracil/leucovorin, bevacizumab, enzastaurin, maintenance therapy, metastatic colorectal cancer.
INTRODUCTION Colorectal cancer (CRC) is the third most common cancer globally for both men and women, accounting for 9% of all cancer deaths in the United States.1 Approximately 25% of patients present with metastatic disease, and almost 50% of patients initially treated for localized disease develop metastatic CRC.2 Corresponding author: Robert A. Wolff, MD, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit Number 421, Room Number FC11.2018, Houston, TX, 77030; Fax: (713) 794-1807;
[email protected] 1 The University of Texas MD Anderson Cancer Center, Houston, Texas; 2Department of Gastroenterology, Hepatology and Gastrointestinal Oncology, Bogenhausen Academic Teaching Hospital, Technical University of Munich, Munich, Germany; 3Medical Oncology Unit 2, Foundation IRCCS National Tumor Institute, Milano, Italy; 4Eli Lilly and Company, Indianapolis, Indiana; 5Lilly Deutschland GmbH, Bad Homburg, Germany; 6Department of Medical Oncology, Campus Grosshadern, University of Munich, Munich, Germany.
We thank Melissa J. Ossanna, PhD, and Noelle Gasco, both employees of Eli Lilly and Company, for their project management, writing, and editorial support during the development of this article. ClinicalTrials.gov identifier: NCT00612586. DOI: 10.1002/cncr.26692, Received: August 23, 2011; Revised: September 29, 2011; Accepted: October 3, 2011, Published online December 27, 2011 in Wiley Online Library (wileyonlinelibrary.com)
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Historically, 5-fluorouracil, modulated by leucovorin, has been the mainstay of treatment in metastatic CRC.3,4 Standard first-line therapies consist of 5-fluorouracil/leucovorin combined with either oxaliplatin (FOLFOX)5-7 or irinotecan (FOLFIRI).8,9 The addition of targeted agents such as bevacizumab, a humanized monoclonal antibody targeting the vascular endothelial growth factor (VEGF), to standard combinations for the treatment of metastatic CRC has further enhanced the outcomes obtained with conventional cytotoxic chemotherapy.10-12 Maintenance therapy is intended to maximize progression-free survival (PFS) and minimize toxicity in advanced CRC.13 Until recently, common clinical practice was to continue first-line treatment for patients with CRC until progression; however, toxicity was reported after multiple cycles of therapy.7 Thus, delivery of maintenance therapy was introduced using a standard regimen, such as FOLFOX, while discontinuing the drug in that regimen responsible for cumulative toxicity, such as oxaliplatin, after 6 cycles (12 weeks) of first-line induction therapy. For example, Chibaudel et al13 studied the role of maintenance therapy by delivering induction chemotherapy consisting of 6 cycles of FOLFOX7 and then randomizing patients without disease progression to undergo a chemotherapy-free interval until progression, or to receive maintenance therapy consisting of bolus 5-fluorouracil/ leucovorin and infusional 5-fluorouracil (LV5FU2). Patients randomized to maintenance LV5FU2 had a longer duration of disease control, longer PFS, and a trend toward improved overall survival (OS) compared with patients randomized to undergo a chemotherapy-free interval until progression.13 The current study was therefore designed to investigate the potential benefit of adding another novel molecular agent to a regimen of maintenance therapy consisting of LV5FU2 and bevacizumab. Enzastaurin is an oral serine/threonine kinase inhibitor that suppresses signaling through the protein kinase C (PKC) b and the phosphoinositide 3-kinase/AKT pathways.14 It inhibits phosphorylation of downstream signal proteins, including glycogen synthase kinase 3b, suppressing tumor proliferation and angiogenesis, and promoting apoptosis. Enzastaurin is highly selective for PKCb, with an inhibition constant of approximately 6 nM. It targets both tumor and endothelial cells to inhibit tumorinduced angiogenesis by suppressing expression of and responses to VEGF. Preclinical and phase 1 studies demonstrated synergistic antitumor effects when enzastaurin was combined with bevacizumab.15
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This randomized, placebo-controlled, phase 2 trial was conducted to assess if adding enzastaurin to the combination of LV5FU2 and bevacizumab as a maintenance therapy would delay progression of advanced/metastatic CRC in patients with objective response or stable disease (SD) after first-line therapy.
