Phase II trial of mapatumumab, a fully human agonistic monoclonal antibody that targets and activates the tumour necrosis factor apoptosis-inducing ligand receptor-1 (TRAIL-R1), in patients with refractory colorectal cancer

Abstract

BACKGROUND: Recombinant tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces tumour-selective apoptosis in various pre-clinical models by binding its specific receptors expressed on cancer cells. Mapatumumab is a fully human monoclonal antibody that is agonistic to the TRAIL Receptor 1 (TRAIL-R1). METHODS: This phase II multicentre study was designed to evaluate the efficacy and safety of mapatumumab in patients with colorectal cancer (CRC) who had failed to respond to, were intolerant to, or not candidates for fluoropyrimidine, oxaliplatin, and irinotecanbased regimens. All patients received two loading doses of mapatumumab (20 mg kg À1 every 14 days), followed by maintenance therapy with 10 mg kg À1 infused every 14 days. RESULTS: A total of 38 patients, who had progressive disease after a median of three earlier chemotherapy lines, were enrolled. No response according to the Response Evaluation Criteria in Solid Tumors was observed. A total of 12 patients (32%) achieved stable disease for a median of 2.6 months. The median progression-free survival was 1.2 months. The most common adverse events reported, regardless of relationship, were fatigue, nausea, anorexia, and abdominal pain. Plasma mapatumumab concentrations were within the range of exposures predicted by the results of phase I studies of mapatumumab. CONCLUSION: No clinical activity of single-agent mapatumumab was observed in patients with advanced refractory CRC. However, on the basis of its favourable safety profile and pre-clinical evidence of potential synergy in combination with agents commonly used in the treatment of colorectal cancer, further evaluation of mapatumumab in combination with chemotherapy is warranted.

Targeting Cell Spreading: A Method of Sensitizing Metastatic Tumor Cells to TRAIL-Induced Apoptosis

“…However, some tumor cells seem resistant to the killing effect of TRAIL, and resistance could be acquired following therapeutic TRAIL delivery in patients (10). This suggests that TRAIL therapies will be most effective when used in combination with agents which can sensitize tumor cells to TRAIL (38,39).…”

Targeting of XIAP Combined with Systemic Mesenchymal Stem Cell-Mediated Delivery of sTRAIL Ligand Inhibits Metastatic Growth of Pancreatic Carcinoma Cells

“…Although clinical trials with recombinant TRAIL protein and agonistic antibodies to TRAIL-receptor 2 (TRAIL-R2) have shown that they are safe, only moderate evidence of therapeutic efficacy has been observed [8][9][10][11]. One of the problems, despite frequent high-dose injections, is insufficient bioavailability at the site of tumor growth owing to a short half-life of TRAIL protein in the circulation [12].…”

An optimized antibody-single-chain TRAIL fusion protein for cancer therapy

“…This clinical failure has been subsequently attributed to the low in vivo bioactivity of the TRAIL molecules administered, and their rather short terminal plasma half-life (»1 hour). 4,6 Consequently, alternative therapeutic strategies targeting TRAIL death receptors have been developed, such as agonistic monoclonal antibodies directed against either DR4, e.g., mapatumumab, 8,9 or DR5, e.g., conatumumab 10 and lexatumumab. 11 However, Phase 1 and 2 clinical studies revealed ambiguous results (for review see refs.…”