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.

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.

Figures

Figure 1

This is the protocol schema. RAIT indicates fractionated radioimmunotherapy; 111In-hPAM4, indium 111-labeled, humanized clivatuzumab tetraxetan; 90Y-hPAM4, yttrium 90-labeled, humanized clivatuzumab tetraxetan; Gem, gemcitabine; PK, pharmacokinetics.

Figure 2

These are examples of imaging from 3 patients. (a,b) These are anterior, planar indium 111-labeled, humanized clivatuzumab tetraxetan (111In-hPAM4) images from 1 patient who received 2 treatment cycles, both at 12.0 mCi/m2 weekly for 3 weeks. Uptake was observed at the site of the known primary pancreatic mass (arrows). (a) The pancreatic mass, initially measured as 3.7 × 2.6 cm, received 39 grays (Gy) in the first cycle. (b) After decreasing to 1.8 × 2.9 cm, the pancreatic mass received 44 Gy in the second cycle. The patient’s disease remained stable until 8 weeks after the second treatment cycle, when disease progression occurred with the finding of new omental lesions. (c) Positron emission tomography–18F-deoxyglucose (PET-FDG) imaging before treatment shows normal heart (H) activity and reveals uptake in the primary pancreatic tail mass (white arrow) and in 3 left-lobe liver metastases (red arrows). (d) The uptake is no longer apparent 4 weeks after treatment. Serum CA19-9 titers decreased from 1297 at study entry to 77 at 4 weeks after treatment. (e) In another patient, PET-FDG imaging before treatment reveals uptake in primary pancreatic mass (yellow arrow), in portacaval lymph nodes (white arrow), and in a large hepatic mass extending from the dome of the liver (red arrow). (f) The uptake is no longer observed 4 weeks after treatment.

Figure 3

These are Kaplan-Meier estimates of overall survival for all 38 treated patients. (a) Results at the 2 highest dose levels (12.0 mCi/m2 and 15.0 mCi/m2 weekly for 3 weeks) are compared with results at the 2 lowest dose levels (6.5 mC1/m2 and 9.0 mCi/m2 weekly for 3 weeks). (B) Results for all patients and for patients who were retreated are compared with results for patients who received only a single cycle of treatment.