Mapatumumab, a fully human agonistic monoclonal antibody that targets TRAIL-R1, in combination with gemcitabine and cisplatin: A phase I study
Purpose: To evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of mapatumumab, a fully human monoclonal antibody targeting tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1), in combination with gemcitabine and cisplatin. Experimental Design: Patients with advanced solid tumors received gemcitabine 1,250 mg/m2 i.v. on days 1 and 8 and cisplatin 80 mg/m2 i.v. on day1 of each 21-day cycle. Escalating mapatumumab doses were administered i.v. every 21 days. Toxicity was evaluated and pharmacokinetic analysis of plasma mapatumumab, gemcitabine, 2-difluoro-2-deoxyuridine, and unbound and total platinum was done. TRAIL-R1 tumor expression was determined immunohistochemically. Results: Forty-nine patients received mapatumumab (1 mg/kg, n = 4; 3 mg/kg, n = 7; 10 mg/kg, n = 12; 20 mg/kg, n = 13; or 30 mg/kg, n = 13). A median of six cycles (range, 1-48) was administered. The adverse events most commonly observed reflect the toxicity profile of gemcitabine and cisplatin. Dose-limiting toxicities were seen in 3 of 12 patients at 10 mg/kg, consisting of grade 3 transaminitis, neutropenic fever, and grade 4 thrombocytopenia. At 20 mg/kg, 2 of 12 patients had dose-limiting toxicities, including grade 4 thrombocytopenia and grade 4 fatigue. The maximum tolerated dose was not reached. Pharmacokinetic interactions have not been observed. Twelve patients had a partial response, and 25 patients showed stable disease with a median duration of 6 months. Conclusions: Mapatumumab in combination with gemcitabine and cisplatin is safe and well tolerated at doses up to 30 mg/kg. Further studies on this combination are warranted.
|Keywords||adenocarcinoma, adult, advanced cancer, aged, alopecia, anemia, anorexia, antineoplastic activity, article, bile duct carcinoma, bladder cancer, carcinoid, cisplatin, clinical article, clinical trial, death receptor 4, diarrhea, disease severity, dose response, drug blood level, drug dose escalation, drug efficacy, drug mechanism, drug safety, drug tolerability, dysgeusia, esophagus cancer, fatigue, febrile neutropenia, female, gallbladder cancer, gemcitabine, head and neck cancer, human, hypokalemia, hypomagnesemia, kidney cancer, leukopenia, lung non small cell cancer, lung small cell cancer, male, mapatumumab, maximum tolerated dose, melanoma, multiple cycle treatment, nausea, neutropenia, pancreas cancer, paresthesia, patient safety, phase 1 clinical trial, priority journal, sensory neuropathy, solid tumor, stomach cancer, stomatitis, thrombocytopenia, thymus cancer, tinnitus, treatment outcome, treatment response, vomiting|
|Persistent URL||dx.doi.org/10.1158/1078-0432.CCR-09-0996, hdl.handle.net/1765/17550|
|Journal||Clinical Cancer Research|
Mom, C.H, Verweij, J, Oldenhuis, C.N.A.M, Gietema, J.A, Fox, N.L, Miceli, R, … Sleijfer, S. (2009). Mapatumumab, a fully human agonistic monoclonal antibody that targets TRAIL-R1, in combination with gemcitabine and cisplatin: A phase I study. Clinical Cancer Research, 15(17), 5584–5590. doi:10.1158/1078-0432.CCR-09-0996