From Bench to Bedside: Promising Colon Cancer Clinical Trials

Colorectal cancer (CRC) was the third-most common cause of cancer-related deaths in the United States in 2012, accounting for around 51,690 deaths. Approximately 143,460 people are diagnosed with CRC annually, making up 9% of all cancer diagnoses.¹ Specifically, colon cancer makes up 72% of the incidence of CRC, with rectal cancers accounting for the remaining 28%. CRC is more common in males and in the African American population compared with other ethnicities. Within the last 35 years, the mortality rates have been decreasing. The 5-year overall survival (OS) of CRC, a non-curable malignancy, is around 64.3%, with stage I disease being 89.9% and stage IV disease being 11.9%.²

The treatment of colon cancer depends upon the stage. For those who have operable disease, surgical resection is preferred. Patients with high-risk stage II or stage III disease should then receive adjuvant chemotherapy with 5-fluorouracil (5-FU), leucovorin (LCV), and oxaliplatin. Oral capecitabine may be substituted for intravenous 5-FU/LCV. In patients with metastatic disease, surgical evaluation should be conducted, especially in those with limited hepatic metastases. If the tumor is deemed unresectable, palliative chemotherapy with a 5-FU/LCV regimen should be offered. Potential regimens include FOLFOX (5-FU/ LCV and oxaliplatin), FOLFIRI (5-FU/LCV and irinotecan), CapeOX (capecitabine and oxaliplatin), 5-FU/LCV alone, and capecitabine alone. Biologic therapy with bevacizumab (with FOLFOX, FOLFIRI, or CapeOX), panitumumab (with FOLFOX or FOLFIRI), or cetuximab (FOLFIRI) may be added to standard regimens. KRAS is an important cellsignaling protein in the growth and progression of tumor cells. Malignancies with mutated KRAS, which occur in 40% of patients with CRC, are associated with poor response to epidermal growth factor receptor (EGFR) inhibitors, including cetuximab and panitumumab. This occurs since KRAS signaling happens downstream from EGFR. With progressive disease, regimens can be changed to another option with medications not already utilized.³ In 2012, 2 new agents were approved for use as second-line therapy. Ziv-alibercept, a vascular endothelial growth factor receptor (VEGFR) 1 and 2 inhibitor, when combined with FOLFIRI in those who had failed a previous oxaliplatinbased regimen, had an improved OS of 1.4 months compared with those who received placebo (13.5 months vs 12.1 months, P = .003).⁴ Regorafenib, an oral multikinase inhibitor, demonstrated an improved OS over placebo in patients who had failed standard therapy in the CORRECT trial (6.4 months vs 5 months, P = .005).⁵ Of note, even though this article will focus on colon cancer, patients with rectal cancers are also included in many of the clinical trials.

Topoisomerase I Inhibitors

In stages III and IV CRC, traditional chemotherapy has been shown to improve OS. Irinotecan, a topoisomerase I inhibitor commonly used in the metastatic setting, is broken down into its active metabolite SN-38. When SN-38 binds to topoisomerase I, it prevents single-strand repair, which causes permanent single- and double-strand DNA breakage.⁶ Two products in phase II and III trials, etirinotecan pegol (NKTR-102) and EZN-2208, are pegylated versions of irinotecan which delay clearance and prolong the half-life of SN-38.^7,8 Specifically, etirinotecan pegol is a pegylated prodrug of irinotecan, while EZN-2208 is the pegylated formulation of SN-38. In a phase I trial of 76 patients, including 17 patients with CRC, etirinotecan pegol was given at a maximum tolerated dose (MTD) of 115 mg/m2 dose in patients treated on days 1, 8, and 15 in a 28-day cycle, and 145 mg/m2 in patients treated once every 2 weeks or once every 3 weeks. Two patients with CRC had a partial response (PR), with 1 of those patients being unconfirmed by traditional response criteria. The dose-limiting toxicity (DLT) was grade 3 diarrhea in all dosing schemata.⁹ The half-life of SN-38 was 50 days compared with only 12 to 47 hours with irinotecan studies.^6,9 EZN- 2208 has been studied as a third-line treatment in 173 metastatic colorectal cancer (mCRC) patients who had previously failed 5-FU, oxaliplatin, and irinotecan. Patients with KRAS mutations received EZN-2208 at 9 mg/m2 once daily on days 1, 8, and 15 of a 28-week cycle, while patients with KRAS wild-type received either EZN-2208 with cetuximab or irinotecan with cetuximab. No responses were seen with the first group who had received single-agent EZN-2208, but 9% of patients had a response to the second arm (EZN-2208 and cetuximab) and 14% had a response to the third arm (irinotecan and cetuximab). The most common adverse effects in all groups were gastrointestinal (GI).¹⁰

