A Phase 1 study of UCN-01 in combination with irinotecan in patients with resistant solid tumor malignancies.

PURPOSE: UCN-01 (7-hydroxystaurosporine) is a multi-targeted protein kinase inhibitor that exhibits synergistic activity with DNA-damaging agents in preclinical studies. We conducted a Phase I study to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetic, and pharmacodynamic effects of UCN-01 and irinotecan in patients with resistant solid tumors. EXPERIMENTAL DESIGN: Patients received irinotecan (75-125 mg/m(2) IV on days 1, 8, 15, 22) and UCN-01 (50-90 mg/m(2) IV on day 2 and 25-45 mg/m(2) on day 23 and subsequent doses) every 42 days. Blood for pharmacokinetics of UCN-01 and irinotecan, and blood, normal rectal mucosa, and tumor biopsies for pharmacodynamic studies were obtained. RESULTS: Twenty-five patients enrolled to 5 dose levels. The MTD was irinotecan 125 mg/m(2) on days 1, 8, 15, 22 and UCN-01 70 mg/m(2) on day 2 and 35 mg/m(2) on day 23. DLTs included grade 3 diarrhea/dehydration and dyspnea. UCN-01 had a prolonged half-life and a low clearance rate. There was a significant reduction in SN-38 C(max) and aminopentanocarboxylic acid (APC) and SN-38 glucuronide half-lives. Phosphorylated ribosomal protein S6 was reduced in blood, normal rectal mucosa, and tumor biopsies at 24 h post-UCN-01. Two partial responses were observed in women with ER, PgR, and HER2-negative breast cancers (TBNC). Both tumors were defective for p53. Twelve patients had stable disease (mean duration 18 weeks, range 7-30 weeks). CONCLUSION: UCN-01 and irinotecan demonstrated acceptable toxicity and target inhibition. Anti-tumor activity was observed and a study of this combination in women with TNBC is underway.

Gemcitabine with carboplatin for advanced biliary tract cancers: a phase II single institution study.

BACKGROUND: Only recently has a standard chemotherapy regimen, gemcitabine plus cisplatin, been established for advanced biliary tract cancers (BTCs) based on a phase III randomized study. The aim of this phase II single-institution trial was to assess the efficacy and safety of gemcitabine combined with carboplatin in the first-line treatment of patients with advanced BTCs. METHODS: Patients with histologically proven BTCs, including cholangiocarcinoma or gallbladder and ampullary carcinomas, were treated with a maximum of nine cycles of intravenous (i.v.) gemcitabine at 1000 mg/m(2) over 30 min on days 1 and 8 with i.v. carboplatin dosed at an area-under-the-curve (AUC) of 5 over 60 min on day 1 of a 21-day cycle. RESULTS: A total of 48 patients with advanced BTCs (35 cholangiocarcinoma, 12 gallbladder and 1 ampullary cancer) were enrolled. A median of four cycles were administered (range: 1-9). The overall response rate for evaluable patients was 31.1%. Median progression-free survival, overall survival and 6-month survival rates are 7.8 months, 10.6 months and 85.4%, respectively. The most common grade 3-4 toxicities include neutropenia and thrombocytopenia. Grade 3 or 4 non-haematological toxicities were rare. CONCLUSIONS: Gemcitabine combined with carboplatin has activity against advanced BTCs. Our results are comparable to other gemcitabine-platinum or gemcitabine-fluoropyrimidine combinations in advanced BTCs.

Targeting colorectal cancer with anti-epidermal growth factor receptor antibodies: focus on panitumumab.

The tumor biology targeted therapies have improved outcomes in colorectal cancer (CRC). The epidermal growth factor receptor (EGFR) inhibitors represent one of these successful strategies. EGFR is frequently overexpressed in CRCs and associated with a malignant phenotype. Two EGFR inhibitors have shown efficacy in metastatic CRC, cetuximab and panitumumab. Cetuximab is a human-mouse chimeric monoclonal antibody that binds to the extracellular domain of the EGF-receptor. Similarly, panitumumab is a fully humanized monoclonal IgG(2) antibody, directed against EGFR. Being fully humanized, panitumumab does not contain mouse protein reducing the risk of hypersensitivity. In a pivotal clinical trial, panitumumab was well tolerated and effective, demonstrating an objective response rate of 10% vs best supportive care (ORR = 0%; P < 0.0001). Panitumumab was approved for the treatment of mCRC by the FDA in 2006. Studies combining panitumumab with cytotoxic chemotherapy and other targeted therapies have been completed while others are ongoing to further evaluate the clinical utility of this agent. Recently it has been demonstrated that mutations in KRAS predict the efficacy of panitumumab and cetuximab, limiting their use to CRC patients with wild-type KRAS, and moving the clinical field towards personalized cancer care.