aprinocarsen and Colorectal-Neoplasms

This phase II study was designed to characterize the clinical activity of ISIS 3521 in patients with metastatic colorectal cancer (CRC). Sixteen patients with pretreated or refractory CRC were treated with ISIS 3521. Eleven patients were given a dose of 2.0 mg/kg per day, and 5 patients received 3.0 mg/kg per day given over 21 days followed by a 7-day rest period. Patients continued with study until evidence of disease progression or unacceptable toxicity was detected. Patients underwent baseline tumor biopsies followed by a second biopsy during the last week of the first 21-day infusion. All 16 patients underwent baseline tumor biopsies, and 12 of the 16 patients underwent on-study tumor biopsies. No evidence of tumor response was observed. One patient had stable disease after 2 cycles and remained on for 1 additional cycle only to demonstrate progression of disease at that time. No dose-limiting or other significant toxicities were observed at both dosages, which could not be explained by progression of disease. Fatigue was common in all patients treated but was not dose limiting, and there was no evidence of coagulopathy. Analysis of the tumor biopsies obtained from the 11 evaluable samples showed marked uptake of ISIS 3521 in the normal liver parenchyma. However, there was minimal uptake within the tumor cells. In addition, no evidence of any alteration in protein kinase C-a within the tumors or any downstream effects leading to apoptosis were observed. ISIS 3521 demonstrated no clinical activity or target modulation in refractory metastatic CRC.

Topics: Adult; Aged; Antineoplastic Agents; Apoptosis; Colorectal Neoplasms; Female; Humans; Immunohistochemistry; Ki-67 Antigen; Male; Middle Aged; Neoplasm Metastasis; Oligodeoxyribonucleotides, Antisense; Protein Kinase C; Thionucleotides

Because treatment of metastatic colon cancer is noncurative, new treatments are needed. This trial evaluated the antitumor effects of two targeted anticancer agents: (a) ISIS 3521, an antisense inhibitor of the protein kinase C alpha; and (b) ISIS 5132, an antisense inhibitor of c-raf kinase in patients untreated previously with recurrent or metastatic colorectal carcinoma.. All patients had colorectal adenocarcinoma with measurable disease and no prior chemotherapy for metastatic disease. Patients were randomized to receive either ISIS 3521 or ISIS 5132 at a dose of 2 mg/kg/day as a continuous i.v. infusion 21 of 28 days. Cycles were repeated as long as progression was not seen, and doses of both agents were modified according to toxic effects. A two-arm study design was used with each study arm considered independently. Steady-state blood levels of both antisense molecules were measured on days 8, 15, and 22 of the first cycle of therapy.. Thirty-seven eligible patients were enrolled, and 32 were evaluable for response (17 receiving ISIS 3521 and 15 receiving ISIS 5132). No responses were noted. Four of the patients receiving ISIS 3521 had stable disease, and 5 patients receiving ISIS 5132 were stable.. Neither ISIS 5132 nor ISIS 3521given in the dose and schedule studied induced objective responses in untreated colorectal cancer patients.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Colorectal Neoplasms; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Humans; Infusions, Intravenous; Isoenzymes; Male; Maximum Tolerated Dose; Middle Aged; Oligodeoxyribonucleotides, Antisense; Protein Kinase C; Protein Kinase C-alpha; Proto-Oncogene Proteins c-raf; Thionucleotides; Treatment Outcome