TAS-102

TAS-102 consists of 2 components: α,α,α-trifluorothymidine (FTD), the active agent, and 5-chloro-6-(2-iminopyrrolidin- 1-yl) methyl-2,4 (1H,3H)-pyrimidinedione hydrochloride utilized to prevent first-pass metabolism and maintain therapeutic FTD concentrations with oral administration. FTD exerts its activity by inhibiting thymidylate synthase and inhibiting DNA transcription by incorporating into base pairs when phosphorylated. A phase II trial included 169 adult patients with mCRC who had failed ≥2 chemotherapy regimens, including 5-FU, irinotecan, and oxaliplatin. TAS- 102 dosed at 35 mg/m2 orally, twice daily or placebo, was given to patients on days 1 to 5 in a 28-day cycle. The median OS for the TAS-102 group was 9 months compared with 6.6 months for the placebo group (P = .001).There was a median progression-free survival (PFS) of 1 month (2 months vs 1 month) for the TAS-102 group (P <.0001). Only 1 patient in the TAS-102 group had a PR, but 43% of patients achieved stable disease (SD). Severe adverse events included bone marrow suppression, fatigue, diarrhea, and febrile neutropenia.¹¹ A phase III trial is under way to compare the OS and toxicity of TAS-102 versus placebo in patients with refractory mCRC.¹²

ThermoDox

ThermoDox is a doxorubicin-based low temperature—sensitive liposome in phase II clinical trials for the treatment of recurrent or refractory unresectable liver metastases (≤4 metastases with a diameter of 2-7 cm) in patients with CRC, along with radiofrequency ablation (RFA) compared with RFA alone.¹³ Use of the nanoparticle ThermoDox with mild hyperthermia (41ºC-42ºC) should allow for doxorubicin to be delivered and released directly into the liver metastases and therefore avoid systemic distribution. Doxorubicin given along with hyperthermia has been shown to potentially cause a synergistic effect by increasing chemotherapy penetration into the tumor.¹⁴

Ramucirumab

Tumor angiogenesis, a crucial mechaon tumor vasculature.¹⁵ Ramucirumab is a human monoclonal antibody targeting VEGF, specifically blocking the interactions between all known VEGFs and VEGFR-2.^15,16 This interaction has been shown to inhibit angiogenesis and tumor growth in preclinical studies.¹⁵ nism in cancer growth and metastasis, occurs as a result of interactions between VEGF and VEGFR. VEGF-A, an important component of tumor angiogenesis, endothelial proliferation, permeability, and survival, binds to both VEGFR- 1 and VEGFR-2, which can be found on tumor vasculature.¹⁵ Ramucirumab is a human monoclonal antibody targeting VEGF, specifically blocking the interactions between all known VEGFs and VEGFR-2.^15,16 This interaction has been shown to inhibit angiogenesis and tumor growth in preclinical studies.¹⁵ Because ramucirumab actually blocks the binding to these receptors, it differs in mechanism from other VEGF-directed therapies already available.¹⁶ A phase I study was completed in patients with advanced solid malignancies who were receiving escalating, once-weekly doses of ramucirumab. Six of the 37 patients included in the study had CRC. Authors observed antitumor activity and antiangiogenic effects with varying doses. Two patients experienced dose-limiting toxicities (grade 3 hypertension and deep vein thrombosis) after receiving a dose of 16 mg/kg; therefore the MTD was set at 13 mg/kg.¹⁵ The primary side effects observed with ramucirumab include hypertension, vascular thrombotic events, proteinuria, and bleeding.^15,16 A phase II study investigating if patients with mCRC have an improved PFS when treated with standard chemotherapy, standard chemotherapy plus ramucirumab, or standard chemotherapy plus icrucumab, a monoclonal antibody targeting VEGFR-1, is currently recruiting patients.^17,18 A phase III study currently recruiting patients will compare OS in mCRC patients treated with either ramucirumab plus FOLFIRI or FOLFIRI monotherapy.¹⁹

