TY - JOUR
T1 - Mapatumumab, a fully human agonistic monoclonal antibody that targets TRAIL-R1, in combination with gemcitabine and cisplatin
T2 - A phase I study
AU - Mom, Constantijne H.
AU - Verweij, Jaap
AU - Oldenhuis, Corina N.A.M.
AU - Gietema, Jourik A.
AU - Fox, Norma Lynn
AU - Miceli, Renée
AU - Eskens, Ferry A.L.M.
AU - Loos, Walter J.
AU - De Vries, Elisabeth G.E.
AU - Sleijfer, Stefan
PY - 2009/9/1
Y1 - 2009/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=69949110775&partnerID=8YFLogxK
U2 - https://doi.org/10.1158/1078-0432.CCR-09-0996
DO - https://doi.org/10.1158/1078-0432.CCR-09-0996
M3 - Article
C2 - 19690193
SN - 1078-0432
VL - 15
SP - 5584
EP - 5590
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 17
ER -