Drug Development in Advanced Colorectal Cancer: Challenges and Opportunities Robin K. Kelley, MD, and Alan P. Venook, MD

Corresponding author Alan P. Venook, MD University of California, San Francisco, 1600 Divisadero Street, Box 1705, San Francisco, CA 94115, USA. E-mail: [email protected] Current Oncology Reports 2009, 11:175–185 Current Medicine Group LLC ISSN 1523-3790 Copyright © 2009 by Current Medicine Group LLC

Despite recent advances in treatment options, advanced colorectal cancer (ACC) remains a leading cause of cancer death worldwide, and new therapies are needed to improve the grim prognosis of this disease. Drug development in ACC faces the challenges of a constrained pipeline, a paucity of patients enrolled in clinical trials, and an outdated “one drug fits all” model of clinical research. This article discusses potential innovations in clinical trial design—including enrichment strategies, novel patient populations, and the use of randomization in the phase 2 setting— to optimize the testing of new therapies. It concludes with a selection of promising agents and pathways under investigation in ACC.

who develop chemotherapy resistance and cumulative toxicity on standard therapies. Ongoing clinical trials in ACC feature a wide array of new drugs directed at validated and not-yet validated targets. As important as the drugs and targets themselves, however, is the clinical trial design required to detect meaningful improvements. The current paradigm of large-scale randomized phase 3 trials has played an important role in establishing the current standards of care for patients with ACC. However, with the evolution of targeted therapies and movement away from a “one drug fits all” therapeutic model, the randomized phase 3 design imposes significant fi nancial and temporal stress on drug development. Innovative trial designs—such as enrichment with molecular biomarkers or randomization in phase 2 instead of a traditional Simon’s model—may offer an efficient means to identify clinically meaningful improvements in outcome. ACC remains a grim diagnosis, and ongoing research is critical to identify new, active drugs and their targets. This article discusses potential adaptations of clinical trial design to best demonstrate efficacy and defi ne the target populations for these new drugs; it also presents a selection of promising agents and pathways under investigation in ACC.

Introduction Treatment options for advanced colorectal cancer (ACC) have evolved dramatically over the past decade, and the median overall survival for patients with metastatic disease has nearly doubled. Since 2000, six new cytotoxic and biologic agents have been approved for use in ACC in the United States. Despite these new treatment options, however, ACC continues to be a leading cause of cancer death. An estimated 677,000 deaths from ACC occur annually worldwide, and the median survival of patients with metastatic disease remains less than 2 years [1]. Furthermore, there are still some patients who demonstrate primary refractory disease despite the expanded armamentarium of therapeutic agents. There is great need for new drugs to treat these primary refractory patients as well as those

Current Therapeutic Agents and Targets Compared with 5-fluorouracil (5-FU), which has been in use for half a century, irinotecan and oxaliplatin are new agents, fi rst approved for use in ACC in 2000 and 2002, respectively. Their rapid integration into standard practice, however, should make them familiar to all clinicians who care for colorectal cancer patients. More recently, three new biologic agents were approved for use in metastatic colorectal cancer, two of which are under investigation in the adjuvant setting. The recombinant, humanized monoclonal antibody bevacizumab, which targets vascular endothelial growth factor (VEGF), received US Food and Drug Administration (FDA) approval in 2004 for use in ACC after demonstrating an