MATERIALS AND METHODS Eligibility Criteria Patients were at least 18 years of age with a histologic diagnosis of locally advanced or metastatic CRC (excluding neuroendocrine carcinoma) that was not amenable to curative therapy; an Eastern Cooperative Oncology Group performance status of 0, 1, or 2; and adequate organ function. Patients must have had documented evidence (confirmation not required) of tumor response or SD by computed tomography scan or magnetic resonance imaging after 6 cycles (3 months [12 weeks]) of first-line therapy with standard bi-weekly regimens of FOLFOX5-7 or FOLFIRI8,9 plus bevacizumab for metastatic CRC or recurrent CRC that had relapsed at least 12 months after completion of adjuvant therapy. Prior radiotherapy must have been completed 30 days before beginning first-line therapy, and no more than 4 weeks may have passed between the end of first-line therapy (day 14 of cycle 6) and randomization. Reasons for exclusion included serious cardiac conditions; central nervous system metastases; inadequately controlled hypertension; proteinuria; or history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months before the study. The study was approved by ethical/institutional review boards and was conducted in accordance with the Declaration of Helsinki and good clinical practices. All patients provided signed informed consent. Study Design and Treatment Plan In this multicenter, double-blind, randomized, phase 2 study, patients with stable or responding disease after 6 cycles of induction therapy for metastatic CRC were randomly assigned (1:1) to receive maintenance therapy of either enzastaurin plus LV5FU2 and bevacizumab (enzastaurin arm) or placebo plus LV5FU2 and bevacizumab (placebo arm). The primary objective was to compare PFS from the time of randomization between the maintenance treatment arms. Secondary objectives were to compare OS from the time of randomization, to
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compare PFS and OS from the start of first-line therapy, and to assess safety and adverse event (AE) profiles. Assignment to treatment groups was determined by a computer-generated random sequence using an Interactive Voice Response System. Randomization was stratified for the following prognostic factors at baseline using the blocked randomization method: prior adjuvant therapy (no vs yes) and response to first-line treatment (complete response or partial response vs SD). In the enzastaurin arm, a loading dose (on day 1 of cycle 1) of enzastaurin (Eli Lilly and Company, Indianapolis, Ind) 1125 mg/d was given (30 minutes after a meal) orally (three 125-mg tablets 3 daily) followed by subsequent doses of 500 mg/d orally (two 125-mg tablets 2 daily). In the placebo arm, placebo was given orally 3 daily (as 3 tablets) on day 1 of cycle 1 followed by subsequent doses given orally 2 times daily (as 2 tablets). Both arms received LV5FU2 plus bevacizumab (Genentech/ Roche, South San Francisco, Calif) on day 1 of each cycle (2 weeks): leucovorin 400 mg/m2 intravenously (IV), then 5-fluorouracil 400-mg/m2 bolus followed by 2400 mg/m2 IV over 46 hours, and bevacizumab 5 mg/kg IV. Maintenance treatment continued until the occurrence of progressive disease (PD) or unacceptable toxicity. Enzastaurin doses were not reduced or omitted for laboratory hematologic toxicity that was clearly attributable to 5-fluorouracil/leucovorin or bevacizumab therapy, with the exception of elevated liver transaminases and febrile neutropenia. Any unusual or unexpected AEs that occurred that were above and beyond the expected safety profile of 5-fluorouracil/leucovorin plus bevacizumab combination therapy required omission of enzastaurin until the event resolved. After the event resolved to grade 1 or baseline, patients were restarted on enzastaurin 250 mg daily. Baseline and Treatment Assessments Efficacy analyses were conducted on all randomized patients; safety analyses were conducted on all randomized patients who received at least 1 dose of enzastaurin/ placebo, 5-fluorouracil, leucovorin, or bevacizumab. Disease assessment was made every 6 weeks (that is, after every 3 cycles of treatment) using a modified version of Response Evaluation Criteria in Solid Tumors.16 PFS was defined as the time from the date of randomization (primary objective) or from the start of first-line therapy to the first date of objectively determined PD, clinical progression (defined as global deterioration of health status requiring discontinuation of treatment without objective
