Fractionated radioimmunotherapy with 90Y-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

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61 Scopus citations

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 (90Y-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/m2 weekly for 4 weeks with 90Y-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 90Y doses of 6.5 mCi/m 2, 9.0 mCi/m2, 12.0 mCi/m2, and 15.0 mCi/m 2. In the second portion, 19 additional patients received weekly doses of 9.0 mCi/m2 or 12.0 mCi/m2. 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 90Y-hPAM4 was 12.0 mCi/m2 weekly for 3 weeks for cycle 1, with ≤9.0 mCi/m2 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 90Y-hPAM4 and low-dose gemcitabine demonstrated promising therapeutic activity and manageable myelosuppression in patients with advanced pancreatic ductal carcinoma.

Original languageEnglish (US)
Pages (from-to)5497-5506
Number of pages10
JournalCancer
Volume118
Issue number22
DOIs
StatePublished - Nov 15 2012

Keywords

  • Y
  • clivatuzumab tetraxetan
  • combination therapy
  • ductal pancreatic cancer
  • gemcitabine
  • radioimmunotherapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Ocean, A. J., Pennington, K. L., Guarino, M. J., Sheikh, A., Bekaii-Saab, T., Serafini, A. N., Lee, D., Sung, M. W., Gulec, S. A., Goldsmith, S. J., Manzone, T., Holt, M., O'Neil, B. H., Hall, N., Montero, A. J., Kauh, J., Gold, D. V., Horne, H., Wegener, W. A., & Goldenberg, D. M. (2012). Fractionated radioimmunotherapy with 90Y-clivatuzumab tetraxetan and low-dose gemcitabine is active in advanced pancreatic cancer: A phase 1 trial. Cancer, 118(22), 5497-5506. https://doi.org/10.1002/cncr.27592