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improved response rate, response duration, and overall survival in combination with 5-FU–based therapies [2–4]. Two agents targeting the epidermal growth factor receptor (EGFR) also have been approved for use in ACC since 2004. The chimeric monoclonal IgG1 antibody, cetuximab, demonstrates modest single-agent response rates and a small but significant improvement in overall survival compared with best standard care alone in heavily pretreated patients with ACC [5,6]. Cetuximab also appears to reverse irinotecan resistance in a subset of cases [7]. The human monoclonal IgG2 antibody, panitumumab, was approved for use in ACC in 2006 after demonstrating improvement in progression-free survival (PFS) compared with best supportive care alone in patients with refractory ACC [8]. Each of these EGFR antibodies was developed in patients selected for tumors overexpressing epidermal growth factor based on immunohistochemistry (IHC). This effort to “select” patients and subsequent developments should make one pause when contemplating clinical trial methodologies. IHC positivity was quickly discredited as an enrichment strategy when it became apparent that some patients without EGFR IHC positivity responded to EGFR-targeted antibodies [7,9]. Thereafter, retrospective analyses of old data and archived tissue identified mutations in exon 2 of the G protein oncogene K-ras as biomarkers for nonresponse to therapy with cetuximab and panitumumab in ACC [10,11,12•,13,14]. This surprise led to a search downstream of K-ras, and it is now apparent that mutations in the serine–threonine tyrosine kinase B-raf also may confer resistance to the EGFR antibodies [15]. The identification of K-ras and, at least preliminarily, B-raf mutational status as biomarkers of nonresponse to EGFR-targeted therapies represents the first step toward individually tailored therapy in this disease. These “targeted therapies” raise the potential for personalized medicine in the treatment of ACC. However, they also have escalated costs of therapy substantially, and improvements in survival have been modest although statistically significant [16]. Yet, probably as many as 20% of patients demonstrate disease refractory to initial therapies, and chemotherapy resistance or treatment-limiting toxicity arises in nearly all patients. Clearly, there remains a great need for new options.

Challenges to New Drug Development in ACC Pipeline problem Although the $800 million price tag for a new drug approval pales in comparison with the global fiscal crisis, drug development in oncology comes with significant financial risk and logistical challenge [17]. In 2006, it was estimated that only 8% of compounds studied in the phase 1 setting would ever be approved [18,19]. To address the decline in new drug and product development, the FDA released the Critical Path Initiative in

2004 to revitalize the medical product development process as well as clinical trial methodology [20]. Acting on this initiative, the FDA presented the Critical Path Opportunities Report and List in 2006, detailing six topic areas to improve upon the current models of medical product development [21]. Relevant to drug development in particular, topics I and II focus on the need to develop new biomarkers and disease models as well as to streamline and innovate in clinical trial design to overcome existing barriers to the approval of new agents. A systematic survey of ongoing therapeutic trials in metastatic colorectal cancer assessed 102 active phase 2 and 3 clinical trials listed in the National Institutes of Health online database [22••]. The cumulative target accrual of these trials was more than 20,000 patients. Most of these trials (54%) evaluated drugs already approved for use in colorectal cancer, whereas a minority (25%) tested at least one agent not FDA approved for any indication. Phase 2 trials using approved drugs in previously untreated patients comprised nearly 30% of all trials. Only 13 trials (13%) applied an enrichment trial design, accounting for 3% of the patients enrolled in trials. The survey concluded that current clinical trials for metastatic colorectal cancer are “deficient in the investigation of agents directed at a novel therapeutic target, commonly overuse phase II studies of existing FDA-approved agents, and largely fail to incorporate enrichment trial designs.” Challenges to patient accrual as well as anachronistic trial design compound these limitations.

Low patient accrual rates Inadequate patient accrual to clinical trials is an age-old challenge to new drug development. Current patient participation in oncology research is estimated to be a mere 3% of cancer patients, most of whom are treatment naïve or minimally treated [22••,23••]. In such populations, very large trials of long duration are required to detect small differences in efficacy between treatment regimens using the conventional end points of response rate and PFS. On the other hand, heavily treated, refractory patients generally demonstrate much shorter PFS, enabling smaller and more expedient trials with a tradeoff: extensive prior therapy decreases the likelihood of demonstrating tumor shrinkage with a new therapeutic agent. Compounding these issues is the practical difficulty of enrolling patients in randomized trials, particularly those with an inactive arm, although these studies offer the greatest ability to demonstrate efficacy (or lack thereof). The reason for low accrual rates is unknown. One possibility is the multiplicity of treatment options for patients with ACC. After progression through multiple standard regimens, many patients demonstrate inadequate performance status for clinical trial participation. Another potential factor contributing to low patient accrual rates may be the perceived burdensome regulatory requirements

Drug Development in Advanced Colorectal Cancer

in clinical research, which mandate research infrastructure and discourage community oncologists from offering clinical trials. As cited earlier, it also is noteworthy that most ongoing trials in ACC involve therapeutic agents already approved for use in colorectal cancer, whereas few trials feature new, unapproved agents. For physicians and patients alike, this may dampen enthusiasm for clinical trial participation and incline them toward off-the-shelf options.

