title: Phase 2, multicenter, open-label study of tigatuzumab (CS-1008), a humanized monoclonal antibody targeting death receptor 5, in combination with gemcitabine in chemotherapy-naive patients with unresectable or metastatic pancreatic cancer.
abstract: Tigatuzumab is the humanized version of the agonistic murine monoclonal antibody TRA-8 that binds to the death receptor 5 and induces apoptosis of human cancer cell lines via the caspase cascade. The combination of tigatuzumab and gemcitabine inhibits tumor growth in murine pancreatic xenografts. This phase 2 trial evaluated the efficacy of tigatuzumab combined with gemcitabine in 62 chemotherapy-naive patients with histologically or cytologically confirmed unresectable or metastatic pancreatic cancer. Patients received intravenous tigatuzumab (8 mg/kg loading dose followed by 3 mg/kg weekly) and gemcitabine (1000 mg/m(2) once weekly for 3 weeks followed by 1 week of rest) until progressive disease (PD) or unacceptable toxicity occurred. The primary end point was progression-free survival (PFS) at 16 weeks. Secondary end points included objective response rate (ORR) (complete responses plus partial responses), duration of response, and overall survival (OS). Safety of the combination was also evaluated. Mean duration of treatment was 18.48 weeks for tigatuzumab and 17.73 weeks for gemcitabine. The PFS rate at 16 weeks was 52.5% (95% confidence interval [CI], 39.3-64.1%). The ORR was 13.1%; 28 (45.9%) patients had stable disease and 14 (23%) patients had PD. Median PFS was 3.9 months (95% CI, 2.2-5.4 months). Median OS was 8.2 months (95% CI, 5.1-9.6 months). The most common adverse events related to tigatuzumab were nausea (35.5%), fatigue (32.3%), and peripheral edema (19.4%). Tigatuzumab combined with gemcitabine was well tolerated and may be clinically active for the treatment of chemotherapy-naive patients with unresectable or metastatic pancreatic cancer.
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Andres
authors.initials: A
authors.lastname: Forero-Torres
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.forename: David
authors.initials: D
authors.lastname: Waterhouse
authors.forename: Lucas
authors.initials: L
authors.lastname: Wong
authors.forename: Selwyn
authors.initials: S
authors.lastname: Vickers
authors.forename: Edward
authors.initials: E
authors.lastname: Arrowsmith
authors.forename: Aiwu Ruth
authors.initials: AR
authors.lastname: He
authors.forename: Lowell
authors.initials: L
authors.lastname: Hart
authors.forename: David
authors.initials: D
authors.lastname: Trent
authors.forename: James
authors.initials: J
authors.lastname: Wade
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Jin
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.forename: Tashara
authors.initials: T
authors.lastname: Austin
authors.forename: Michael
authors.initials: M
authors.lastname: Rosen
authors.forename: Robert
authors.initials: R
authors.lastname: Beckman
authors.forename: Reinhard
authors.initials: R
authors.lastname: von Roemeling
authors.forename: Jonathan
authors.initials: J
authors.lastname: Greenberg
authors.forename: Mansoor
authors.initials: M
authors.lastname: Saleh
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology; D000093542:Gemcitabine
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D003841:Deoxycytidine; C552861:tigatuzumab; D000093542:Gemcitabine
keywords: Monoclonal antibodies; TNF-related apoptosis-inducing ligand; pancreatic cancer; phase 2; tigatuzumab