A phase I trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone in combination with gemcitabine for patients with advanced cancer

Yun Yen, Kim Margolin, James Doroshow, Mayer Fishman, Bonny Johnson, Caroline Clairmont, Dan Sullivan, Mario Sznol

Research output: Contribution to journalArticle

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Abstract

Purpose: 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP), a new and potent inhibitor of ribonucleotide reductase (RR), increases the cellular uptake, DNA incorporation, and cytotoxicity of gemcitabine in tumor cell lines. A phase I trial was initiated to determine the safety profile and maximum tolerated doses of 3-AP and gemcitabine when used in combination in patients with advanced cancer. Study design: 3-AP and gemcitabine were administered on days 1, 8, and 15 of each 28-day cycle. Initially, 3-AP was infused over 2 h at a fixed dose of 105 mg/m2. Gemcitabine was given over 30 min beginning no less than 1 and no more than 4 h after 3-AP. The first cohort received 3-AP alone in the first cycle. Subsequently, the gemcitabine dose was escalated beginning at 600 mg/m2 in cohorts of three to six patients. Following the gemcitabine 1000 mg/m2 dose level, the study was amended to determine if the 3-AP dose could be escalated above 105 mg/m 2. Results: 3-AP at 105 mg/m2 administered over 2 h followed in 1-4 h by gemcitabine at 1000 mg/m2 produced a toxicity profile similar to that expected for gemcitabine alone at the same dose. When the dose of 3-AP was escalated to 140 and 185 mg/m2 administered over 2 h and subsequently over 4 h, acute hypotension, hypoxia, and EKG changes including non-specific ST-T wave changes and mild QT prolongation were observed, and one patient with underlying diffuse coronary artery disease had an asymptomatic myocardial infarction. 3-AP was shown to cause mild, reversible methemoglobinemia. Average end-of infusion serum concentrations for 3-AP at all doses were within the range capable of enhancing gemcitabine cytotoxicity in vitro. Gemcitabine plasma concentrations at end-of-infusion and elimination half-life were consistent with values reported in the literature. Among 22 evaluable patients, one complete response and two partial responses were observed, and an additional patient had prolonged stabilization of a large liver metastasis. Conclusions: 3-AP at 105 mg/m2 infused over 2-4 h followed by gemcitabine at 1000 mg/m2 on a days 1, 8, and 15 schedule every 28 days was generally well-tolerated and had a toxicity profile similar to that of gemcitabine alone. 3-AP produced mild to modest methemoglobinemia, which could cause acute symptoms in patients with limited pulmonary or cardiovascular reserve. The combination demonstrated antitumor activity and merits further exploration in phase II trials.

Original languageEnglish
Pages (from-to)331-342
Number of pages12
JournalCancer Chemotherapy and Pharmacology
Volume54
Issue number4
DOIs
Publication statusPublished - Oct 1 2004
Externally publishedYes

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gemcitabine
Neoplasms
Methemoglobinemia
Cytotoxicity
Toxicity
3-aminopyridine-2-carboxaldehyde thiosemicarbazone
Ribonucleotide Reductases

Keywords

  • 3-Aminopyridine-2- carboxaldehyde thiosemicarbazone
  • Cancer
  • Clinical trial
  • Gemcitabine
  • Phase I
  • Ribonucleotide reductase

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

A phase I trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone in combination with gemcitabine for patients with advanced cancer. / Yen, Yun; Margolin, Kim; Doroshow, James; Fishman, Mayer; Johnson, Bonny; Clairmont, Caroline; Sullivan, Dan; Sznol, Mario.

In: Cancer Chemotherapy and Pharmacology, Vol. 54, No. 4, 01.10.2004, p. 331-342.