The “one drug fits all” model The EGFR inhibitors cetuximab and panitumumab in ACC illustrate another challenge in drug development: the identification of patients most likely to benefit from a new therapy. Failure to study targeted drugs in a selective fashion significantly hinders the ability to detect treatment effect, requiring larger studies and greatly increasing time and expense [24]. Furthermore, new targeted agents may confer toxicity without any promise of benefit to the subsets of patients destined not to respond. The identification of K-ras and potentially B-raf mutational status as predictive biomarkers of nonresponse to EGFR inhibitors heralds a new era of personalized medicine in colorectal cancer, as discussed earlier [10,11,12•,13,14,25]. However, identification of such biomarkers of response to a targeted therapy requires a strong preclinical model and clinical validation. As noted earlier, this is exemplified by the case of EGFR IHC, which despite a strong molecular rationale, does not correlate with clinical response to cetuximab or panitumumab in ACC [7,9].

Anachronistic trial design Conventional clinical trial designs present additional impediments to new drug development, particularly now, in the era of targeted therapeutics. The advent of biologic therapies requires reevaluation of the standard dose-fi nding “3 + 3” phase 1 design to defi ne a maximum tolerated dose, because biologic agents may not operate in a linear dose–response fashion. Assessment of the toxicities of chronic biologic therapeutics requires additional changes in the standard safety monitoring protocols used in phase 1 studies of cytotoxic therapy. It is noteworthy that certain toxicities may correlate with on-target efficacy, requiring careful consideration of defi nitions of dose-limiting toxicity [26–28]. In later-phase studies, conventional clinical trial end points of response rate and PFS also are problematic. In particular, biologic agents are more likely to lead to disease stabilization, rather than tumor shrinkage, as best response [29•]. Furthermore, in heavily treated, refractory patients with colorectal cancer, responses as defi ned by the heavily criticized Response Evaluation Criteria in Solid Tumor (RECIST) are rare. To demonstrate that RECIST are of uncertain value in current drug development, one need look no further than the remarkable story of gastrointestinal stromal tumor and its sensitivity to imatinib [30].

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Although disease stabilization as measured by radiographic end points such as PFS and time to progression may be a more clinically meaningful end point in the study of new agents and in refractory patient populations, these end points demonstrate wide variability, even among untreated patients [29•]. A control group is required, therefore, to substantiate progression or stability end points. The traditional phase 2 trial design of a single-arm study relies on historical controls and the premise that tumor shrinkage in the absence of therapy is exceedingly unlikely. This paradigm therefore may be inadequate to evaluate end points such as PFS or disease stability in testing new targeted therapies or refractory patient populations.

Opportunities Biomarkers and trial enrichment Looking forward, key opportunities arise from these challenges. During the past year, the concept of the enrichment trial has become a reality. K-ras and B-raf mutations now can inform enrichment in trials evaluating EGFR inhibitors. Furthermore, patients with K-ras– and B-raf–mutant tumors are a unique population in which to test novel agents in ACC, because they will have received fewer lines of prior standard therapy and therefore may represent a fitter population for clinical trials in refractory ACC. This premise is supported by the recently presented data from several large randomized phase 3 trials demonstrating that K-ras mutation does not appear to be an independent prognostic factor [12•,14]. Cohen et al. [31•] recently published a study demonstrating that levels of circulating tumor cells (CTCs) are predictive of response to therapy and independently prognostic of survival in ACC patients. Stratification by CTC levels in clinical trials may enhance the ability to identify efficacious treatments, and serial monitoring of CTC levels during therapy may provide an early biologic surrogate of response that could influence subsequent decision making. Genomics expression profiles also may prove an important tool to stratify or enrich patients participating in therapeutic trials for ACC by markers of sensitivity or resistance to a given cytotoxic therapy, following the precedent of excision repair cross-complementation group 1 (ERCC1) polymorphisms, which predict responsiveness to cisplatin in multiple malignancies [23••,32]. Genomic markers such as loss of heterozygosity at the 18q locus or mismatch repair protein deficiency also may confer prognostic information in ACC.

