Investigational New Drugs

, Volume 26, Issue 4, pp 369–379 | Cite as

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 C. Pitot
  • Daniel Laheru
  • James Heun
  • Wei Huang
  • Jens Eickhoff
  • Charles Erlichman
  • Kyle D. Holen


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.


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



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).


  1. 1.
    Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ (2007) Cancer statistics, 2007. CA Cancer J Clin 57:43–66PubMedCrossRefGoogle Scholar
  2. 2.
    Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15:2403–2413PubMedGoogle Scholar
  3. 3.
    Colucci G, Giuliani F, Gebbia V, Biglietto M, Rabitti P, Uomo G, Cigolari S, Testa A, Maiello E, Lopez M (2002) Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: a prospective, randomized phase III study of the Gruppo Oncologia dell’Italia Meridionale. Cancer 94:902–910PubMedCrossRefGoogle Scholar
  4. 4.
    Berlin JD, Catalano P, Thomas JP, Kugler JW, Haller DG, Benson AB, (2002) Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol 20:3270–3275PubMedCrossRefGoogle Scholar
  5. 5.
    Rocha Lima CM, Green MR, Rotche R, Miller WH Jr., Jeffrey GM, Cisar LA, Morganti A, Orlando N, Gruia G, Miller LL (2004) Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol 22:3776–3783PubMedCrossRefGoogle Scholar
  6. 6.
    Oettle H, Richards D, Ramanathan RK, van Laethem JL, Peeters M, Fuchs M, Zimmermann A, John W, Von Hoff D, Arning M, Kindler HL (2005) A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann Oncol 16:1639–1645PubMedCrossRefGoogle Scholar
  7. 7.
    Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, Andre T, Zaniboni A, Ducreux M, Aitini E, Taieb J, Faroux R, Lepere C, de Gramont A (2005) Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol 23:3509–3516PubMedCrossRefGoogle Scholar
  8. 8.
    Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960–1966PubMedCrossRefGoogle Scholar
  9. 9.
    Finch RA, Liu MC, Cory AH, Cory JG, Sartorelli AC (1999) Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone; 3-AP): an inhibitor of ribonucleotide reductase with antineoplastic activity. Adv Enzyme Regul 39:3–12PubMedCrossRefGoogle Scholar
  10. 10.
    Cory JG, Cory AH, Rappa G, Lorico A, Liu MC, Lin TS, Sartorelli AC (1994) Inhibitors of ribonucleotide reductase. Comparative effects of amino- and hydroxy-substituted pyridine-2-carboxaldehyde thiosemicarbazones. Biochem Pharmacol 48:335–344PubMedCrossRefGoogle Scholar
  11. 11.
    Murren J, Modiano M, Clairmont C, Lambert P, Savaraj N, Doyle T, Sznol M (2003) Phase I and pharmacokinetic study of triapine, a potent ribonucleotide reductase inhibitor, administered daily for five days in patients with advanced solid tumors. Clin Cancer Res 9:4092–4100PubMedGoogle Scholar
  12. 12.
    Feun L, Modiano M, Lee K, Mao J, Marini A, Savaraj N, Plezia P, Almassian B, Colacino E, Fischer J, MacDonald S (2002) Phase I and pharmacokinetic study of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) using a single intravenous dose schedule. Cancer Chemother Pharmacol 50:223–229PubMedCrossRefGoogle Scholar
  13. 13.
    Wadler S, Makower D, Clairmont C, Lambert P, Fehn K, Sznol M (2004) Phase I and pharmacokinetic study of the ribonucleotide reductase inhibitor, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, administered by 96-hour intravenous continuous infusion. J Clin Oncol 22:1553–1563PubMedCrossRefGoogle Scholar
  14. 14.
    Fromm MF (2002) The influence of MDR1 polymorphisms on P-glycoprotein expression and function in humans. Adv Drug Deliv Rev 54:1295–1310PubMedCrossRefGoogle Scholar
  15. 15.
    Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A, Cascorbi I, Gerloff T, Roots I, Eichelbaum M, Brinkmann U (2000) Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 97:3473–3478PubMedCrossRefGoogle Scholar
  16. 16.
    Rappa G, Lorico A, Liu MC, Kruh GD, Cory AH, Cory JG, Sartorelli AC (1997) Overexpression of the multidrug resistance genes mdr1, mdr3, and mrp in L1210 leukemia cells resistant to inhibitors of ribonucleotide reductase. Biochem Pharmacol 54:649–655PubMedCrossRefGoogle Scholar
  17. 17.
    Marzolini C, Paus E, Buclin T, Kim RB (2004) Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther 75:13–33PubMedCrossRefGoogle Scholar
  18. 18.
    Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI, Taylor A, Xie HG, McKinsey J, Zhou S, Lan LB, Schuetz JD, Schuetz EG, Wilkinson GR (2001) Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 70:189–199PubMedCrossRefGoogle Scholar
  19. 19.
    Rittberg DA, Wright JA (1989) Relationships between sensitivity to hydroxyurea and 4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone (MAIO) and ribonucleotide reductase RNR2 mRNA levels in strains of Saccharomyces cerevisiae. Biochem Cell Biol 67:352–357PubMedCrossRefGoogle Scholar
  20. 20.
    Wright JA, Cory JG (1983) Alterations in the components of ribonucleotide reductase in hydroxyurea-resistant hamster cells. Biosci Rep 3:741–748PubMedCrossRefGoogle Scholar
  21. 21.
    Yen Y, Grill SP, Dutschman GE, Chang CN, Zhou BS, Cheng YC (1994) Characterization of a hydroxyurea-resistant human KB cell line with supersensitivity to 6-thioguanine. Cancer Res 54:3686–3691PubMedGoogle Scholar
  22. 22.
    Zhou BS, Hsu NY, Pan BC, Doroshow JH, Yen Y (1995) Overexpression of ribonucleotide reductase in transfected human KB cells increases their resistance to hydroxyurea: M2 but not M1 is sufficient to increase resistance to hydroxyurea in transfected cells. Cancer Res 55:1328–1333PubMedGoogle Scholar
  23. 23.
    Maurer-Schultze B, Siebert M, Bassukas ID (1988) An in vivo study on the synchronizing effect of hydroxyurea. Exp Cell Res 174:230–243PubMedCrossRefGoogle Scholar
  24. 24.
    Foltz LM, Dalal BI, Wadsworth LD, Broady R, Chi K, Eisenhauer E, Kobayashi K, Kollmannsburger C (2006) Recognition and management of methemoglobinemia and hemolysis in a G6PD-deficient patient on experimental anticancer drug Triapine. Am J Hematol 81:210–211PubMedCrossRefGoogle Scholar
  25. 25.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216PubMedCrossRefGoogle Scholar
  26. 26.
    Boom R, Sol CJ, Heijtink R, Wertheim-van Dillen PM, van der Noordaa J (1991) Rapid purification of hepatitis B virus DNA from serum. J Clin Microbiol 29:1804–1811PubMedGoogle Scholar
  27. 27.
    Camp RL, Chung GG, Rimm DL (2002) Automated subcellular localization and quantification of protein expression in tissue microarrays. Nat Med 8:1323–1327PubMedCrossRefGoogle Scholar
  28. 28.
    Dolled-Filhart M, McCabe A, Giltnane J, Cregger M, Camp RL, Rimm DL (2006) Quantitative in situ analysis of beta-catenin expression in breast cancer shows decreased expression is associated with poor outcome. Cancer Res 66:5487–5494PubMedCrossRefGoogle Scholar
  29. 29.
    Rubin MA, Zerkowski MP, Camp RL, Kuefer R, Hofer MD, Chinnaiyan AM, Rimm DL (2004) Quantitative determination of expression of the prostate cancer protein alpha-methylacyl-CoA racemase using automated quantitative analysis (AQUA): a novel paradigm for automated and continuous biomarker measurements. Am J Pathol 164:831–840PubMedGoogle Scholar
  30. 30.
    Rothenberg ML, Moore MJ, Cripps MC, Andersen JS, Portenoy RK, Burris HA 3rd, Green MR, Tarassoff PG, Brown TD, Casper ES, Storniolo AM, Von Hoff DD (1996) A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann Oncol 7:347–353PubMedGoogle Scholar
