A dose escalation and pharmacodynamic study of triapine and radiation in patients with locally advanced pancreas cancer

Ludmila Katherine Martin, John Grecula, Guang Jia, Lai Wei, Xiangyu Yang, Gregory A. Otterson, Xin Wu, Erica Harper, Cheryl Kefauver, Bing Sen Zhou, Yun Yen, Mark Bloomston, Michael Knopp, S. Percy Ivy, Michael Grever, Tanios Bekaii-Saab

Research output: Contribution to journalArticle

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Abstract

Purpose: Triapine, a novel inhibitor of the M2 subunit of ribonucleotide reductase (RR), is a potent radiosensitizer. This phase 1 study, sponsored by the National Cancer Institute Cancer Therapy Evaluation Program, assessed the safety and tolerability of triapine in combination with radiation (RT) in patients with locally advanced pancreas cancer (LAPCA). Methods and Materials: We evaluated 3 dosage levels of triapine (24 mg/m2, 48 mg/m 2, 72 mg/m2) administered with 50.4 Gy of RT in 28 fractions. Patients with LAPCA received triapine thrice weekly, every other week during the course of RT. Dose-limiting toxicity (DLT) was assessed during RT and for 4 weeks after its completion. Dynamic contrast-enhanced magnetic resonance imaging and serum RR levels were evaluated as potential predictors for early response. Results: Twelve patients were treated. Four patients (1 nonevaluable) were enrolled at dosage level 1 (DL1), 3 patients at DL2, and 5 patients (2 nonevaluable) at DL3. No DLTs were observed, and the maximum tolerated dose was not reached. Two patients (17%) achieved partial response, and 6 patients (50%) had stable disease. One patient underwent R0 resection after therapy. Ninety-two percent of patients (100% at DL3) experienced freedom from local tumor progression. In 75% of patients who eventually experienced progression, metastases developed without local progression. RR levels did not seem to predict outcome. In 4 patients with available data, dynamic contrast-enhanced magnetic resonance imaging may predict early response or resistance to therapy. Conclusion: The combination of triapine at 72 mg/m 3 times weekly every other week and standard RT is tolerable with interesting activity in patients with LAPCA.

Original languageEnglish
JournalInternational Journal of Radiation Oncology Biology Physics
Volume84
Issue number4
DOIs
Publication statusPublished - Nov 15 2012
Externally publishedYes

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pancreas
Pancreatic Neoplasms
cancer
Radiation
dosage
radiation
progressions
Ribonucleotide Reductases
therapy
3-aminopyridine-2-carboxaldehyde thiosemicarbazone
magnetic resonance
Magnetic Resonance Imaging
Radiation Dosage
Maximum Tolerated Dose
National Cancer Institute (U.S.)
Program Evaluation
metastasis
toxicity
serums
inhibitors

ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

A dose escalation and pharmacodynamic study of triapine and radiation in patients with locally advanced pancreas cancer. / Martin, Ludmila Katherine; Grecula, John; Jia, Guang; Wei, Lai; Yang, Xiangyu; Otterson, Gregory A.; Wu, Xin; Harper, Erica; Kefauver, Cheryl; Zhou, Bing Sen; Yen, Yun; Bloomston, Mark; Knopp, Michael; Ivy, S. Percy; Grever, Michael; Bekaii-Saab, Tanios.

In: International Journal of Radiation Oncology Biology Physics, Vol. 84, No. 4, 15.11.2012.

Research output: Contribution to journalArticle

Martin, LK, Grecula, J, Jia, G, Wei, L, Yang, X, Otterson, GA, Wu, X, Harper, E, Kefauver, C, Zhou, BS, Yen, Y, Bloomston, M, Knopp, M, Ivy, SP, Grever, M & Bekaii-Saab, T 2012, 'A dose escalation and pharmacodynamic study of triapine and radiation in patients with locally advanced pancreas cancer', International Journal of Radiation Oncology Biology Physics, vol. 84, no. 4. https://doi.org/10.1016/j.ijrobp.2012.06.003
Martin, Ludmila Katherine ; Grecula, John ; Jia, Guang ; Wei, Lai ; Yang, Xiangyu ; Otterson, Gregory A. ; Wu, Xin ; Harper, Erica ; Kefauver, Cheryl ; Zhou, Bing Sen ; Yen, Yun ; Bloomston, Mark ; Knopp, Michael ; Ivy, S. Percy ; Grever, Michael ; Bekaii-Saab, Tanios. / A dose escalation and pharmacodynamic study of triapine and radiation in patients with locally advanced pancreas cancer. In: International Journal of Radiation Oncology Biology Physics. 2012 ; Vol. 84, No. 4.
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abstract = "Purpose: Triapine, a novel inhibitor of the M2 subunit of ribonucleotide reductase (RR), is a potent radiosensitizer. This phase 1 study, sponsored by the National Cancer Institute Cancer Therapy Evaluation Program, assessed the safety and tolerability of triapine in combination with radiation (RT) in patients with locally advanced pancreas cancer (LAPCA). Methods and Materials: We evaluated 3 dosage levels of triapine (24 mg/m2, 48 mg/m 2, 72 mg/m2) administered with 50.4 Gy of RT in 28 fractions. Patients with LAPCA received triapine thrice weekly, every other week during the course of RT. Dose-limiting toxicity (DLT) was assessed during RT and for 4 weeks after its completion. Dynamic contrast-enhanced magnetic resonance imaging and serum RR levels were evaluated as potential predictors for early response. Results: Twelve patients were treated. Four patients (1 nonevaluable) were enrolled at dosage level 1 (DL1), 3 patients at DL2, and 5 patients (2 nonevaluable) at DL3. No DLTs were observed, and the maximum tolerated dose was not reached. Two patients (17{\%}) achieved partial response, and 6 patients (50{\%}) had stable disease. One patient underwent R0 resection after therapy. Ninety-two percent of patients (100{\%} at DL3) experienced freedom from local tumor progression. In 75{\%} of patients who eventually experienced progression, metastases developed without local progression. RR levels did not seem to predict outcome. In 4 patients with available data, dynamic contrast-enhanced magnetic resonance imaging may predict early response or resistance to therapy. Conclusion: The combination of triapine at 72 mg/m 3 times weekly every other week and standard RT is tolerable with interesting activity in patients with LAPCA.",
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AU - Yang, Xiangyu

AU - Otterson, Gregory A.

AU - Wu, Xin

AU - Harper, Erica

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AU - Zhou, Bing Sen

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AU - Bloomston, Mark

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AU - Ivy, S. Percy

AU - Grever, Michael

AU - Bekaii-Saab, Tanios

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