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evidence of progression), or death. OS was defined as the time from the date of randomization or from the start of first-line therapy to the date of death. Toxicity was assessed at each cycle using the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 3.0. Statistical Considerations The purpose of this phase 2 study was to detect an improvement in PFS with the addition of enzastaurin to 5-fluorouracil/leucovorin plus bevacizumab, not to rigorously demonstrate superiority. Originally, enrollment of approximately 150 patients (75 patients per arm) was planned, with the expectation of 118 PFS events for the primary efficacy analysis. However, a decision was made to perform an earlier evaluation of the primary endpoint to assess the relevance of outcomes from additional CRC studies, and the study was amended to perform the primary efficacy analysis after at least 50 events of clinical progression, objective progression, or death. At this point, enrollment was stopped, the study treatment assignment was unblinded, and the final analysis was performed. The study was thus powered to detect a 36% improvement in PFS by showing a median PFS of 7.5 months for the enzastaurin arm. By using a log-rank test, the study had at least 60% power to achieve statistical significance at a 1-sided level of .20, assuming at least 50 PFS events at the final analysis and a true PFS hazard ratio (HR) of the enzastaurin arm to the placebo arm of .73.17 PFS and OS were compared between the 2 treatment arms using the log-rank test at the 1-sided significance level of .20. In addition, Kaplan-Meier estimations18 were performed on the observed distributions of PFS and OS, and Kaplan-Meier curves were generated. The Cox regression model19 was used to estimate treatment group differences adjusted for prognostic factors. The incidences of selected AEs from the 2 treatment arms were compared using the Fisher’s exact test at a 1sided significance level of .20. In addition, an interim analysis was conducted to assess the safety parameters of LV5FU2 plus bevacizumab with or without enzastaurin after 15 patients had been randomized and completed at least 1 cycle of study treatment. A post hoc power analysis was also done to estimate the probability of the study’s success if the primary efficacy analysis had been performed as originally planned, that is, after achieving 118 PFS events.20
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Table 1. Patient Demographics and Disease Characteristics at Baseline
Characteristic
Enzastaurin Arm, n558
Placebo Arm, n559
Median age (range), y
63 (34-82)
65 (33-82)
21 [36.2] 37 [63.8]
21 [35.6] 38 [64.4]
55 [94.8] 1 [1.7] 2 [3.4]
54 [91.5] 2 [3.4] 3 [5.1]
Sex, No. [%] Female Male
Race, No. [%] Caucasian African Hispanic
Figure 1. Median progression-free survival (PFS) from randomization is shown. CI, confidence interval.
Prior adjuvant therapy, No. [%] 11 [19.0] 47 [81.0]
Yes No
9 [15.3] 50 [84.7]
Response to first-line treatment, No. [%] Complete or partial response Stable disease
32 [55.2]
34 [57.6]
26 [44.8]
25 [42.4]
42 [72.4] 16 [27.6] 0 [0.0]
45 [76.3] 13 [22.0] 1 [1.7]
n¼53
n¼54
0 [0.0] 6 [11.3] 47 [88.7]
1 [1.9] 1 [1.9] 52 [96.3]
ECOG performance status, No. [%] 0 1 2
Disease stage at study entry, No. [%] IIA IIIA-C IV
Abbreviation: ECOG, Eastern Cooperative Oncology Group.
RESULTS Patient Characteristics From March 7, 2008 to January 27, 2010, 123 patients were entered into the study. Of the 123 patients, 117 patients were randomly assigned to receive enzastaurin (58 patients) or placebo (59 patients; Table 1). Approximately 2=3 (64.1%) of the patients were male, with a median age of 64 years. Greater than 90% of patients presented with stage IV disease. Drug Administration A total of 115 patients were treated, with 57 patients in the enzastaurin arm and 58 patients in the placebo arm completing at least 1 cycle of treatment. The median number of cycles received was 9 (range, 1-36) in the enzastaurin arm and 10 (range, 2-37) in the placebo arm. A total of 27 patients (47.4%) in the enzastaurin arm completed at least 10 cycles of treatment, as did 33 patients (56.9%) in the placebo arm.