Brivanib

A new approach to intracellular signal blockade is noted with brivanib, a novel receptor tyrosine kinase inhibitor (TKI). In addition to VEGFR-2, which was previously discussed, fibroblast growth factor-1 (FGF-1) and -2 (FGF-2) plays a role in both angioneogenesis and tumorigenesis. In order to combat the resistance seen with bevacizumab, an FDA-approved VEGF-2 inhibitor, it has been theorized that the FGF pathway should be targeted. Brivanib works by targeting FGF and VEGF signaling simultaneously.²⁰ Brivanib alaninate is an oral L-alanine ester pro-drug which is hydrolyzed into its active form, brivanib.^20,21 Preclinical studies indicate that brivanib has antiangiogenic and antitumor effects in colon cancer.²⁰ In 1 pharmacokinetic study of only 4 patients, brivanib was well tolerated, with fatigue occurring in all patients and the second-most common adverse events being GI (nausea, diarrhea, and constipation).²¹ Advantages of this new agent include that it is taken orally on a daily basis. A phase I dose-escalation study evaluating brivanib plus cetuximab in advanced GI malignancies included 59 participants with CRC.²⁰ Six patients received 320 mg, 5 patients received 600 mg, and 51 patients received 800 mg of brivanib. Overall, brivanib was well tolerated in this study; however, 4 patients in the 800-mg group discontinued the study due to drug-related toxicities, including sepsis, aspartate aminotransferase elevations, dehydration, and angioedema. One patient died due to sepsis from rectal perforation, which was possibly due to brivanib. The majority of adverse effects were grade 1/2 and the most frequently reported grade 3/4 adverse effects were fatigue and elevated hepatic transaminases. Approximately 10% of patients in the 800-mg group experienced grade 1/2 palmar-plantar erythrodysesthesia. 20 A randomized phase III study is under way to evaluate whether or not brivanib plus cetuximab is more effective than cetuximab monotherapy in treating patients with mCRC.²²

Tivantinib

Several cancers have been linked to mutations in the mesenchymal—epithelial transition (MET) gene including CRC.^23-25 Gene mutations, gene amplifications, and protein overexpression are a few ways c-MET receptor tyrosine kinase can be activated. Activation of c-Met can trigger several oncogenic processes, including tumor cell proliferation, migration, invasion, angiogenesis, development of metastases, and protection from apoptosis, thus leading to poorer clinical outcomes and drug resistance.²⁵ The c-MET inhibitor, tivantinib, is an orally administered TKI which is selective for hepatocyte growth factor receptor (HGFR). HGFR is a product of the MET gene that can induce cell growth and reduce apoptosis, among other detrimental effects.²³ A phase I dose escalation study in 79 patients with metastatic solid tumors did not determine an MTD; however, it was concluded that 360 mg twice a day was well tolerated, with patients experiencing mild to moderate toxicities. In this study, 4% of patients achieved a PR while approximately 50% maintained SD for a median of about 20 weeks.²⁶ A phase I/II study evaluating tivantinib in CRC is currently ongoing. The phase I part of the study will determine the efficacy, safety, and recommended dose of tivantinib in combination with irinotecan and cetuximab. The phase II part will be a randomized, double-blind, placebo-controlled study to determine safety and efficacy of tivantinib plus irinotecan and cetuximab by measuring time to PFS in subjects with wildtype KRAS CRC.²⁷

