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Journal of Clinical Oncology, Vol 26, No 14 (May 10), 2008: pp. 2320-2326 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.0152 Bortezomib With or Without Irinotecan in Relapsed or Refractory Colorectal Cancer: Results From a Randomized Phase II Study
From the Continuum Cancer Centers of New York, St Luke's-Roosevelt Hospital; Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL; Arizona Cancer Center, Tucson, AZ; New York University School of Medicine, New York, NY; University of North Carolina School of Medicine, Chapel Hill, NC; Arkansas Cancer Institute, Pine Bluff, AK; Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, Lebanon, NH; Massachusetts General Hospital, Harvard Medical School, Boston, MA; and the University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA Corresponding author: Heinz-Josef Lenz, MD, University of Southern California Norris Comprehensive Cancer Center, 1441 Eastlake Ave, NOR 3456, Los Angeles, CA 90033; e-mail: lenz{at}usc.edu
Purpose To evaluate the efficacy and toxicity of bortezomib with or without irinotecan, in patients with relapsed or refractory colorectal cancer (CRC). Patients and Methods Patients were randomly assigned in a 3:4 ratio to bortezomib 1.5 mg/m2 (arm A) or bortezomib 1.3 mg/m2 plus irinotecan 125 mg/m2 (arm B). A treatment cycle of 21 days consisted of four bortezomib doses on days 1, 4, 8, and 11, plus, in arm B, irinotecan on days 1 and 8. The primary objective of this randomized, multicenter, open-label, phase II study was to determine tumor response to treatment. Secondary objectives were safety and tolerability.
Results A preplanned interim analysis to assess efficacy revealed inadequate activity, resulting in early termination of this study. A total of 102 patients were treated, 45 in arm A and 57 in arm B. Baseline characteristics were comparable. The investigator-assessed response rate was 0 in arm A and 3.5% in arm B (all partial responses). Adverse events in both treatment arms were as expected, with no significant additive toxicity. The most common grade Conclusion Bortezomib alone or in combination with irinotecan was not effective in patients with relapsed or refractory CRC.
Colorectal cancer (CRC) is the third most common cancer and cause of cancer deaths in the United States (US), and the second leading cause of cancer deaths in Europe. An estimated 153,760 new cases and 52,180 deaths are expected to occur in the US in 2007.1,2 The incidence and mortality rates for CRC have been declining; this is believed to be due, at least in part, to improvements in early detection and screening. However, at the time of diagnosis, 61% of patients with CRC have disease that has spread beyond the localized stage,1 and 19% of patients have metastatic disease.3 Fluorouracil (FU) plus leucovorin (LV) has been the standard of care for treatment-naïve metastatic CRC, with median survival outcomes of 12 months. The incorporation of the topoisomerase I inhibitor irinotecan (Camptosar, CPT-11), the third generation platinum compound, oxaliplatin, and the antivascular endothelial growth factor agent, bevacizumab, has increased median survival, measured from initiation of first-line therapy to approximately 20 months.4 However, once disease progression after first-line therapy with FU occurs, prognosis is guarded; combination therapy in this setting results in an overall survival of 9.2 to 12.2 months.5-7 The addition of cetuximab, which blocks the epidermal growth factor receptor, or bevacizumab may provide additional benefit for patients with advanced CRC whose disease failed to respond to irinotecan- or oxaliplatin-based first-line regimens.8-10 Therefore, given the poor prognosis of advanced disease, and the development of resistance to chemotherapeutic agents over time, new, more effective agents and combinations to treat CRC are needed. Bortezomib (Velcade; Millennium Pharmaceuticals Inc, Cambridge, MA, and Johnson & Johnson Pharmaceutical Research & Development LLC, Raritan, NJ), is a potent, reversible, and specific proteasome inhibitor that has been approved in the US and European Union for the treatment of patients with multiple myeloma or mantle-cell lymphoma (US) after one prior therapy. Preliminary activity has been seen in some types of solid tumors in early phase toxicity and dose-finding clinical trials.11-13 In patients with CRC, treatment with single agent bortezomib resulted in stable disease in two of 16 patients in a phase I study,14 and in three of 19 patients in a phase II study.15 Treatment with bortezomib combined with FU/LV in a phase I study also resulted in stable disease in six of 10 assessable patients with CRC.16
