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

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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.

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Acknowledgements

This study was supported by NCI grant N01 CM-62205; NCI Translational Research Initiative Subcontract 24XS090; grant 1UL1RR025011 from the Clinical and Translational Science Award program of the National Center for Research Resources, National Institutes of Health (NIH); and NIH grant T32 CA009614 Physician Scientist Training in Cancer Medicine (Dr. Attia).

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Authors and Affiliations

  1. University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, 600 Highland Avenue, K4/528, Madison, WI, 53792, USA

    Steven Attia, Jill Kolesar, James Heun, Wei Huang, Jens Eickhoff & Kyle D. Holen

  2. Mayo Clinic Cancer Center, Rochester, MN, USA

    Michelle R. Mahoney, Henry C. Pitot & Charles Erlichman

  3. The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA

    Daniel Laheru

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Attia, S., Kolesar, J., Mahoney, M.R. et al. A phase 2 consortium (P2C) trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) for advanced adenocarcinoma of the pancreas. Invest New Drugs 26, 369–379 (2008). https://doi.org/10.1007/s10637-008-9123-6

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