Anticancer Drug Development in Pediatric Patients

Chapter
First Online:
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

The incidence of pediatric cancer is relatively rare, particularly when compared to rates in the adult oncology. Despite the relative low numbers, death due to cancer remains the primary cause of death due to disease in the pediatric population. Pediatric cancer cure rates have markedly improved in the past several decades with well over 70% of pediatric cancer patients achieving cure. However, there remains a subset of patients who have a dismal prognosis either due to tumor type or stage at presentation or relapse. As a result, there is a great need for novel therapeutics and innovative approaches in this population. The development of new therapies is being extensively explored in the adult oncology population; however, the advancement of such drugs in pediatrics has been much slower.

Keywords

Acute Lymphoblastic Leukemia Maximally Tolerate Dose Pediatric Research Pediatric Tumor Pediatric Cancer Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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References

  1. 1.
    Department of Health and Human Services, Protection of Human Subjects. Revised June 23, 2005.Google Scholar
  2. 2.
    Cuzzolin, L., A. Atzei, and V. Fanos, Off-label and unlicensed prescribing for newborns and children in different settings: a review of the literature and a consideration about drug safety. Expert Opin Drug Saf, 2006. 5(5): pp. 703–18.PubMedCrossRefGoogle Scholar
  3. 3.
    Best Pharmaceuticals Act, in PL107-109, 2002.Google Scholar
  4. 4.
    Miller, R.P., R.J. Roberts, and L.J. Fischer, Acetaminophen elimination kinetics in neonates, children, and adults. Clin Pharmacol Ther, 1976. 19(3): pp. 284–94.PubMedGoogle Scholar
  5. 5.
    Kearns, G.L., Impact of developmental pharmacology on pediatric study design: overcoming the challenges. J Allergy Clin Immunol, 2000. 106(3 Suppl): pp. S128–38.PubMedCrossRefGoogle Scholar
  6. 6.
    Kearns, G.L., et al., Developmental pharmacology – drug disposition, action, and therapy in infants and children. N Engl J Med, 2003. 349(12): pp. 1157–67.PubMedCrossRefGoogle Scholar
  7. 7.
    Gibbs, J.P., et al., Up-regulation of glutathione S-transferase activity in enterocytes of young children. Drug Metab Dispos, 1999. 27(12): pp. 1466–9.PubMedGoogle Scholar
  8. 8.
    McLeod, H.L., et al., Disposition of antineoplastic agents in the very young child. Br J Cancer Suppl, 1992. 18: pp. S23–9.PubMedGoogle Scholar
  9. 9.
    Strolin Benedetti, M. and E.L. Baltes, Drug metabolism and disposition in children. Fundam Clin Pharmacol, 2003. 17(3): pp. 281–99.PubMedCrossRefGoogle Scholar
  10. 10.
    Bartelink, I.H., et al., Guidelines on paediatric dosing on the basis of developmental physiology and pharmacokinetic considerations. Clin Pharmacokinet, 2006. 45(11): pp. 1077–97.PubMedCrossRefGoogle Scholar
  11. 11.
    Ginsberg, G., et al., Evaluation of child/adult pharmacokinetic differences from a database derived from the therapeutic drug literature. Toxicol Sci, 2002. 66(2): pp. 185–200.PubMedCrossRefGoogle Scholar
  12. 12.
    Zwerdling, T., et al., Phase II investigation of docetaxel in pediatric patients with recurrent solid tumors: a report from the Children’s Oncology Group. Cancer, 2006. 106(8): pp. 1821–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Irken, G., et al., Treatment outcome of adolescents with acute lymphoblastic leukemia. Ann Hematol, 2002. 81(11): pp. 641–5.PubMedCrossRefGoogle Scholar
  14. 14.
    Kantarjian, H., et al., Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer, 2004. 101(12): pp. 2788–801.PubMedCrossRefGoogle Scholar
  15. 15.
    Gaynon, P.S., et al., Expression of BCR-ABL, E2A-PBX1, and MLL-AF4 fusion transcripts in newly diagnosed children with acute lymphoblastic leukemia: a Children’s Cancer Group initiative. Leuk Lymphoma, 1997. 26(1–2): pp. 57–65.PubMedGoogle Scholar
  16. 16.
    Rambaldi, A., et al., Molecular diagnosis and clinical relevance of t(9;22), t(4;11) and t(1;19) chromosome abnormalities in a consecutive group of 141 adult patients with acute lymphoblastic leukemia. Leuk Lymphoma, 1996. 21(5–6): pp. 457–66.PubMedCrossRefGoogle Scholar
  17. 17.
    Schlieben, S., et al., Incidence and clinical outcome of children with BCR/ABL-positive acute lymphoblastic leukemia (ALL). A prospective RT-PCR study based on 673 patients enrolled in the German pediatric multicenter therapy trials ALL-BFM-90 and CoALL-05-92. Leukemia, 1996. 10(6): pp. 957–63.PubMedGoogle Scholar