Innovations in clinical trial design and patient population With a few biomarkers now a reality, clinical trial design must move away from the “one drug fits all” model toward smaller, enrichment trials designed to test novel agents in the subset of patients most likely to respond, as discussed earlier. The selection of end points must reflect

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not only the patient population being tested, but also the potential mechanism of the therapeutic agent in question, noting that disease stabilization end points rather than RECIST may be more relevant in some cases, as discussed earlier. Novel imaging modalities also may play a role in earlier assessment of the efficacy of new agents, although these new modalities will require validation as surrogates for proven efficacy end points. Randomized, phase 2 trial designs improve the detection efficacy of new agents using radiographic progression end points. Enrichment and randomization in phase 2 trials also may reduce the incidence of expensive late-phase drug development failures [22••]. Novel patient populations may complement novel trial designs. For example, patients with ACC demonstrating stable disease after 6 months of fi rst-line therapy could be randomly assigned to placebo or a new agent, or treated with a run-in period of a new agent, followed by a randomized discontinuation strategy in patients maintaining stable disease [23••,29•]. Patients with tumors harboring mutations in K-ras or B-raf are another valuable population for clinical trials, enabling comparison of new agents in patients with mutations against the benchmark of EGFR inhibitor therapy in those with wild-type tumors. Other unique populations for clinical trials include patients with no evidence of disease after resection of solitary liver or lung metastases but with high risk for recurrence. Phase 2 studies of new agents with placebo randomization and time-to-recurrence end points may prove a rapid means of demonstrating efficacy in this population [23••].

Promising New Agents in the Pipeline There are nearly 300 ongoing clinical trials in metastatic colorectal cancer listed in the US National Cancer Institute Clinical Trials Registry. Table 1 and Table 2 present a subset of important phase 2 and 3 trials of novel drugs featured in this registry. These studies collectively involve a wide array of new therapeutic agents, combinations, and delivery methods. Following is a discussion of a small selection of experimental agents and targets. However, there is significant interplay among these mechanisms and pathways, rendering the categories somewhat arbitrary. It also is important to remember that some of these pathways and drugs under investigation have yet to be validated in the clinical arena, and their categorization as “promising” may be interpreted alternatively as “not proven to be unpromising.” In general, to maximize the proportion of new agents proceeding beyond phase 1 testing, clinical trials evaluating new agents and targets should be promoted over those evaluating approved agents [22••].

New drugs, old targets Thymidylate synthase (TS) was the fi rst target in ACC, based largely on the clinical success of the fluoropyrimi-

dines in this disease. Two oral fluoropyrimidine prodrugs, tegafur-uracil (UFT) and S1, have been tested in ACC, with promising results. Two randomized phase 3 studies demonstrated similar response and survival outcomes and improved toxicity profi les with the use of UFT plus leucovorin compared with 5-FU/leucovorin [33,34]. The agent S1, a combination of tegafur and the biomodulators 5-chloro-2,4-dihydroxypyridine and potassium oxonate, is designed to prolong half-life by impairing dihydropyrimidine dehydrogenase drug metabolism and to reduce gastrointestinal toxicity [35]. In a small phase 2 trial, S1 demonstrated activity as monotherapy in patients with previous 5-FU chemoresistance and is currently being studied in combination regimens [36]. Neither S1 nor UFT/leucovorin has been compared directly with capecitabine in ACC, and neither is likely to be approved by the FDA in the near future. Early-phase clinical trials evaluating several other novel approaches to TS inhibition are underway. These include liposomal formulations, administration of 5-FU prodrugs as maintenance therapies, and use in combination with immune strategies [37,38]. Preclinical studies have identified additional potential therapeutic targets in the dTTP (thymidine triphosphate) synthetic pathway to address the problem of chemotherapy resistance.

Topoisomerase I Liposomal formulations of the camptothecin irinotecan as well as its active metabolite, SN-38, are under investigation in a variety of solid tumor types, including ACC. Liposomal incorporation of topoisomerase I inhibitors has shown promising results in mouse xenograft models of colorectal cancer liver metastases [39,40]. In ACC patients, preliminary results from a phase 2 clinical trial of a novel liposomal formulation of irinotecan and floxuridine (FLOX) suggest a tolerable side effect profi le and an encouraging response rate in irinotecan-naïve patients after progression on FOLFOX (leucovorin, 5-FU, and oxaliplatin) therapy [41]. Other irinotecan formulations are in clinical trials, including an agent that incorporates hyaluronic acid into the molecule, potentially improving targeted delivery to tumor. Preliminary randomized phase 2 data suggest that hyaluronic acid labeling may confer increased efficacy, and a phase 3 trial of this agent is in the planning stage [42].