The rationale for combining bortezomib with irinotecan was based on observations of antitumor activity in a murine model of colon tumor xenografts. Growth was inhibited to a greater extent by bortezomib plus SN-38, the active metabolite of irinotecan, than the sum of the activities of either agent alone. This suggested, given the different mechanisms of action, that the two agents might be synergistic in a clinical setting.17 Moreover, bortezomib inhibited SN-38-induced activation of the transcription factor nuclear factor In a phase I trial in patients with advanced solid tumors, including 23 patients with CRC, bortezomib plus irinotecan was well-tolerated without additive toxicities.19 Nausea, vomiting, and diarrhea were the principle dose-limiting toxicities, leading to maximum tolerated doses (MTD) of 1.3 mg/m2 bortezomib and 125 mg/m2 irinotecan. The most common grade 3 or higher bortezomib-related adverse events (AE) were fatigue, diarrhea, nausea, neutropenia, and thrombocytopenia, which were rarely dose limiting. Although there were no objective responses, stable disease was observed in 10 (29%) of 34 assessable patients, four of whom had received prior irinotecan, suggesting efficacy studies were warranted. The purpose of this study was to evaluate the efficacy and toxicity of bortezomib alone and in combination with irinotecan in patients with relapsed or refractory CRC.
Patients Patients at least 18 years of age with histologically confirmed, inoperable, locally advanced or metastatic CRC, without symptomatic brain metastases, were eligible to enroll. Patients were required to have a Karnofsky performance status of  70%, a life expectancy of at least 3 months, adequate organ function on day 1 of the first cycle of treatment, and progressive disease after one or two prior therapies. Relapsed or refractory disease was defined as disease recurrence or progression within 6 months of the last dose of an irinotecan- or nonirinotecan-containing regimen; documentation of irinotecan-refractory disease was not required. The trial was conducted in accordance with Good Clinical Practice guidelines as described in the International Conference on Harmonisation final guideline (May 1, 1996) after approval by each study center's institutional review board. All patients provided written informed consent.
Study Design and Drug Administration Patients were randomly assigned in a 3:4 ratio to bortezomib 1.5 mg/m2 (arm A) or bortezomib 1.3 mg/m2 plus irinotecan 125 mg/m2 (arm B). The study was not powered to detect a difference between arms; rather the size of each arm was calculated to detect a response to treatment as described below. Because more patients were required to characterize response rate for arm B, a 3:4 randomization scheme was used. A treatment cycle of 21 days comprised four bortezomib doses on days 1, 4, 8, and 11, plus, in arm B, irinotecan 125 mg/m2 on days 1 and 8. Bortezomib was administered as a 3- to 5-second intravenous push. Irinotecan was administered as a 90-minute intravenous infusion once a week immediately before bortezomib administration.
Efficacy and Safety Assessments
Statistical Analyses
Patient Demographics and Disposition Patients were enrolled from December 23, 2002, until the study was terminated on December 23, 2003. Among 107 patients randomly assigned, 102 patients were treated, 45 in the bortezomib only arm and 57 in the bortezomib plus irinotecan arm. Patient baseline demographics, disease characteristics, and history of prior treatment are presented in Table 1. Notably, nearly all patients on both arms had prior exposure to irinotecan and/or FU. The median number of bortezomib doses received was eight in each treatment group (two cycles).
