PT  - JOURNAL ARTICLE
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
TI  - Mapatumumab, a Fully Human Agonistic Monoclonal Antibody That Targets TRAIL-R1, in Combination with Gemcitabine and Cisplatin: a Phase I Study
AID  - 10.1158/1078-0432.CCR-09-0996
DP  - 2009 Sep 01
TA  - Clinical Cancer Research
PG  - 5584--5590
VI  - 15
IP  - 17
4099  - http://clincancerres.aacrjournals.org/content/15/17/5584.short
4100  - http://clincancerres.aacrjournals.org/content/15/17/5584.full
SO  - Clin Cancer Res2009 Sep 01; 15
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 day 1 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. (Clin Cancer Res 2009;15(17):5584–90)