VEGF and angiogenesis Given the success of bevacizumab in ACC, many other antiangiogenic agents are being explored in ACC. The multikinase inhibitor sunitinib demonstrated modest single-agent activity in a phase 2 study in ACC patients [43]. Sunitinib and the serine–threonine kinase inhibitor sorafenib also are being studied in combination regimens in ACC. Brivanib, another new oral multikinase inhibitor with antiangiogenic activity, targets the VEGF receptor

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(VEGFR) as well as fibroblast growth factor receptor (FGFR); this agent has demonstrated antitumor effects in multiple human tumor xenograft models [44,45]. In humans, brivanib has been studied in the phase 1 setting as monotherapy as well as in combination with cetuximab and is now in phase 2 trials [46,47]. In addition to these small molecule tyrosine kinase inhibitors, several new antibodies are in development to target elements in the VEGF pathway, including VEGFR, integrins, FGFR, and platelet-derived growth factor receptor [48]. Other antiangiogenic approaches undergoing preclinical and early-phase study include afl ibercept (VEGF Trap), a fully human, soluble VEGFR fusion protein, and RNA-interference mechanisms [48].

Cell survival: mammalian target of rapamycin and the phosphoinositide 3-kinase pathway

EGFR

Growth factor receptors: insulin-like growth factor type I receptor

Additional EGFR-targeted therapies under investigation in ACC include several small molecule tyrosine kinase inhibitors, including erlotinib, and the dualkinase inhibitor lapatinib, which targets EGFR as well as another molecule in the EGFR family of receptors: Her2/neu (human EGFR type 2) [49]. These agents have been approved for use in lung cancer and breast cancer, respectively. As has been demonstrated with monoclonal antibody EGFR inhibitors in ACC and tyrosine kinase inhibitors in lung cancer, the future use of these small molecules in ACC may require testing for K-ras and B-raf mutational status.

The mammalian target of rapamycin (mTOR) is a serine–threonine kinase downstream of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway, a key mediator of cell growth and survival involved in several human malignancies [58]. Preclinical studies suggest that activated, phosphorylated mTOR protein levels are increased in colorectal cancers [59]. In a small phase 1 study in patients with advanced solid tumors, the oral mTOR inhibitor everolimus produced a sustained partial response in a patient with refractory ACC [60]. Other mTOR inhibitors, as well as upstream PI3K/AKT inhibitors, also are in clinical trials.

New Agents and Targets on the Horizon in ACC

Insulin-like growth factor type I receptor (IGF-IR) is a receptor tyrosine kinase involved in tumor progression in multiple malignancies, and elevated levels of IGF-I are associated with increased risk of developing certain malignancies, including colorectal cancer [61]. In colorectal cancer cell lines, blockade of IGF-IR with a monoclonal antibody or tyrosine kinase inhibitor has been shown to inhibit proliferation and induce cell cycle arrest and apoptosis [62–64]. A small phase 1 trial of a monoclonal antibody targeting IGF-IR, CP-751,871, demonstrated minimal toxicity in patients with refractory solid tumors [65]. Sponsored by Pfi zer, a phase 2 trial of this antibody is currently underway to evaluate single-agent efficacy in patients with treatment-refractory ACC.

Cell differentiation: the Notch, hedgehog, and Wnt pathways

Mitosis/cell cycle

Human colorectal cancer tumor specimens demonstrate activated Notch signaling, a pathway involved in cell differentiation and organogenesis [50]. In a mouse model of APC mutation, a γ-secretase inhibitor of Notch induced goblet cell differentiation in adenomas, suggesting a potential therapeutic role for this class of agents in ACC [51]. A novel oral Notch inhibitor, MK-0752, has been tested in the phase 1 setting in patients with advanced solid tumors [52]. Hedgehog and Wnt, two other important pathways in human development, may influence tumorigenesis and invasion in ACC, although the regulatory interactions between these pathways are complex, vary among different tissue types, and depend on many other proteins and pathways [53–56]. GDC-0449 is an oral inhibitor of smoothened, a protein in the hedgehog pathway, that has demonstrated safety and tolerability in the phase 1 setting as well as preliminary evidence of efficacy in patients with basal cell carcinoma [57]. A phase 2 clinical trial cosponsored by Genentech and Roche is in development to test this agent in combination with fi rst-line cytotoxic therapy in colorectal cancer [57].