  31. 31.
    Sargent DJ, Chan V, Goldberg RM (2001) A three-outcome design for phase II clinical trials. Control Clin Trials 22:117–125PubMedCrossRefGoogle Scholar
  32. 32.
    Kaplan EMP (1958) Nonparametric estimation for incomplete observations. J Am Stat Assoc 53:457–481CrossRefGoogle Scholar
  33. 33.
    Cox D (1972) Regression models and life tables. J R Stat Soc Ser B 34:187–202Google Scholar
  34. 34.
    Mackenzie MJ, Saltman D, Hirte H, Low J, Johnson C, Pond G, Moore MJ (2007) A Phase II study of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) and gemcitabine in advanced pancreatic carcinoma. A trial of the Princess Margaret hospital Phase II consortium. Invest New Drugs 25:553–558PubMedCrossRefGoogle Scholar
  35. 35.
    Greeno E, Kindler HL, Peeters M, Trowbridge RC, Chong G, Valle JW, Johnson B, Allain EL, Burris HA (2006) A phase II study of triapine in combination with gemcitabine (G) in patients (pts) with unresectable or metastatic pancreatic cancer (PC). Abstract. J Clin Oncol, 2006 ASCO Annual Meeting Proceedings Part I 24:4123Google Scholar
  36. 36.
    Knox JJ, Hotte SJ, Kollmannsberger C, Winquist E, Fisher B, Eisenhauer EA (2007) Phase II study of Triapine in patients with metastatic renal cell carcinoma: a trial of the National Cancer Institute of Canada Clinical Trials Group (NCIC IND.161). Invest New Drugs 25:471–477PubMedCrossRefGoogle Scholar
  37. 37.
    Atieh DMM, Shriberg L, Brafman L, Szno M, Vahdat L (2004) A phase II trial of 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone (3-AP) in patients with metastatic breast cancer. Abstract. J Clin Oncol, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition) 22:864Google Scholar
  38. 38.
    Ma B, Goh BC, Tan EH, Lam KC, Soo R, Leong SS, Wang LZ, Mo F, Chan AT, Zee B, Mok T (2007) A multicenter phase II trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine((R))) and gemcitabine in advanced non-small-cell lung cancer with pharmacokinetic evaluation using peripheral blood mononuclear cells. Invest New DrugsGoogle Scholar
  39. 39.
    Barker CA, Burgan WE, Carter DJ, Cerna D, Gius D, Hollingshead MG, Camphausen K, Tofilon PJ (2006) In vitro and in vivo radiosensitization induced by the ribonucleotide reductase inhibitor Triapine (3-aminopyridine-2-carboxaldehyde-thiosemicarbazone). Clin Cancer Res 12:2912–2918PubMedCrossRefGoogle Scholar
  40. 40.
    Gojo I, Tidwell ML, Greer J, Takebe N, Seiter K, Pochron MF, Johnson B, Sznol M, Karp JE (2007) Phase I and pharmacokinetic study of Triapine, a potent ribonucleotide reductase inhibitor, in adults with advanced hematologic malignancies. Leuk Res 31:1165–1173PubMedCrossRefGoogle Scholar
  41. 41.
    Karp JE, Giles FJ, Gojo I, Morris L, Greer J, Johnson B, Thein M, Sznol M, Low J (2008) A Phase I study of the novel ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine((R))) in combination with the nucleoside analog fludarabine for patients with refractory acute leukemias and aggressive myeloproliferative disorders. Leuk Res 32:71–77PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Steven Attia
    • 1
  • Jill Kolesar
    • 1
  • Michelle R. Mahoney
    • 2
  • Henry C. Pitot
    • 2
  • Daniel Laheru
    • 3
  • James Heun
    • 1
  • Wei Huang
    • 1
  • Jens Eickhoff
    • 1
  • Charles Erlichman
    • 2
  • Kyle D. Holen
    • 1
  1. 1.University of Wisconsin Paul P. Carbone Comprehensive Cancer CenterMadisonUSA
  2. 2.Mayo Clinic Cancer CenterRochesterUSA
  3. 3.The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins UniversityBaltimoreUSA

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