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At least 1 dose reduction occurred because of AEs in 2 patients (3.5%) in the enzastaurin arm (AEs of diarrhea, nausea, and vomiting) and 2 patients (3.4%) in the placebo arm (AEs of diarrhea and dizziness). Eighteen patients (31.6%) in the enzastaurin arm and 15 patients (25.9%) in the placebo arm had at least 1 dose omission because of an AE. AEs resulting in a dose omission that occurred in >1 patient in either treatment arm included diarrhea, dizziness, mucosal inflammation, fatigue, and vomiting.
Efficacy In the 117 patients randomized, there were 73 PFS events (39 in the enzastaurin arm, 34 in the placebo arm) for the primary efficacy analysis. The median PFS from randomization was 5.8 months in the enzastaurin arm and 8.1 months in the placebo arm (HR, 1.35; 95% confidence interval [CI], 0.84-2.16; P ¼ .896; Fig. 1). Censoring rates were 32.8% and 42.4% in the enzastaurin and placebo arms, respectively. No significant differences in treatment effect were found when PFS from randomization was analyzed by subgroup (prior adjuvant therapy, response to first-line therapy, and prior FOLFOX/FOLFIRI use). The median PFS from the start of first-line therapy was 8.9 months in the enzastaurin arm and 11.3 months in the placebo arm (HR, 1.39; 95% CI, 0.86-2.23; P ¼ .913). The median OS from randomization was not calculable because of high censoring rates of 77.6% and 91.5% for enzastaurin and placebo, respectively; 41 patients in the enzastaurin arm and 39 patients in the placebo arm had discontinued study treatment at the time of
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Original Article Table 2. Summary of Possibly Drug-Related Maximum Grade 3 to 4 CTCAEs Occurring in >1 Patient
CTCAE Term
Enzastaurin Arm, n557, No. (%)
Placebo Arm, n558, No. (%)
2 (3.5) 4 (7.0)
0 (0.0) 2 (3.4)
2 2 2 2 2 2 1 3 9 1
2 1 2 2 1 0 2 5 1 2
Pa
Grade 3-4 laboratory event Hemoglobin Neutrophils/granulocytes
.243 .438
Grade 3-4 nonlaboratory event Diarrhea Dizziness Fatigue Hypertension Mucositis/stomatitis, clinical exam Mucositis/stomatitis, functional/symptomatic Nausea Rash: hand-foot skin reaction Thrombosis/thrombus/embolism Vomiting
(3.5) (3.5) (3.5) (3.5) (3.5) (3.5) (1.8) (5.3) (15.8) (1.8)
(3.4) (1.7) (3.4) (3.4) (1.7) (0.0) (3.4) (8.6) (1.7) (3.4)
1.000 .618 1.000 1.000 .618 .243 1.000 .717 .008 1.000
Abbreviation: CTCAE, Common Terminology Criteria for Adverse Events. a P value based on Fisher’s exact test.
the analysis. The HR for OS was 3.03 (95% CI, 1.088.51; P ¼ .987). Safety Table 2 summarizes laboratory and nonlaboratory grade 3 and 4 AEs possibly related to study drug. Most AEs occurring during treatment within either arm were grade 1 or 2. More patients developed thrombosis or embolism in the enzastaurin arm than in the placebo arm: 15.8% (grade 3 to 4) and 1.7% (grade 4), respectively (P ¼ .008). Three patients, all in the enzastaurin arm, received transfusions while on study: 2 patients received packed red blood cells (RBCs), and 1 patient received leukoreduced packed RBCs. Six patients in the enzastaurin arm discontinued treatment because of drug-related serious AEs of diarrhea and fatigue (in 2 patients each) and nausea and pulmonary embolism (in 1 patient each). Two patients in the placebo arm discontinued treatment because of drug-related AEs of atrial fibrillation and chapped skin. One patient in the enzastaurin arm died during the study (cycle 10) because of possibly drug-related arrhythmia.