Several new biologic agents targeting enzymes involved in mitosis and the cell cycle are in development, in hopes of achieving greater efficacy and less toxicity than conventional chemotherapeutic agents that inhibit cell division, such as the antitubulins. One example is the aurora kinase family of serine–threonine kinases, which are overexpressed in several human malignancies, including colorectal cancer [66–68]. Small phase 1 clinical trials of two aurora kinase inhibitors, AZD1152 and PHA-739358, in patients with advanced solid malignancies have demonstrated acceptable safety profi les and the suggestion of disease stabilization in several heavily pretreated patients [69,70]. Early-phase clinical trials are underway to evaluate other new aurora kinase inhibitors. Epothilones are derived from myxobacteria and exert an antimitotic effect by inducing tubulin polymerization, thereby inhibiting microtubule formation. Epothilone analogues have demonstrated preclinical activity in several malignancies, including colorectal cancer. The novel epothilone analogue BMS-247550 (ixabepilone) was approved recently for use in refractory breast cancer. However, multiple early-phase trials of epothilone analogues,

Study of NGR-hTNF as Single Agent in Patients Affected by Colorectal Cancer (CRC) NGR-hTNF Administered in Combination With a Standard Oxaliplatin Based Regimen in Patients With Metastatic Colorectal Cancer A Study Combining FOLFOX or FOLFIRI With AG-013736 or Avastin in Patients With Metastatic Colorectal Cancer After Failure of One First Line Regimen

NCT00483080

NCT00675012

NCT00615056

Study Using CP-751,871 in Patients With Stage IV Colorectal Cancer That Has Not Responded to Previous Anti-Cancer Treatments A Study to Determine the Activity of SCH 717454 in Subjects With Relapsed or Recurrent Colorectal Cancer (Study P04721AM1)

NCT00560560

NCT00551213

SCH 717454 (IGF-IR antibody)

CP-751,871 (IGF-IR antibody)

Schering-Plough

Pfizer

Merck

Merck

Vorinostat (SAHA; HDAC inhibitor) MK0646 (IGF-IR antibody)

Novartis

Genentech

Novartis

Taiho

LBH589 (HDAC inhibitor)

GDC-0449 (hedgehog antagonist)

Celebrex, EPO906 (epothilone)

TAS-109 (novel deoxycytidine analogue)

Amgen

Pfizer

*Information from the National Cancer Institute (NCI) website http://www.cancer.gov. DR5—death receptor 5; HDAC—histone deacetylase; IGF-IR—insulin-like growth factor type I receptor; MCRC—metastatic colorectal cancer; mTOR—mammalian target of rapamycin; NGR-hTNF—tumor-homing peptide plus human tumor necrosis factor; PDGFR—platelet-derived growth factor receptor; SAHA—suberoylanilide hydroxamic acid; VEGFR—vascular endothelial growth factor receptor.

Study of MK0646 in Combination With Cetuximab and Irinotecan in Metastatic Colon Cancer

Vorinostat and IV Fluorouracil/Leucovorin (5FU/LV) in Patients With Metastatic Colorectal Cancer

NCT00336141

NCT00614393

Phase II Trial of LBH589 in Refractory Colorectal Cancer

NCT00690677

HDAC inhibitors

Phase I/II Study of Celebrex and EPO906 in Patients With Metastatic Colorectal Cancer

NCT00159484

A Study of Systemic Hedgehog Antagonist With Concurrent Chemotherapy and Bevacizumab as First-Line Therapy for Metastatic Colorectal Cancer

Phase II Study of TAS-109 to Treat Advanced Colorectal Cancer

NCT00824161

NCT00636610

IGF-IR antibodies

AG-013736 (axitinib, oral VEGFR/ c-kit/PDGFR inhibitor)

MolMed

MolMed

NGR-hTNF (novel vascular targeting agent) NGR-hTNF (novel vascular targeting agent)

Cancer and Leukemia Group B

Eisai

Sponsor(s)

Cediranib (VEGFR tyrosine kinase inhibitor)

E7820 (antiangiogenic agent targeting α2 integrin)

Investigational agent(s)

