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

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/m2, 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/m2 3 times weekly every other week and standard RT is tolerable with interesting activity in patients with LAPCA.

• Authors: 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
• Journal: International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 84 Issue 4 Pg. e475-81 (Nov 15 2012) ISSN: 1879-355X [Electronic] United States
• PMID: 22818416 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Contrast Media
• Pyridines
• Radiation-Sensitizing Agents
• Thiosemicarbazones
• Tumor Suppressor Proteins
• 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
• ribonucleotide reductase M2
• RRM1 protein, human
• Ribonucleoside Diphosphate Reductase

Topics

• Aged
• Aged, 80 and over
• Combined Modality Therapy (methods)
• Contrast Media
• Disease Progression
• Drug Administration Schedule
• Female
• Humans
• Magnetic Resonance Imaging (methods)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Pancreatic Neoplasms (metabolism, pathology, radiotherapy)
• Pyridines (administration & dosage, pharmacokinetics)
• Radiation-Sensitizing Agents (administration & dosage, pharmacokinetics)
• Radiotherapy Dosage
• Ribonucleoside Diphosphate Reductase (antagonists & inhibitors, blood)
• Thiosemicarbazones (administration & dosage, pharmacokinetics)
• Tumor Suppressor Proteins (blood)