Fractionated radioimmunotherapy with ⁹⁰Y‐clivatuzumab tetraxetan and low‐dose gemcitabine is active in advanced pancreatic cancer

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/m2, 9.0 mCi/m2, 12.0 mCi/m2, and 15.0 mCi/m2. 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.

Targeted Chemoradiation in Metastatic Colorectal Cancer: A Phase I Trial of 131I-huA33 with Concurrent Capecitabine

“…The combination of radioimmunotherapy with chemotherapy to induce enhanced antitumor effects has been extensively explored in preclinical models (23)(24)(25)(26)(27)(28) and in a small number of phase I/II studies in patients with advanced solid tumors, with a suggestion of antitumor activity in some (29)(30)(31)(32)(33)(34). The aim of this approach is to use chemotherapy as a radiosensitizer, so that cancer cell cycle is arrested in the radiosensitive G(2)/M phase and efficacy is improved.…”

Personalized medicine in sporadic pancreatic cancer without homologous recombination-deficiency: are we any closer?

“…A phase I study of single dose [90]Y-labeled hPAM4 demonstrated its safety and also potential efficacy with 3 out of 21 patients achieving partial response (69). A second phase I study of repeated cycles of the same drug in combination with low dose gemcitabine demonstrated an encouraging response rate of 16% and a disease control rate of 42%, translating into a median survival of 7.7 months (including 11.8 months for those who received repeated cycles) (70). Guided by these results, a phase 3 study in the third line setting of low-dose gemcitabine with [90]Y-hPAM4 or placebo with a 2:1 randomization was undertaken (NCT01956812).…”

Immunotherapy of Pancreatic Cancer

“…Anti-Muc-1 antibody, PAM4, is expressed in 85 % of pancreatic cancers, but not in normal pancreatic tissue [ 95 ]. Humanized PAM4 (clivatuzumab tetraxetan) conjugated with yttrium-90, a beta-emitting nucleotide with a radiation path length of 5 mm ( Y-hPAM4 has promising therapeutic activity with manageable side effects [ 96 ].…”