A Phase 2, Randomized, Double Blind, Placebo Controlled Study AMG 386 (peptibody that neutralof AMG 386 in Combination With FOLFIRI in Subjects With izes angiopoietins 1 and 2) Previously Treated Metastatic Colorectal Carcinoma

Phase II Study of Irinotecan Hydrochloride and Cediranib in Patients With Metastatic Colorectal Cancer That Progressed During Treatment With Either FOLFOX and Cetuximab or FOLFOX and Bevacizumab and Cetuximab

NCT00588900

NCT00752570

A Phase II Study of the Safety and Efficacy of E7820 Plus Cetuximab in Colorectal Cancer, Preceded by a Run-in Study in Advanced Solid Tumors

NCT00309179

Title

Hedgehog antagonists

Antiproliferative agents

Antiangiogenic agents

Study no.

I

Drug type

Table 1. Selected important ongoing phase 2 trials of new agents in advanced colorectal cancer*

180 Gastrointestinal Cancers

Phase 2 Study of ABT-869 in Combination With mFOLFOX6 Versus Bevacizumab in Combination With mFOLFOX6 to Treat Advanced Colorectal Cancer Phase II Study of Dasatinib in Patients With Previously Treated Metastatic Colorectal Cancer

NCT00707889

NCT00504153 Phase 1b/2 Study of AMG 655 With mFOLFOX6 and Bevacizumab for First-Line Metastatic Colorectal Cancer

Phase II Study of Sorafenib Tosylate and Bevacizumab in Patients With Metastatic Colorectal Cancer

NCT00826540

NCT00625651

Phase II Study of Sorafenib and Cetuximab in Patients With Epidermal Growth Factor Receptor–Expressing Metastatic Colorectal Cancer

NCT00343772

Expanded Cohort for MCRC Using Bevacizumab + Everolimus

NCT00597506

Title Phase I/Randomized Phase II Study of Second Line Therapy With Irinotecan + Cetuximab +/- RAD001 for Colorectal Cancer

Study no.

NCT00522665

AMG 655 (monoclonal antibody to DR5)

Dasatinib (BCR-ABL and src-family tyrosine kinase inhibitor)

ABT-869 (multitarget receptor tyrosine kinase inhibitor including VEGFRs)

Sorafenib (multikinase inhibitor/ antiangiogenic agent)

Sorafenib (multikinase inhibitor/ antiangiogenic agent)

Everolimus (mTOR inhibitor)

RAD001 (everolimus, mTOR inhibitor)

Investigational agent(s)

(Continued)

Sponsor(s)

Amgen

NCI

Abbott

North Central Cancer Treatment Group

NCI

Duke Comprehensive Cancer Center, Novartis, Genentech

Hoosier Oncology Group, Novartis, Pfizer

*Information from the National Cancer Institute (NCI) website http://www.cancer.gov. DR5—death receptor 5; HDAC—histone deacetylase; IGF-IR—insulin-like growth factor type I receptor; MCRC—metastatic colorectal cancer; mTOR—mammalian target of rapamycin; NGR-hTNF—tumor-homing peptide plus human tumor necrosis factor; PDGFR—platelet-derived growth factor receptor; SAHA—suberoylanilide hydroxamic acid; VEGFR—vascular endothelial growth factor receptor.

Proapoptotic agents

Multikinase inhibitors

mTOR inhibitors

Drug type

Table 1. Selected important ongoing phase 2 trials of new agents in advanced colorectal cancer*

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NCT00419159

NCT00457691

mTOR inhibitors

Multikinase inhibitors

Cediranib (VEGFR tyrosine kinase inhibitor)

Cediranib (VEGFR tyrosine kinase inhibitor)

Aflibercept (VEGF Trap)

Study of FOLFIRI Chemotherapy With or Without Sunitinib In Patients With Metastatic Colorectal Cancer

Efficacy and Safety of Everolimus in Patients With Metastatic Colorectal Cancer Who Have Failed Prior Chemotherapy

Phase III Randomized Study of Combination Chemotherapy Comprising Oxaliplatin, Leucovorin Calcium, and Fluorouracil (Modified FOLFOX) or Oxaliplatin and Capecitabine (XELOX) in Combination With Bevacizumab With Versus Without Erlotinib in Patients With Unresectable Metastatic Colorectal Adenocarcinoma