Ornatuzumab

The monoclonal antibody, ornatuzumab, another agent that targets HGFR, is a monovalent HGF antagonist antibody against MET.²³ No phase II or III trials have been completed in patients with CRC; however, preliminary results from a phase II trial in patients with small cell lung cancer receiving either ornatuzumab plus erlotinib or erlotinib alone demonstrated that only patients who overexpress HGFR may benefit. Patients with c-MET negative tumors had worse OS when compared with placebo.²⁸ Investigators are actively recruiting for a randomized, doubleblind placebo-controlled trial evaluating FOLFOX plus bevacizumab and ornatuzumab or placebo as first-line treatment in mCRC.²⁹

Lapatinib

Lapatinib is an oral TKI for human epidermal growth factor 2 (HER2) and EGFR currently approved for treatment in HER2+ metastatic breast cancer after failure of trastuzumab. HER2 and EGFR are enzymes essential for tumor growth and development. HER2 overexpression is only found in a small fraction of colon cancer patients, but patients with wild-type KRAS have been shown to respond to EGFR inhibitors. Adults with advanced mCRC or mCRC with progression during or within 6 months of chemotherapy with 5-FU, oxaliplatin, or irinotecan were eligible for a phase II study in which lapatinib was given at 1250 mg orally daily and capecitabine 2000 mg/m2 orally twice daily on days 1 to 14 of a 21-day cycle. Enrollment was stopped at 29 patients due to an ORR of 0%. The incidence of SD at the time of study termination was 41.4%, with the most severe toxicities being palmar-plantar erythrodysesthesia, GI, and fatigue.³⁰ Even though this study did not show a benefit with lapatinib, there is a phase I trial recruiting patients with CRC, lung, or head and neck cancer looking at the MTD and DLT of cetuximab and lapatinib together.³¹

Entinostat

Histone deacetylases (HDACs) are enzymes that cause the binding of DNA phosphate group to histones and therefore prevent DNA transcription. Inhibition of this process causes a buildup of acetyl groups, leading to transcription factor abnormalities and, ultimately, cell apoptosis. Numerous cancers are associated with abnormalities in the histone acetylase and HDAC enzymes.³² Entinostat (MS-275 or SNDX-275) is an oral HDAC inhibitor being studied in a phase II trial along with azacitidine for patients with mCRC who have failed ≥2 previous regimens.33 In a phase I study, 4 out of the 27 patients treated with entinostat had mCRC. The MTD was 4 mg/m2 orally once daily on days 1, 8, and 15 of a 28-day cycle, with the DLT being both asthenia and hypophosphatemia. One patient with colon cancer obtained SD.³²

Sorafenib

Sorafenib, an oral multikinase inhibitor, is currently FDA approved for the treatment of unresectable hepatocellular and renal cell carcinoma. Sorafenib’s mechanisms of action include inhibition of BRAF, VEGF-1/-2/-3, plateletderived growth factor β, c-KIT, FLT-3 (fms-like tyrosine kinase receptor-3), and RET (“rearranged during transfection”) tyrosine kinases. BRAF, a Raf kinase, is essential for activating cancer cell growth, division, and maturation.³⁴ are being conducted in patients with relapsed or refractory mCRC, utilizing sorafenib along with standard secondline agents.³⁵ Twenty-six patients with mCRC were included in a Phase I trial that combined sorafenib along with 2 different 5-FU/LCV infusion schedules, the Mayo Clinic and Roswell Park regimens. Two patients diagnosed with colon cancer achieved a PR and 42% achieved SD, but the original diagnoses for these patients achieving SD were not defined. Severe adverse effects occurred in the majority of patients (55%), with the most common organ systems affected being the GI and hepatic systems.³⁴

Veliparib (ABT-888)

