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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
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


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 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


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, 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


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