Treatment of advanced pancreatic carcinoma with 90Y-clivatuzumab tetraxetan: A phase I single-dose escalation trial

Seza A. Gulec, Steven J. Cohen, Kenneth L. Pennington, Lionel S. Zuckier, Ralph J. Hauke, Heather Horne, William A. Wegener, Nick Teoh, David V. Gold, Robert M. Sharkey, David M. Goldenberg

Research output: Contribution to journalArticle

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Abstract

Purpose: Humanized antibody hPAM4 specifically binds a mucin glycoprotein expressed in pancreatic adenocarcinomas. This phase I study evaluated a single dose of 90Y-clivatuzumab tetraxetan (90Y-labeled hPAM4) in patients with advanced pancreatic cancer. Experimental Design: Twenty-one patients (4 stage III; 17 stage IV) received 111In-hPAM4 for imaging and serum sampling before 90Y-hPAM4. Study procedures evaluated adverse events, safety laboratories, computed tomography (CT) scans, biomarkers, pharmacokinetics, radiation dosimetry, and immunogenicity (HAHA). Results: 111In-hPAM4 showed normal biodistribution with radiation dose estimates to red marrow and solid organs acceptable for radioimmunotherapy and with tumor targeting in 12 patients. One patient withdrew before 90Y-hPAM4; otherwise, 20 patients received 90Y doses of 15 (n = 7), 20 (n = 9), and 25 mCi/m2 (n = 4). Treatment was well tolerated; the only significant drug-related toxicities were (NCI CTC v.3) grade 3 to 4 neutropenia and thrombocytopenia increasing with 90Y dose. There were no bleeding events or serious infections, and most cytopenias recovered to grade 1 within 12 weeks. Three patients at 25 mCi/m2 encountered dose-limiting toxicity with grade 4 cytopenias more than 7 days, establishing 20 mCi/m2 as the maximal tolerated 90Y dose. Two patients developed HAHA of uncertain clinical significance. Most patients progressed rapidly and with CA19-9 levels increasing within 1 month of therapy, but 7 remained progression-free by CT for 1.5 to 5.6 months, including 3 achieving transient partial responses (32%-52% tumor diameter shrinkage). Conclusion: 90Y-Clivatuzumab tetraxetan was well tolerated with manageable hematologic toxicity at the maximal tolerated 90Y dose, and is a potential new therapeutic for advanced pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)4091-4100
Number of pages10
JournalClinical Cancer Research
Volume17
Issue number12
DOIs
StatePublished - Jun 15 2011
Externally publishedYes

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Maximum Tolerated Dose
Therapeutics
Pancreatic Neoplasms
Tomography
Radiometry
Radioimmunotherapy
Antibodies, Monoclonal, Humanized
Pancreatic Carcinoma
clivatuzumab
Mucins
Neutropenia
Drug-Related Side Effects and Adverse Reactions
Neoplasms
Glycoproteins
Adenocarcinoma
Research Design
Pharmacokinetics
Biomarkers
Bone Marrow
Radiation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Treatment of advanced pancreatic carcinoma with 90Y-clivatuzumab tetraxetan : A phase I single-dose escalation trial. / Gulec, Seza A.; Cohen, Steven J.; Pennington, Kenneth L.; Zuckier, Lionel S.; Hauke, Ralph J.; Horne, Heather; Wegener, William A.; Teoh, Nick; Gold, David V.; Sharkey, Robert M.; Goldenberg, David M.

In: Clinical Cancer Research, Vol. 17, No. 12, 15.06.2011, p. 4091-4100.

Research output: Contribution to journalArticle

Gulec, SA, Cohen, SJ, Pennington, KL, Zuckier, LS, Hauke, RJ, Horne, H, Wegener, WA, Teoh, N, Gold, DV, Sharkey, RM & Goldenberg, DM 2011, 'Treatment of advanced pancreatic carcinoma with 90Y-clivatuzumab tetraxetan: A phase I single-dose escalation trial', Clinical Cancer Research, vol. 17, no. 12, pp. 4091-4100. https://doi.org/10.1158/1078-0432.CCR-10-2579
Gulec, Seza A. ; Cohen, Steven J. ; Pennington, Kenneth L. ; Zuckier, Lionel S. ; Hauke, Ralph J. ; Horne, Heather ; Wegener, William A. ; Teoh, Nick ; Gold, David V. ; Sharkey, Robert M. ; Goldenberg, David M. / Treatment of advanced pancreatic carcinoma with 90Y-clivatuzumab tetraxetan : A phase I single-dose escalation trial. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 12. pp. 4091-4100.
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abstract = "Purpose: Humanized antibody hPAM4 specifically binds a mucin glycoprotein expressed in pancreatic adenocarcinomas. This phase I study evaluated a single dose of 90Y-clivatuzumab tetraxetan (90Y-labeled hPAM4) in patients with advanced pancreatic cancer. Experimental Design: Twenty-one patients (4 stage III; 17 stage IV) received 111In-hPAM4 for imaging and serum sampling before 90Y-hPAM4. Study procedures evaluated adverse events, safety laboratories, computed tomography (CT) scans, biomarkers, pharmacokinetics, radiation dosimetry, and immunogenicity (HAHA). Results: 111In-hPAM4 showed normal biodistribution with radiation dose estimates to red marrow and solid organs acceptable for radioimmunotherapy and with tumor targeting in 12 patients. One patient withdrew before 90Y-hPAM4; otherwise, 20 patients received 90Y doses of 15 (n = 7), 20 (n = 9), and 25 mCi/m2 (n = 4). Treatment was well tolerated; the only significant drug-related toxicities were (NCI CTC v.3) grade 3 to 4 neutropenia and thrombocytopenia increasing with 90Y dose. There were no bleeding events or serious infections, and most cytopenias recovered to grade 1 within 12 weeks. Three patients at 25 mCi/m2 encountered dose-limiting toxicity with grade 4 cytopenias more than 7 days, establishing 20 mCi/m2 as the maximal tolerated 90Y dose. Two patients developed HAHA of uncertain clinical significance. Most patients progressed rapidly and with CA19-9 levels increasing within 1 month of therapy, but 7 remained progression-free by CT for 1.5 to 5.6 months, including 3 achieving transient partial responses (32{\%}-52{\%} tumor diameter shrinkage). Conclusion: 90Y-Clivatuzumab tetraxetan was well tolerated with manageable hematologic toxicity at the maximal tolerated 90Y dose, and is a potential new therapeutic for advanced pancreatic cancer.",
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AU - Zuckier, Lionel S.

AU - Hauke, Ralph J.

AU - Horne, Heather

AU - Wegener, William A.

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