Novartis

Pfizer

Sunitinib (multikinase inhibitor/ antiangiogenic agent)

GERCOR Groupe Cooperateur Multidisciplinaire en Oncologie

Tel Aviv Sourasky Medical Center

AstraZeneca

AstraZeneca

Sanofi-Aventis

Everolimus (mTOR inhibitor)

Erlotinib (EGFR tyrosine kinase inhibitor)

Sponsor(s) NCIC Clinical Trials Group

*Information from the National Cancer Institute website http://www.cancer.gov. 5-FU—5-fluorouracil; EGFR—epidermal growth factor receptor; mTOR—mammalian target of rapamycin; NCIC—National Cancer Institute of Canada; VEGF—vascular endothelial growth factor; VEGFR—VEGF receptor.

NCT00265824

EGFR inhibitors

First Line Metastatic Colorectal Cancer Therapy in Combination With FOLFOX

NCT00384176

Investigational agent(s) Brivanib (VEGFR2 inhibitor)

Phase III Trial of Gemcitabine, Curcumin and Celebrex Curcumin (antiproliferative agent) in Patients With Metastatic Colon Cancer

Cediranib (AZD2171, Recentin) in Addition to Chemotherapy in Patients With Untreated Metastatic Colorectal Cancer

NCT00399035

NCT00295035

Aflibercept Versus Placebo in Combination With Irinotecan and 5-FU in the Treatment of Patients With Metastatic Colorectal Cancer After Failure of an Oxaliplatin Based Regimen

NCT00561470

Title Phase III Randomized Study of Cetuximab With Versus Without Brivanib Alaninate in Patients With Metastatic Colorectal Carcinoma Previously Treated With Combination Chemotherapy

Study no.

NCT00640471

Antiproliferative agents

Antiangiogenic agents

I

Drug type

Table 2. Selected important ongoing phase 3 trials of new agents in advanced colorectal cancer*

182 Gastrointestinal Cancers

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including ixabepilone, have failed to demonstrate efficacy in ACC [71]. Clinical trials to evaluate other new drugs in the epothilone class are ongoing.

No other potential confl icts of interest relevant to this article were reported.

Apoptosis

References and Recommended Reading

Like many tumors, colorectal cancers demonstrate reduced susceptibility to apoptosis [72–74]. A potential therapeutic target to induce tumor apoptosis is the Apo2 ligand/tumor necrosis factor–related apoptosis ligand (Apo2L/TRAIL), which initiates a death-signaling process via death receptor 5 (DR5). Recombinant agonists of Apo2L/TRAIL as well as monoclonal antibodies targeting DR5 have demonstrated antitumor effect by inducing apoptosis in preclinical models of colorectal cancer [73,75,76]. Earlyphase clinical trials of recombinant Apo2L/TRAIL as well as apomab, a fully human monoclonal antibody targeting DR5, are underway in patients with ACC.

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

Novel strategies Many “nontargeted” strategies are in clinical use or are being investigated in ACC. These range from new delivery methods to target inoperable liver metastases, such as yttrium-90 microspheres, to chronic “metronomic” therapies to target tumor angiogenesis [77,78]. Also in development are immune therapies such as dendritic cell vaccines and a vaccine directed against mutant KRAS proteins [79]. Further discussion of all the potential strategies is beyond the scope of our review.

Conclusions Replacement of the “one drug fits all” model by a patienttailored approach poses challenges as well as opportunities in drug development. The era of biologic therapies requires strong preclinical models and the incorporation of molecularly based correlative studies into clinical trials to achieve a better understanding of targets, potential effects, and biomarkers to identify patients likely to respond. Enrichment trials, innovative clinical trial designs, reexamination of end points, and involvement of novel patient populations will improve the ability to identify efficacious new agents. We must continue to shift the emphasis in clinical trials toward the testing of novel rather than approved agents to maintain this active pipeline and ensure rigorous but expedient testing for efficacy. Although the investigational agents discussed in this article remain unvalidated, they represent a mere fraction of the ongoing research in ACC, and we have great hope that this pipeline will yield a multitude of new active therapies to improve treatment options and prognoses for patients with ACC.

Disclosure Dr. Venook has received research funding from Genentech, Pfi zer, GlaxoSmithKline, Amgen, and Novartis.

1.

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