TRAIL receptor agonist conatumumab with modified FOLFOX6 plus bevacizumab for first‐line treatment of metastatic colorectal cancer

Abstract

BACKGROUND:In patients with previously untreated metastatic colorectal cancer (mCRC), we conducted a phase 1b/randomized phase 2 trial to define the safety, tolerability, and efficacy of mFOLFOX6 plus bevacizumab (mFOLFOX6/bev) with conatumumab, an investigational, fully human monoclonal IgG1 antibody that specifically activates death receptor 5 (DR5). METHODS: Twelve patients were enrolled in a phase 1b open-label dose-escalation trial of conatumumab with mFOLFOX6/bev; thereafter, 190 patients were randomized 1:1:1 to receive mFOLFOX6/bev in combination with 2 mg/kg conatumumab, 10 mg/kg conatumumab, or placebo. Therapy cycles were repeated every 2 weeks until disease progression or the occurrence of unacceptable toxicity. RESULTS: In phase 1b, conatumumab with mFOLFOX6/bev was tolerated without apparent added toxicity over mFOLFOX6/bev alone. In phase 2, conatumumab with mFOLFOX6/bev did not confer a benefit in progression-free survival when compared with placebo with mFOLFOX6/ bev. Toxicity was similar in all treatment arms. Following treatment, similar increases in circulating caspase-3 levels were observed in all arms. CONCLUSIONS: Conatumumab with mFOLFOX6/bev did not offer improved efficacy over the same chemotherapy with placebo in first-line treatment of patients with mCRC. These data do not support further development of conatumumab in advanced CRC. Cancer 2013;119:4290-8.

From conventional chemotherapy to targeted therapy: use of monoclonal antibodies (moAbs) in gastrointestinal (GI) tumors

“…Conatumumab with mFOLFOX6/bev did not offer improved efficacy over the same chemotherapy with placebo in first-line treatment of patients with mCRC. These data do not support further development of conatumumab in advanced CRC [95].…”

Metformin sensitizes triple-negative breast cancer to proapoptotic TRAIL receptor agonists by suppressing XIAP expression

“…Despite promising preclinical results, TRAIL receptor agonists have failed to demonstrate significant efficacy, either alone or in combination with chemotherapy, in multiple clinical trials in advanced malignancies [3][4][5][6][7][8]. These disappointing results in clinical trials have been attributed to a number of factors, including de novo and/or acquired resistance to TRAIL receptor agonists, inadequate receptor oligomerization on ligand binding, limiting procaspase-8/10 activation, and lack of biomarkers to predict treatment response [1,2].…”

LB100, a small molecule inhibitor of PP2A with potent chemo- and radio-sensitizing potential

“…As interest for therapeutic development of TRAIL agonists continues to rise, LB100 may warrant further study as an adjuvant therapy, particularly in TRAIL-resistant cancers. [105][106][107] Nasopharyngeal carcinoma Nasopharyngeal carcinoma (NPC) affects approximately one in every 100,000 individuals per year worldwide. However, in certain regions including Southeast Asia, North Africa and Middle East the incidence is nearly 25 cases per 100,000 people per year.…”