DISCUSSION The role and timing of maintenance therapy remain uncertain in the management of metastatic CRC. Previously, patients were administered standard first-line therapy of FOLFOX or FOLFIRI until progression; however, because of cumulative toxicities, first-line induction ther-
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apy is now often given followed by complete treatment cessation or by maintenance therapy with LV5FU2.7,13 In the current phase 2 study, patients received 6 cycles of induction FOLFOX or FOLFIRI followed by maintenance treatment with the 5-fluorouracil/leucovorin portion of the induction regimen combined with the targeted agent bevacizumab and either enzastaurin or placebo. Enrollment in the trial was stopped, the study results were unblinded, and the final analysis was conducted after 73 PFS events. The addition of enzastaurin to bevacizumab and LV5FU2 failed to improve PFS compared with placebo as maintenance therapy. On the basis of the observed data, the post hoc power analysis showed that even if the study was analyzed after achieving the originally planned 118 events, the probability of the study being successful would be very low (2.8%). It is noteworthy that the study has limited power (60%) and a high type-I error rate (1-sided alpha ¼ .20), thus the results of the study should be interpreted with caution. Nevertheless, the clinically meaningful results in favor of the placebo arm suggest that the termination of further development of maintenance therapy with enzastaurin plus 5-fluorouracil/leucovorin and bevacizumab was in the best interest of the patients. Consistent with the current study, recent results of other phase 2 studies have shown that enzastaurin does not improve efficacy when combined with chemotherapy and bevacizumab in nonsmall cell lung cancer.21 Activity was insufficient in epithelial ovarian or primary peritoneal
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carcinoma, and no PFS benefit was demonstrated with the combination of enzastaurin and capecitabine in metastatic breast cancer that progressed after anthracycline treatment.22,23 The reasons for poor PFS in the enzastaurin arm compared with placebo are uncertain. Because preclinical studies had demonstrated synergistic antitumor effects when enzastaurin was combined with bevacizumab, it seems unlikely that this combination had a negative impact on tumor biology. It is possible that there was a negative interaction between 5-fluorouracil and enzastaurin, which may have compromised the antitumor effect of leucovorin, 5-fluorouracil, and bevacizumab, although no findings currently support that hypothesis. Alternatively, the dual inhibition of the VEGF pathway achieved by combining bevacizumab with enzastaurin to abrogate downstream signaling may have caused more robust compensatory up-regulation of other angiogenic factors such as basic fibroblast growth factor, placental growth factor, or hepatocyte growth factor.24 However, the results of this underpowered study do not support any clear conclusions regarding these hypotheses. In addition, because of the high rate of censoring, the median OS was not calculable. Although this study of maintenance therapy with enzastaurin did not demonstrate efficacy, maintenance with other compounds has shown promise. Bevacizumab has been shown to improve efficacy when added to 5-fluorouracil/leucovorin plus oxaliplatin10,25 or irinotecan.11,12 Additional trials on the optimal duration of chemotherapy plus targeted agents are ongoing, such as OPTIMOX3 (capecitabine or 5-fluorouracil with oxaliplatin plus bevacizumab followed by bevacizumab and erlotinib)26 and CAIRO3 (oxaliplatin, capecitabine, and bevacizumab followed by bevacizumab plus capecitabine or observation).27 The outcome of these ongoing trials may provide guidance on the future direction for the study of maintenance therapy in CRC treatment. In conclusion, although the regimen was tolerable, further development of maintenance therapy with enzastaurin plus LV5FU2 and bevacizumab is not recommended for metastatic CRC based on the results of the current study. Nevertheless, maintenance therapy with other compounds in metastatic CRC is feasible and deserves further study as a means to prolong PFS, decrease toxicity, and ultimately improve survival and enhance quality of life. The current trial design (with a robust sam-
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ple size) could be an effective basis for evaluation of other agents.
FUNDING SOURCES This study was funded by Eli Lilly and Company.
CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures.