Efficacy No objective response was seen in the bortezomib only arm; there were two PRs (3.5%) in patients in the bortezomib plus irinotecan arm (Table 2). In the bortezomib only arm, nine patients (20%) had stable disease; stable disease was observed in 22 patients (38.6%) in the bortezomib plus irinotecan arm. The preplanned interim analysis revealed inadequate activity, resulting in early termination of this study.27 Patients who had been randomly assigned continued to receive treatment until the results of the interim analysis were available. The Kaplan-Meier survival curve for the two treatment arms is shown in Figure 1. The median TTP was 43 days for patients receiving bortezomib alone (90% CI, 40 to 46) and 84 days for patients receiving bortezomib plus irinotecan (90% CI, 51 to 100). The median overall survival was 7.8 months for bortezomib alone (90% CI, 5.9 to 10.1) and 5.5 months for bortezomib plus irinotecan (90% CI, 5.0 to 7.6). The 6-month and 1-year survival probabilities were 62% and 25%, respectively, for bortezomib alone, and 50% and 18%, for the combination, respectively. There were insufficient responses to the QOL assessment questionnaires to draw any meaningful conclusions about QOL.
Safety The median number of bortezomib doses received was eight in each treatment group, or two cycles (range, 0 to 4 in bortezomib only arm and 0 to 9 in bortezomib plus irinotecan arm). AEs in both treatment arms were as expected for each agent individually, with no significant additive toxicity. All patients in both treatment arms had at least one AE; 93% of patients in the bortezomib arm and 96% of patients in the bortezomib plus irinotecan arm experienced at least one AE that was considered to be related to study medication. The most common treatment-emergent AEs, reported in 20% of patients in either treatment arm, are listed in Table 3. Common ( 10% of patients) treatment-emergent grade 3 AE are listed in Table 4. Grade 3 AE were reported in 73% of patients in the bortezomib alone arm and 75% of patients in the bortezomib plus irinotecan arm and included fatigue (27%), vomiting (13%), nausea (11%), and peripheral sensory neuropathy (11%) in arm A, and diarrhea (33%), fatigue (25%), neutropenia (23%), thrombocytopenia (18%), dyspnea (12%), abdominal pain (12%), dehydration (12%), and anemia (11%) in arm B. The incidence of serious AE (SAE) was similar between the two treatment arms: 38% in the bortezomib alone arm and 40% in the bortezomib plus irinotecan arm. Gastrointestinal SAE occurred in 25% of patients in both arms and included diarrhea (7%), vomiting (6%), intestinal obstruction (5%), and nausea (5%). Other SAEs included blood and lymphatic disorders (10%); general disorders and administration site conditions (9%); respiratory, thoracic, and mediastinal disorders (7%); nervous system disorders (6%); and vascular disorders (5%). The remaining SAEs occurred at a frequency of 3% or less. Treatment-emergent AEs caused 16% in the bortezomib alone arm and 18% in the bortezomib plus irinotecan arm to discontinue therapy. Other reasons for discontinuation included lack of efficacy, withdrawal of consent, protocol violations, investigator's decision, study termination, elevated bilirubin, clinical progression, and patient death. Within 30 days of the last dose of study drug, 9% of patients in the bortezomib only arm and 7% of patients in the bortezomib plus irinotecan arm had died.
Several important lessons can be learned from analysis of this trial. The obvious one is that bortezomib does not have activity against relapsed and resistant metastatic CRC when given alone or in combination with irinotecan. This negative trial also highlights the inefficiencies that frustrate the current mechanism used to transition novel agents or combinations from the preclinical to the clinical arena. The typical paradigm is that of identifying agents with novel mechanisms of action against known pathogenic targets and then assessing activity in cancer cell lines and in xenograft animal models. Disease-specific activity is then evaluated in phase I and/or II testing. Unfortunately, however, the harvest of clinically relevant cancer drugs by this route is approximately 5% compared with 20% with cardiovascular drugs or slightly more than 15% with infectious disease drugs.28 Obviously, improvement in either or both preclinical identification of novel drugs/combinations and phase I/II strategies will make drug development more efficient.