Research output: Contribution to journalArticle

Yen, Yun ; Margolin, Kim ; Doroshow, James ; Fishman, Mayer ; Johnson, Bonny ; Clairmont, Caroline ; Sullivan, Dan ; Sznol, Mario. / A phase I trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone in combination with gemcitabine for patients with advanced cancer. In: Cancer Chemotherapy and Pharmacology. 2004 ; Vol. 54, No. 4. pp. 331-342.
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abstract = "Purpose: 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP), a new and potent inhibitor of ribonucleotide reductase (RR), increases the cellular uptake, DNA incorporation, and cytotoxicity of gemcitabine in tumor cell lines. A phase I trial was initiated to determine the safety profile and maximum tolerated doses of 3-AP and gemcitabine when used in combination in patients with advanced cancer. Study design: 3-AP and gemcitabine were administered on days 1, 8, and 15 of each 28-day cycle. Initially, 3-AP was infused over 2 h at a fixed dose of 105 mg/m2. Gemcitabine was given over 30 min beginning no less than 1 and no more than 4 h after 3-AP. The first cohort received 3-AP alone in the first cycle. Subsequently, the gemcitabine dose was escalated beginning at 600 mg/m2 in cohorts of three to six patients. Following the gemcitabine 1000 mg/m2 dose level, the study was amended to determine if the 3-AP dose could be escalated above 105 mg/m 2. Results: 3-AP at 105 mg/m2 administered over 2 h followed in 1-4 h by gemcitabine at 1000 mg/m2 produced a toxicity profile similar to that expected for gemcitabine alone at the same dose. When the dose of 3-AP was escalated to 140 and 185 mg/m2 administered over 2 h and subsequently over 4 h, acute hypotension, hypoxia, and EKG changes including non-specific ST-T wave changes and mild QT prolongation were observed, and one patient with underlying diffuse coronary artery disease had an asymptomatic myocardial infarction. 3-AP was shown to cause mild, reversible methemoglobinemia. Average end-of infusion serum concentrations for 3-AP at all doses were within the range capable of enhancing gemcitabine cytotoxicity in vitro. Gemcitabine plasma concentrations at end-of-infusion and elimination half-life were consistent with values reported in the literature. Among 22 evaluable patients, one complete response and two partial responses were observed, and an additional patient had prolonged stabilization of a large liver metastasis. Conclusions: 3-AP at 105 mg/m2 infused over 2-4 h followed by gemcitabine at 1000 mg/m2 on a days 1, 8, and 15 schedule every 28 days was generally well-tolerated and had a toxicity profile similar to that of gemcitabine alone. 3-AP produced mild to modest methemoglobinemia, which could cause acute symptoms in patients with limited pulmonary or cardiovascular reserve. The combination demonstrated antitumor activity and merits further exploration in phase II trials.",
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T1 - A phase I trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone in combination with gemcitabine for patients with advanced cancer

AU - Yen, Yun

AU - Margolin, Kim

AU - Doroshow, James

AU - Fishman, Mayer

AU - Johnson, Bonny

AU - Clairmont, Caroline

AU - Sullivan, Dan

AU - Sznol, Mario

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N2 - Purpose: 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP), a new and potent inhibitor of ribonucleotide reductase (RR), increases the cellular uptake, DNA incorporation, and cytotoxicity of gemcitabine in tumor cell lines. A phase I trial was initiated to determine the safety profile and maximum tolerated doses of 3-AP and gemcitabine when used in combination in patients with advanced cancer. Study design: 3-AP and gemcitabine were administered on days 1, 8, and 15 of each 28-day cycle. Initially, 3-AP was infused over 2 h at a fixed dose of 105 mg/m2. Gemcitabine was given over 30 min beginning no less than 1 and no more than 4 h after 3-AP. The first cohort received 3-AP alone in the first cycle. Subsequently, the gemcitabine dose was escalated beginning at 600 mg/m2 in cohorts of three to six patients. Following the gemcitabine 1000 mg/m2 dose level, the study was amended to determine if the 3-AP dose could be escalated above 105 mg/m 2. Results: 3-AP at 105 mg/m2 administered over 2 h followed in 1-4 h by gemcitabine at 1000 mg/m2 produced a toxicity profile similar to that expected for gemcitabine alone at the same dose. When the dose of 3-AP was escalated to 140 and 185 mg/m2 administered over 2 h and subsequently over 4 h, acute hypotension, hypoxia, and EKG changes including non-specific ST-T wave changes and mild QT prolongation were observed, and one patient with underlying diffuse coronary artery disease had an asymptomatic myocardial infarction. 3-AP was shown to cause mild, reversible methemoglobinemia. Average end-of infusion serum concentrations for 3-AP at all doses were within the range capable of enhancing gemcitabine cytotoxicity in vitro. Gemcitabine plasma concentrations at end-of-infusion and elimination half-life were consistent with values reported in the literature. Among 22 evaluable patients, one complete response and two partial responses were observed, and an additional patient had prolonged stabilization of a large liver metastasis. Conclusions: 3-AP at 105 mg/m2 infused over 2-4 h followed by gemcitabine at 1000 mg/m2 on a days 1, 8, and 15 schedule every 28 days was generally well-tolerated and had a toxicity profile similar to that of gemcitabine alone. 3-AP produced mild to modest methemoglobinemia, which could cause acute symptoms in patients with limited pulmonary or cardiovascular reserve. The combination demonstrated antitumor activity and merits further exploration in phase II trials.

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KW - 3-Aminopyridine-2- carboxaldehyde thiosemicarbazone

KW - Cancer

KW - Clinical trial

KW - Gemcitabine

KW - Phase I

KW - Ribonucleotide reductase

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