REFERENCES 1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277-300. 2. Van Cutsem E, Nordlinger B, Cervantes A. ESMO Guidelines Working Group. Advanced colorectal cancer: ESMO Clinical Practice Guidelines for treatment. Ann Oncol. 2010;21(suppl 5):v93-v97. 3. Anderson N, Lokich J. Controversial issues in 5-fluorouracil infusion use. Dose intensity, treatment duration, and cost comparisons. Cancer. 1992;70(suppl):998-1002. 4. Machover D. A comprehensive review of 5-fluorouracil and leucovorin in patients with metastatic colorectal carcinoma. Cancer. 1997;80:1179-1187. 5. Giacchetti S, Perpoint B, Zidani R, et al. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2000;18:136-147. 6. Andre T, Boni C, Mounedji-Boudiaf L, et al. Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350: 2343-2351. 7. Tournigand C, Cervantes A, Figer A, et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer—a GERCOR study. J Clin Oncol. 2006;24:394-400. 8. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000;355: 1041-1047. 9. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med. 2000;343:905-914. 10. Giantonio BJ, Catalano PJ, Meropol NJ, et al. Eastern Cooperative Oncology Group Study E3200. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25:1539-1544. 11. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335-2342. 12. Sobrero A, Ackland S, Clarke S, et al. AVIRI Trial investigators. Phase IV study of bevacizumab in combination with infusional fluorouracil, leucovorin and irinotecan (FOLFIRI) in first-line metastatic colorectal cancer. Oncology. 2009;77: 113-119.
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Original Article 13. Chibaudel B, Maindrault-Goebel F, Lledo G, et al. Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study. J Clin Oncol. 2009;27:5727-5733. 14. Graff JR, McNulty AM, Hanna KR, et al. The protein kinase Cbeta-selective inhibitor, Enzastaurin (LY317615.HCl), suppresses signaling through the AKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts. Cancer Res. 2005;65:7462-7469. 15. Resta LP, Ermisch S, Collins C, et al. Phase I study of enzastaurin (ENZ) and bevacizumab (BV) in patients with advanced cancer [abstract]. J Clin Oncol. 2008;26(suppl). Abstract 3529. 16. Therasse P, Arbuck SG, Eisenhauer EA, et al. 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. 2000;92: 205-216. 17. Freedman LS. Tables of the number of patients required in clinical trials using the logrank test. Stat Med. 1982;1:121129. 18. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457-481. 19. Cox DR. Regression models and life tables (with discussion). J Royal Stat Soc B. 1972;74:187-220. 20. Crowley J, Ankerst DP, eds. Handbook of Statistics in Clinical Oncology. 2nd ed. Boca Raton, FL: CRC Press; 2006: 232-233. 21. Casey EM, Harb W, Bradford D, et al. Randomized, double-blinded, multicenter, phase II study of pemetrexed, carboplatin, and bevacizumab with enzastaurin or placebo in chemonaive patients with stage IIIB/IV non-small cell lung
4138
22.
23.
24.
25.
26.
27.
cancer: Hoosier Oncology Group LUN06-116. J Thorac Oncol. 2010;11:1815-1820. Usha L, Sill MW, Darcy KM, et al. A Gynecologic Oncology Group phase II trial of the protein kinase C-beta inhibitor, enzastaurin and evaluation of markers with potential predictive and prognostic value in persistent or recurrent epithelial ovarian and primary peritoneal malignancies. Gynecol Oncol. 2011;121:455-461. Clemons M, Joy AA, Abdulnabi R, et al. Phase II, doubleblind, randomized trial of capecitabine plus enzastaurin versus capecitabine plus placebo in patients with metastatic or recurrent breast cancer after prior anthracycline and taxane therapy. Breast Cancer Res Treat. 2010;124:177-186. Kopetz S, Hoff PM, Morris JS, et al. 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. 2010;28:453-459. Hochster HS, Hart LL, Ramanathan RK, et al. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE study. J Clin Oncol. 2008;26:3523-3529. Tournigand C, Lledo G, Delord J, et al. Modified (m) Folfox7/bevacizumab (B) or modified (m) Xelox/bevacizumab with or without erlotinib (E) in first-line metastatic colorectal cancer (MCRC): results of the feasibility phase of the DREAM-OPTIMOX3 study (GERCOR) [abstract]. J Clin Oncol. 2007;25(suppl). Abstract 4097. Simkens L, Tol J, Koopman M, et al. Current questions in the treatment of advanced colorectal cancer: the CAIRO studies of the Dutch Colorectal Cancer Group. Clin Colorectal Cancer. 2008;7:105-109.
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