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Evidence-Based Oncology January/February

From Bench to Bedside: Promising Colon Cancer Clinical Trials

Jill M. Comeau, PharmD, BCOP; and Brice Labruzzo Mohundro, PharmD, BCACP
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

 
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