Veliparib inhibits PARP-1 and -2 enzymes (poly[ADP-ribose] polymerase), which are necessary for repairing DNA. When combined with alkylating agents, such as cyclophosphamide, PARP inhibitors enhance the DNA damage caused by the alkylating agents. Forty-seven patients with mCRC who had progressed on “all” standard therapies received temozolomide, an alkylating agent, at 150 mg/m2 orally once daily on days 1 to 5 and veliparib 40 mg orally twice daily on days 1 to 7 of a 28- day cycle until progression. Five percent of patients obtained a PR and 18% had SD. The most severe adverse effect was myelosuppression, which only occurred in 11% of patients.³⁶ Two clinical trials are actively recruiting participants: a phase II trial utilizing the temozolomide/veliparib regimen and a phase I trial using veliparib, oxaliplatin, and capecitabine in patients with treatment-naïve or relapsed mCRC along with other predefined malignancies.³⁷

HMG CoA Reductase Inhibitors

A class of anti-lipid agents called 3-hydroxy-3-methylglutaryl (HMG) CoA reductase inhibitors, also known as statins, is thought to have antineoplastic effects in colon cancer by inducing apoptosis, inhibiting angioneogenesis and cell proliferation, and decreasing metastatic capacity.³⁸ A phase II study evaluating the addition of 40 mg simvastatin daily to FOLFIRI treatment in mCRC in 49 patients demonstrated an ORR of 46.9% (95% confidence interval, 31.0-58.8) by intent-totreat analysis.³⁹ Currently, there are 3 studies evaluating simvastatin added to other regimens in mCRC open to accrual. ⁴⁰ A phase II study closed to accrual is ongoing to determine if conventional cetuximab treatment with 40 mg simvastatin added is effective in mCRC patients with KRAS mutation.⁴¹ A randomized phase III study is currently recruiting patients to determine how the HMG reductase inhibitor, rosuvastatin, compares with placebo in treating patients with stage I or II colon cancer removed by surgery.⁴²

Monoclonal Antibodies

The lysol oxidase family of proteins contain a conserved catalytic region and are thought to play a role in cancer progression.⁴³ One of the 5 LOX proteins, LOX-like 2 (LOXL2), is an extracellular matrix which has been shown to play a role in several disease states, including colon cancer.^43,44 GS-6624, formerly AB0024, is a humanized monoclonal antibody that targets LOXL-2.⁴⁵ A phase I study was completed in March 2012 that investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of AB0024 in adult patients with advanced malignant solid tumors.⁴⁶ A phase II randomized, double-blind, placebo-controlled study is currently recruiting patients with KRAS mutant mCRC to determine the efficacy and safety of GS-6624 when combined with FOLFIRI as second-line treatment. To be included in the study, patients had to have had disease progression after first-line treatment with an oxaliplatin and 5-FU—containing regimen. The primary outcome of this study is PFS.⁴⁷

Imprime PGG

Currently undergoing phase III trials for KRAS wild type mCRC,⁴⁸ Imprime PGG is a beta-glucan polymer that sensitizes neutrophils to target cancer cells already treated with a monoclonal antibody. This synergistic activity is thought to improve the response to traditional cancer therapies. Imprime PGG has been given along with cetuximab, a monoclonal antibody which targets EGFR. Twenty-two patients with KRAS wild-type CRC were enrolled in a phase Ib/II trial and received weekly Imprime PGG with cetuximab and irinotecan or Imprime PGG with cetuximab alone. Patients who received cetuximab alone with Imprime PGG had a 24% ORR and 38% obtained SD. Time to progression was found to be 4 months. Adverse effects were similar to those found with cetuximab administration.⁴⁹