Specific to this trial, several preclinical observations justified attempts to develop bortezomib in metastatic CRC. In vitro, irinotecan resistance has been associated with upregulation of NF Unfortunately, only 33% to 45% of agents with activity in human xenografts show activity in the clinic31,32 thus the utility of these models is being extensively re-examined.31-36 The overall consensus is that human xenograft models need improvement if we are to see higher rates of translation of activity between the preclinical and clinical setting. Interestingly, predictive accuracy may depend on tumor type. For example, a Canadian retrospective study found xenograft models to be more predictive for non–small-cell lung and ovarian cancer, and less predictive for breast or colon cancer.33 Another issue with xenograft models is that they poorly mimic advanced high-volume metastatic disease.37 Hopefully, genetically engineered mouse models that harbor specific mutations linked to respective human cancers38,39 and systems biology models40-42 will better predict clinical activity. One hundred two patients were treated on this trial. Treatment options for these patients were more limited than they are now and therefore patients were enrolled rapidly. Notably, although oxaliplatin was approved several months before this trial began, no patients on this trial had received prior oxaliplatin. Other drugs for metastatic CRC (eg, bevacuzimab and cetuximab) were not approved until after this trial had been discontinued. Accrual of new patients continued during the interim analysis, as specified by the protocol. The phase II trial mechanism can and should be improved by consistent use of earlier stopping rules so that effective or ineffective treatment may be identified with as few patients as possible. Treatment with the dose and schedule of bortezomib alone and with irinotecan in this study was associated with rates of SAE of 38% and 40%, respectively. These rates are comparable with the 40% SAE rate for either bortezomib or dexamethasone in the phase III trial in patients with multiple myeloma,43 as well as to the hospitalization rate of 39% for patients receiving irinotecan for metastatic CRC that progressed after prior FU therapy; 27% of these SAEs were attributable to irinotecan. In this study, the addition of irinotecan to bortezomib did not significantly enhance toxicity with the exception of a higher than expected rate of grade 3 or higher thrombocytopenia for second-line single-agent irinotecan.44 Bortezomib is known to cause a peripheral neuropathy that is predominantly sensory in nature and is reversible in a majority of patients.43,45-47 The incidence of peripheral sensory neuropathy was similar for bortezomib alone and bortezomib plus irinotecan. Bortezomib will continue to be developed in hematologic malignancies. and certain subtypes of non-Hodgkin's lymphoma, particularly mantle cell lymphoma. Bortezomib has also shown activity in some solid tumor types, particularly in combination therapy (eg, advanced androgen-independent prostate cancer),48-50 recurrent ovarian cancer,51 and non–small-cell lung cancer.52,53 However, bortezomib has minimal activity in other solid tumor types, including metastatic breast cancer, renal cell carcinoma, and metastatic melanoma.54-59 The reasons for this variable activity are not known, but might include differences in the reliance on proteasome-dependent pathways and the ability of proteasome inhibition to interfere with tumor type-specific cell cycle and antiapoptotic mechanisms. It is also possible that CRC metastases are less permeable to bortezomib than other tumor types.14,19,58 Combination of irinotecan plus bortezomib may be active in an irinotecan-naïve or less heavily pretreated CRC patient population, and other agents, including novel and targeted therapies now in development may be more effective in patients with advanced, refractory CRC when used in combination with bortezomib. A phase I trial of bortezomib in combination with FU/LV plus oxaliplatin in patients with advanced or metastatic CRC who have received no prior oxaliplatin and no prior palliative chemotherapy, is ongoing. Patients will receive escalating doses of bortezomib on days 1, 8, and 15 of a 28-day cycle until the MTD is determined. Additional patients will receive treatment at the MTD to a maximum of 12 patients. The results of this study and the lack of responses with bortezomib alone reported in a recent nonrandomized phase II study of patients with previously treated metastatic CRC suggest that single-agent bortezomib should not be further investigated in relapsed CRC.15
