A phase 2 consortium (P2C) trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) for advanced adenocarcinoma of the pancreas

Steven Attia, Jill Kolesar, Michelle R. Mahoney, Henry Clement Pitot, Daniel Laheru, James Heun, Wei Huang, Jens Eickhoff, Charles Erlichman, Kyle D. Holen

Research output: Contribution to journalArticle

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Abstract

3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine®) is a novel small molecule inhibitor of ribonucleotide reductase (RR) with clinical signs of activity in pancreatic cancer. Therefore, the Phase 2 Consortium (P2C) initiated a trial (two single stage studies with planned interim analysis) of 3-AP at 96 mg/m2 intravenously days 1-4 and 15-18 of a 28-day cycle in both chemotherapy-naive and gemcitabine-refractory (GR) patients with advanced pancreatic cancer. The primary endpoint was survival at six months (chemotherapy-naive) and four months (GR). Secondary endpoints were toxicity, response, overall survival, time to progression and mechanistic studies. Fifteen patients were enrolled including one chemotherapy-naïve and 14 GR. The chemotherapy-naïve patient progressed during cycle 1 with grade 3 and 4 toxicities. Of 14 GR patients, seven received two cycles, six received one cycle and one received eight cycles. Progression precluded further treatment in 11 GR patients. Additionally, one died of an ileus in cycle 1 considered related to treatment and two stopped treatment due to toxicity. Five GR patients had grade 4 toxicities possibly related to 3-AP and six GR patients had grade 3 fatigue. Toxicities and lack of meaningful clinical benefit prompted early study closure. Four-month survival in GR patients was 21% (95% CI: 8-58%). Correlative studies confirmed that 3-AP increased the percentage of S-phase buccal mucosal cells, the presence of multidrug resistance gene polymorphisms appeared to predict leukopenia, and baseline pancreatic tumor RR M2 expression was low relative to other tumors treated with 3-AP. In conclusion, this regimen appears inactive against predominantly GR pancreatic cancer. RR M2 protein may not have a critical role in the malignant potential of pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)369-379
Number of pages11
JournalInvestigational New Drugs
Volume26
Issue number4
DOIs
StatePublished - Aug 2008

Fingerprint

gemcitabine
Pancreas
Adenocarcinoma
Pancreatic Neoplasms
Drug Therapy
Survival
MDR Genes
Ribonucleotide Reductases
3-aminopyridine-2-carboxaldehyde thiosemicarbazone
Ileus
Cheek
Leukopenia
S Phase

Keywords

  • 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
  • 3-AP
  • Pancreatic cancer
  • Ribonucleotide reductase
  • Triapine

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

A phase 2 consortium (P2C) trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) for advanced adenocarcinoma of the pancreas. / Attia, Steven; Kolesar, Jill; Mahoney, Michelle R.; Pitot, Henry Clement; Laheru, Daniel; Heun, James; Huang, Wei; Eickhoff, Jens; Erlichman, Charles; Holen, Kyle D.

In: Investigational New Drugs, Vol. 26, No. 4, 08.2008, p. 369-379.

Research output: Contribution to journalArticle

Attia, Steven ; Kolesar, Jill ; Mahoney, Michelle R. ; Pitot, Henry Clement ; Laheru, Daniel ; Heun, James ; Huang, Wei ; Eickhoff, Jens ; Erlichman, Charles ; Holen, Kyle D. / A phase 2 consortium (P2C) trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) for advanced adenocarcinoma of the pancreas. In: Investigational New Drugs. 2008 ; Vol. 26, No. 4. pp. 369-379.
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abstract = "3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine{\circledR}) is a novel small molecule inhibitor of ribonucleotide reductase (RR) with clinical signs of activity in pancreatic cancer. Therefore, the Phase 2 Consortium (P2C) initiated a trial (two single stage studies with planned interim analysis) of 3-AP at 96 mg/m2 intravenously days 1-4 and 15-18 of a 28-day cycle in both chemotherapy-naive and gemcitabine-refractory (GR) patients with advanced pancreatic cancer. The primary endpoint was survival at six months (chemotherapy-naive) and four months (GR). Secondary endpoints were toxicity, response, overall survival, time to progression and mechanistic studies. Fifteen patients were enrolled including one chemotherapy-na{\"i}ve and 14 GR. The chemotherapy-na{\"i}ve patient progressed during cycle 1 with grade 3 and 4 toxicities. Of 14 GR patients, seven received two cycles, six received one cycle and one received eight cycles. Progression precluded further treatment in 11 GR patients. Additionally, one died of an ileus in cycle 1 considered related to treatment and two stopped treatment due to toxicity. Five GR patients had grade 4 toxicities possibly related to 3-AP and six GR patients had grade 3 fatigue. Toxicities and lack of meaningful clinical benefit prompted early study closure. Four-month survival in GR patients was 21{\%} (95{\%} CI: 8-58{\%}). Correlative studies confirmed that 3-AP increased the percentage of S-phase buccal mucosal cells, the presence of multidrug resistance gene polymorphisms appeared to predict leukopenia, and baseline pancreatic tumor RR M2 expression was low relative to other tumors treated with 3-AP. In conclusion, this regimen appears inactive against predominantly GR pancreatic cancer. RR M2 protein may not have a critical role in the malignant potential of pancreatic cancer.",
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