Fractionated radioimmunotherapy with (90) Y-clivatuzumab tetraxetan and low-dose gemcitabine is active in advanced pancreatic cancer: A phase 1 trial
Allyson J Ocean, Kenneth L Pennington, Michael J Guarino, Arif Sheikh, Tanios Bekaii-Saab, Aldo N Serafini, Daniel Lee, Max W Sung, Seza A Gulec, Stanley J Goldsmith, Timothy Manzone, Michael Holt, Bert H O'Neil, Nathan Hall, Alberto J Montero, John Kauh, David V Gold, Heather Horne, William A Wegener, David M Goldenberg, Allyson J Ocean, Kenneth L Pennington, Michael J Guarino, Arif Sheikh, Tanios Bekaii-Saab, Aldo N Serafini, Daniel Lee, Max W Sung, Seza A Gulec, Stanley J Goldsmith, Timothy Manzone, Michael Holt, Bert H O'Neil, Nathan Hall, Alberto J Montero, John Kauh, David V Gold, Heather Horne, William A Wegener, David M Goldenberg
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.
Conflict of interest statement
CONFLICT OF INTEREST DISCLOSURES
H.H., W.A.W., and D.M.G. are employed by or have financial interests in Immunomedics. S.J.G. owns shares in Immunomedics. The other authors who participated in the clinical trial received research support from Immunomedics through their institutions for conducting this study.
Copyright © 2012 American Cancer Society.
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Source: PubMed