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: None Consultant or Advisory Role: Bert H. O'Neil, Pfizer (C); David P. Ryan, Pfizer (C); Heinz-Josef Lenz, Pfizer (C) Stock Ownership: None Honoraria: Caio Max Rocha-Lima, Pfizer; Bert H. O'Neil, Pfizer; David P. Ryan, Pfizer; Heinz-Josef Lenz, Pfizer Research Funding: Caio Max Rocha-Lima, Pfizer; Bert H. O'Neil, Millenium; Omar T. Atiq, Millenium Pharmaceuticals; Heinz-Josef Lenz, Pfizer, Millenium Expert Testimony: None Other Remuneration: None
Conception and design: Caio Max Rocha-Lima, Tomislav Dragovich, Howard Hochster, Bert H. O'Neil, David P. Ryan Provision of study materials or patients: Peter S. Kozuch, Caio Max Rocha-Lima, Tomislav Dragovich, Howard Hochster, Bert H. O'Neil, Omar T. Atiq, J. Marc Pipas, Heinz-Josef Lenz Collection and assembly of data: Peter S. Kozuch, Omar T. Atiq, Heinz-Josef Lenz Data analysis and interpretation: Peter S. Kozuch, Tomislav Dragovich, Heinz-Josef Lenz Manuscript writing: Peter S. Kozuch, Tomislav Dragovich, J. Marc Pipas Final approval of manuscript: Peter S. Kozuch, Caio Max Rocha-Lima, Tomislav Dragovich, Howard Hochster, Bert H. O'Neil, Omar T. Atiq, J. Marc Pipas, David P. Ryan, Heinz-Josef Lenz
The 049 Study Group. Omar Atiq, Arkansas Cancer Institute, Pine Bluff, AR; Ahmed Behairy, West Michigan Regional Cancer and Blood Center, Ludington, MI; Charles Blanke, Oregon Health Sciences University, Portland, OR; Joseph Bond, Bond Clinic Inc, Rolla, MO; Gregory Brouse, Piedmont Oncology Specialists, Monroe, NC; Tomislav Dragovich, Arizona Cancer Center, Tucson, AZ; Peter Eisenberg, California Cancer Care, Greenbrae, CA; Susan Ferguson, Jefferson Clinic P.C./Cooper Green Hospital, Birmingham, AL; Howard Hochster, New York University School of Medicine, New York, NY; David Irwin, Alta Bates Comprehensive Cancer Center, Berkley, CA; Peter Kozuch, St Lukes-Roosevelt Hospital, New York, NY; Renato LaRocca, Kentuckiana Cancer Institute, Louisville, KY; Heinz-Josef Lenz, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; William Leslie, Rush Cancer Institute, Chicago, IL; Mark McNamara, City of Hope Medical Group, Pasadena, CA; Donald Northfelt, Mayo Clinic Arizona, Scottsdale, AZ; Bert O'Neil, University of North Carolina School of Medicine, North Carolina Clinical Cancer Center, Chapel Hill, NC; Amita Patnaik, University of Texas Health Sciences Center at San Antonio, San Antonio, TX; Marc Pipas, Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, Lebanon, NH; Elizabeth Poplin, The Cancer Institute of New Jersey, New Brunswick, NJ; Caio Max Rocha-Lima, H. Lee Moffitt Cancer Center, Tampa, FL; Donald Strickland, Memphis Cancer Center, PC, Memphis, TN; Miguel Villalona, Ohio State University Medical Center, Columbus, OH; and Nikolaos Touroutoglou, Nevada Cancer Center, Las Vegas, NV.
The authors thank Lynne Lederman, PhD, for assistance in preparation of the manuscript.
Supported by Millennium Pharmaceuticals Inc, and Johnson & Johnson Pharmaceutical Research and Development. Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Davis NB, Taber DA, Ansari RH, et al: Phase II trial of PS-341 in patients with renal cell cancer: A University of Chicago Phase II Consortium study. J Clin Oncol 22:115-119, 2004 57. Kondagunta GV, Drucker B, Schwartz L, et al: Phase II trial of bortezomib for patients with advanced renal cell carcinoma. J Clin Oncol 22:3720-3725, 2004 58. Caravita T, de Fabritiis P, Palumbo A, et al: Bortezomib: Efficacy comparisons in solid tumors and hematologic malignancies. Nature Clinical Practice Oncology 3:374-387, 2006[CrossRef][Medline] 59. Rajkumar SV, Richardson PG, Hideshima T, et al: Proteasome inhibition as a novel therapeutic target in human cancer. J Clin Oncol 23:630-639, 2005 Submitted August 15, 2007; accepted January 22, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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TOP
ABSTRACT
INTRODUCTION
B (NF
