A phase I delayed-start, randomized and pharmacodynamic study of metformin and chemotherapy in patients with solid tumors.

PURPOSE: Metformin activates AMP-related pathways leading to inactivation of mammalian target of rapamycin (mTOR) and suppression of its downstream effectors, crucial for cancer growth. Epidemiologic studies showed a reduced incidence and improved survival in cancer patients. We conducted a prospective phase I study to assess the safety of metformin in combination with chemotherapy in patients with solid tumors. METHODS: We conducted a delayed-start randomized trial of non-diabetic patients in two stages. In Stage 1, we randomized patients to two arms: concurrent arm (metformin with chemo) vs. delayed arm (chemo alone). In Stage 2, patients in delayed arm were crossed over to receive metformin. Patients received metformin 500 mg twice daily with chemotherapy to define dose-limiting toxicities (DLTs) in both stages. Secondary endpoints assessed adverse events (AEs) and response rates. Translational correlates included effects of metformin on expression and phosphorylation of 5' adenosine monophosphate-activated protein kinase (AMPK) by western blot in PBMCs. RESULTS: A total of 100 patients were enrolled (51 in delayed arm vs. 49 concurrent arm). Rate of DLTs in patients receiving metformin with chemotherapy was 6.1% vs. 7.8% in patients receiving chemotherapy alone. DLTs seen with addition of metformin included those associated with established chemo adverse events. No lactic acidosis or hypoglycemia occurred. Restaging showed stable disease in 46% at cessation of metformin. 28% of patients with measurable tumor markers showed improvement. AMPK phosphorylation showed a four- to sixfold increase in AMPK phosphorylation after metformin. CONCLUSIONS: This is the largest phase I study of metformin combined with chemotherapy, which suggests that metformin can be given safely with chemotherapy, and offers a platform for future studies. Post-metformin increase in AMPK phosphorylation may potentially explain lack of disease progression in nearly half of our patients. FUNDING: UL1 TR001064. CLINICAL TRIAL INFORMATION: NCT01442870.

Role of panitumumab in the management of metastatic colorectal cancer.

Panitumumab (formerly known as ABX-EGF) is the first fully human monoclonal antibody directed against the epidermal growth factor receptor in clinical use. It has proven to be very well tolerated alone and in combination with other cytotoxic chemotherapeutic agents. Panitumumab has demonstrated efficacy as monotherapy and with standard chemotherapeutic agents in a wide variety of cancer types, including non-small-cell lung cancer, renal, and colorectal cancer (CRC). To date, no human antihuman antibodies have been detected, and unlike cetuximab, infusion reactions are infrequent, and no premedications are required when administering panitumumab. The only significant toxicity has been a rash similar to that seen with other agents targeting the epidermal growth factor receptor, and such reactions have been predominantly mild to moderate. In metastatic CRC, panitumumab has been safe and efficacious when given with other commonly used agents in this disease, including irinotecan and fluorouracil. Current studies under way are looking at panitumumab in combination with FOLFOX (fluorouracil/leucovorin/oxaliplatin) plus bevacizumab as well as with novel agents that have yet to come into common clinical practice. Recent progress in development of panitumumab in the management of CRC is reviewed, and management of associated rash is discussed herein.

Targeted agents for adjuvant therapy of colon cancer.

Among patients with colorectal cancer (CRC) diagnosed in the United States, 37.2% are diagnosed with stage III and 27.9% with stage II disease. In locoregionally advanced CRC, surgery is the primary treatment modality and has a curative intent. The survival depends on the pathologic stage and varies from 30%-60% for stage III to 60%-80% for stage II. However, as much as 40%-50% of patients will relapse and require additional treatment of the disease. Clinical failure after resection of CRC is predominantly secondary to the clinical progression of previously undetected distant metastatic disease. Until very recently, the absolute benefit for survival obtained with adjuvant therapy compared with control was about 6%. Introduction of oxaliplatin in the adjuvant setting has shown a reduction of 23% in the risk of relapse when compared with 5-fluorouracil alone (MOSAIC). Recent phase III studies have shown that targeted agents improved survival in patients with advanced-stage CRC. Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, is the first antiangiogenic drug to show improved efficacy when used in combination with irinotecan and oxaliplatin for first- and second-line treatment of CRC. Cetuximab, another monoclonal antibody targeting epidermal growth factor receptor, has shown efficacy in third-line therapy and promising results in first-line phase II studies. There is great interest in whether the biologic agents bevacizumab and cetuximab can improve survival in the adjuvant-therapy setting. This article reviews the adjuvant therapy for colon cancer and discusses the potential role and current trials involving the targeted agents.