title: Fractionated radioimmunotherapy with (90) Y-clivatuzumab tetraxetan and low-dose gemcitabine is active in advanced pancreatic cancer: A phase 1 trial.
abstract: BACKGROUND
  It has been demonstrated that the humanized clivatuzumab tetraxetan (hPAM4) antibody targets pancreatic ductal carcinoma selectively. After a trial of radioimmunotherapy that determined the maximum tolerated dose of single-dose yttrium-90-labeled hPAM4 ((90) Y-hPAM4) and produced objective responses in patients with advanced pancreatic ductal carcinoma, the authors studied fractionated radioimmunotherapy combined with low-dose gemcitabine in this disease.
  
  
  METHODS
  Thirty-eight previously untreated patients (33 patients with stage IV disease and 5 patients with stage III disease) received gemcitabine 200 mg/m(2) weekly for 4 weeks with (90) Y-hPAM4 given weekly in Weeks 2, 3, and 4 (cycle 1), and the same cycle was repeated in 13 patients (cycles 2-4). In the first part of the study, 19 patients received escalating weekly (90) Y doses of 6.5 mCi/m(2) , 9.0 mCi/m(2) , 12.0 mCi/m(2) , and 15.0 mCi/m(2) . In the second portion, 19 additional patients received weekly doses of 9.0 mCi/m(2) or 12.0 mCi/m(2) .
  
  
  RESULTS
  Grade 3/4 thrombocytopenia or neutropenia (according to version 3.0 of the National Cancer Institute's Common Terminology Criteria for Adverse Events) developed in 28 of 38 patients after cycle 1 and in all retreated patients; no grade >3 nonhematologic toxicities occurred. Fractionated dosing of cycle 1 allowed almost twice the radiation dose compared with single-dose radioimmunotherapy. The maximum tolerated dose of (90) Y-hPAM4 was 12.0 mCi/m(2) weekly for 3 weeks for cycle 1, with ≤9.0 mCi/m(2) weekly for 3 weeks for subsequent cycles, and that dose will be used in future trials. Six patients (16%) had partial responses according to computed tomography-based Response Evaluation Criteria in Solid Tumors, and 16 patients (42%) had stabilization as their best response (58% disease control). The median overall survival was 7.7 months for all 38 patients, including 11.8 months for those who received repeated cycles (46% [6 of 13 patients] ≥1 year), with improved efficacy at the higher radioimmunotherapy doses.
  
  
  CONCLUSIONS
  Fractionated radioimmunotherapy with (90) Y-hPAM4 and low-dose gemcitabine demonstrated promising therapeutic activity and manageable myelosuppression in patients with advanced pancreatic ductal carcinoma.
authors.affiliation: Department of Medicine, Division of Hematology and Medical Oncology, New York Presbyterian Hospital, Weill Medical College of Cornell University, New York, New York 10021, USA. ajo9001@med.cornell.edu
authors.forename: Allyson J
authors.initials: AJ
authors.lastname: Ocean
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Pennington
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Guarino
authors.forename: Arif
authors.initials: A
authors.lastname: Sheikh
authors.forename: Tanios
authors.initials: T
authors.lastname: Bekaii-Saab
authors.forename: Aldo N
authors.initials: AN
authors.lastname: Serafini
authors.forename: Daniel
authors.initials: D
authors.lastname: Lee
authors.forename: Max W
authors.initials: MW
authors.lastname: Sung
authors.forename: Seza A
authors.initials: SA
authors.lastname: Gulec
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Goldsmith
authors.forename: Timothy
authors.initials: T
authors.lastname: Manzone
authors.forename: Michael
authors.initials: M
authors.lastname: Holt
authors.forename: Bert H
authors.initials: BH
authors.lastname: O'Neil
authors.forename: Nathan
authors.initials: N
authors.lastname: Hall
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Montero
authors.forename: John
authors.initials: J
authors.lastname: Kauh
authors.forename: David V
authors.initials: DV
authors.lastname: Gold
authors.forename: Heather
authors.initials: H
authors.lastname: Horne
authors.forename: William A
authors.initials: WA
authors.lastname: Wegener
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000532:radiotherapy; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009503:Neutropenia / Q000209:etiology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D011829:Radiation Dosage; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use; D016499:Radioimmunotherapy; D013921:Thrombocytopenia / Q000209:etiology; D015021:Yttrium Radioisotopes / Q000009:adverse effects / Q000627:therapeutic use*; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D000964:Antimetabolites, Antineoplastic; D011838:Radiation-Sensitizing Agents; D015021:Yttrium Radioisotopes; D003841:Deoxycytidine; D000093542:Gemcitabine