FANG Vaccine

This vaccine consists of autologous tumor cells from the patient and a plasmid expressing growth macrophage colony stimulating factor (GM-CSF) and bifunctional short hairpin RNAfurin (bi-shRNAfurin). GM-CSF induces growth and production of dendritic cells, or essential antigen-presenting cells, in the bone marrow. Bi-shRNAifurin inhibits production of furin, an enzyme that transforms precursor proteins into active proteins. The specific target for Bi-shRNAifurin is transforming growth factor β 1 and 2 (TGFβ). TGFβ is associated with both normal and tumor cell growth, with the overexpression of this protein often being linked to cancer progression. Also, TGFβ causes immune suppression specifically inhibiting GMCSF, making all components essential for vaccine response. According to phase I data, 6 patients with colon cancer received this vaccine and all patients obtained SD after 3 to 5 vaccine administrations.⁵⁰ Further studies are planning to utilize the FANG vaccine for 5 to 12 doses in patients following curative resection of liver metastases caused by CRC, along with 6 cycles of modified FOLFOX6 chemotherapy.⁵¹

GI-4000 Vaccine

GI-4000 is a patient-specific vaccine for the treatment of mCRC along with standard chemotherapy treatment. The specific mutation of KRAS is identified in each patient and the appropriate targeted molecular immunogens (tarmogens) are created out of heat-killed recombinant S cerevisiae yeast. Use of GI-4000 activates T cells, which cause selective killing of mutant KRAS cells or tumor cells.⁵² FOLFOX or FOLFIRI chemotherapy, along with adjuvant and maintenance bevacizumab, is being given along with GI-4000 in all patients in a current phase II trial. GI-4000 is given prior to starting chemotherapy, then administered 7 days after each chemotherapy cycle begins (FOLFOX/ FOLFIRI) for up to 8 cycles. During bevacizumab maintenance, GI-4000 is to be given every 2 weeks. Currently, patients may be enrolled prior to starting chemotherapy or prior to starting maintenance bevacizumab.⁵³

Conclusion

Similar to most malignancies, the future of colon cancer research is focused on targeted and personalized therapy, with VEGF being the most commonly targeted pathway in current clinical trials. With the utilization of targeted therapy, the focus of treatment becomes the identification of patients who will benefit from this therapy. This is already seen in current practices, with the use of KRAS testing becoming the standard of care prior to initiating treatment for mCRC and utilization of EGFR inhibitors. Other pathways which are utilized or have been studied in other malignancies are also being studied in CRC, including HDAC, c-MET, and PARP. Along with traditional chemotherapy agents, new agents NKTR-102, EZN-2208, and ThermoDox are being created to improve the pharmacokinetics and delivery of the drug, which will hopefully improve both clinical benefit and patient tolerability. Immunomodulatory pathways, previously not found to be beneficial, have shown some promise in phase I and II trials. Currently, the main concern from a managed care perspective is the cost-benefit ratio of these medications. With 2 new agents approved in 2012, with only a 1.4-month OS benefit, the question that arises is the cost, both economic and quality of life. Past pharmacoeconomic studies have looked at the use of currently approved targeted therapies and the incremental cost-effectiveness ratio (ICER) per discounted life-year. Based upon 2008 Medicare reimbursements, the ICER in $/year, or the cost of saving a life-year, with targeted therapies (bevacizumab or cetuximab) added to conventional chemotherapy, was $170,896 per year compared with $102,336 per year for conventional chemotherapy. ⁵⁴ With the approval of more targeted therapies, pharmacoeconomic studies are pivotal in assessing the effects on future healthcare costs. Future QOL studies would be also useful to demonstrate if the response or small survival gains are worth the toxicities, especially in non-curable diseases like CRC.

Author Affiliations: University of Louisiana at Monroe College of Pharmacy— Shreveport Campus (JMC), Shreveport, LA; University of Louisiana at Monroe College of Pharmacy–Baton Rouge Campus (BLM), Baton Rouge, LA.

Funding Source: None.

Author Disclosures: The authors (JMC, BLM) report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (JMC, BLM); acquisition of data (JMC, BLM); analysis and interpretation of data (JMC, BLM); drafting of the manuscript (JMC, BLM); critical revision of the manuscript for important intellectual content (JMC, BLM); and administrative, technical, or logistic support (JMC, BLM).

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