Fractionated radioimmunotherapy with (90) Y-clivatuzumab tetraxetan and low-dose gemcitabine is active in advanced pancreatic cancer: A phase 1 trial.

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.