  18. 18.
    Tuszynski, A., et al., Detection and significance of bcr-abl mRNA transcripts and fusion proteins in Philadelphia-positive adult acute lymphoblastic leukemia. Leukemia, 1993. 7(10): pp. 1504–8.PubMedGoogle Scholar
  19. 19.
    Shurtleff, S.A., et al., TEL/AML1 fusion resulting from a cryptic t(12;21) is the most common genetic lesion in pediatric ALL and defines a subgroup of patients with an excellent prognosis. Leukemia, 1995. 9(12): pp. 1985–9.PubMedGoogle Scholar
  20. 20.
    McLean, T.W., et al., TEL/AML-1 dimerizes and is associated with a favorable outcome in childhood acute lymphoblastic leukemia. Blood, 1996. 88(11): pp. 4252–8.PubMedGoogle Scholar
  21. 21.
    Smith, M., et al., Conduct of phase I trials in children with cancer. J Clin Oncol, 1998. 16(3): pp. 966–78.PubMedGoogle Scholar
  22. 22.
    Lee, D.P., J.M. Skolnik, and P.C. Adamson, Pediatric phase I trials in oncology: an analysis of study conduct efficiency. J Clin Oncol, 2005. 23(33): pp. 8431–41.PubMedCrossRefGoogle Scholar
  23. 23.
    Skolnik, J.M., et al., Shortening the timeline of pediatric phase I trials: the rolling six design. J Clin Oncol, 2008. 26(2): pp. 190–5.PubMedCrossRefGoogle Scholar
  24. 24.
    Kim, A., et al., Characteristics and outcome of pediatric patients enrolled in phase I oncology trials. Oncologist, 2008. 13(6): pp. 679–89.PubMedCrossRefGoogle Scholar
  25. 25.
    Shah, S., et al., Phase I therapy trials in children with cancer. J Pediatr Hematol Oncol, 1998. 20(5): pp. 431–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Horstmann, E., et al., Risks and benefits of phase 1 oncology trials, 1991 through 2002. N Engl J Med, 2005. 352(9): pp. 895–904.PubMedCrossRefGoogle Scholar
  27. 27.
    Italiano, A., et al., Treatment outcome and survival in participants of phase I oncology trials carried out from 2003 to 2006 at Institut Gustave Roussy. Ann Oncol, 2008. 19(4): pp. 787–92.PubMedCrossRefGoogle Scholar
  28. 28.
    Roberts, T.G., Jr., et al., Trends in the risks and benefits to patients with cancer participating in phase 1 clinical trials. JAMA, 2004. 292(17): pp. 2130–40.PubMedCrossRefGoogle Scholar
  29. 29.
    Furman, W.L., et al., Direct translation of a protracted irinotecan schedule from a xenograft model to a phase I trial in children. J Clin Oncol, 1999. 17(6): pp. 1815–24.PubMedGoogle Scholar
  30. 30.
    Houghton, P.J., et al., The pediatric preclinical testing program: description of models and early testing results. Pediatr Blood Cancer, 2007. 49(7): pp. 928–40.PubMedCrossRefGoogle Scholar
  31. 31.
    Carlson, L., et al., Pediatric phase I drug tolerance: a review and comparison of recent adult and pediatric phase I trials. J Pediatr Hematol Oncol, 1996. 18(3): pp. 250–6.PubMedCrossRefGoogle Scholar
  32. 32.
    Parker, W.B., et al., Effects of 2-Chloro-9-(2-deoxy-2-fluoro-{beta}-D-arabinofuranosyl)adenine on K562 cellular metabolism and the inhibition of human ribonucleotide reductase and DNA polymerases by its 5’-triphosphate. Cancer Res, 1991. 51(9): pp. 2386–94.PubMedGoogle Scholar
  33. 33.
    Xie, C. and W. Plunkett, Metabolism and actions of 2-Chloro-9-(2-deoxy-2-fluoro-{beta}-D-arabinofuranosyl)-adenine in human lymphoblastoid cells. Cancer Res, 1995. 55(13): pp. 2847–52.PubMedGoogle Scholar
  34. 34.
    Estey, E., et al., Fludarabine and arabinosylcytosine therapy of refractory and relapsed acute myelogenous leukemia. Leuk Lymphoma, 1993. 9(4–5): pp. 343–50.PubMedCrossRefGoogle Scholar
  35. 35.
    Gandhi, V., et al., Biochemical modulation of arabinosylcytosine for therapy of leukemias. Leuk Lymphoma, 1993. 10(Suppl): pp. 109–14.PubMedCrossRefGoogle Scholar
  36. 36.
    Gandhi, V., et al., Fludarabine potentiates metabolism of cytarabine in patients with acute myelogenous leukemia during therapy. J Clin Oncol, 1993. 11(1): pp. 116–24.PubMedGoogle Scholar
  37. 37.
    Chow, K.U., et al., In AML cell lines Ara-C combined with purine analogues is able to exert synergistic as well as antagonistic effects on proliferation, apoptosis and disruption of mitochondrial membrane potential. Leuk Lymphoma, 2003. 44(1): pp. 165–73.PubMedCrossRefGoogle Scholar
  38. 38.
    Han, T., et al., Quantitation of synergism of arabinosylcytosine and cladribine against the growth of arabinosylcytosine-resistant human lymphoid cells. J Cancer Res Clin Oncol, 2005. 131(9): pp. 609–16.PubMedCrossRefGoogle Scholar
  39. 39.
    Cooper, T., et al., Biochemical modulation of cytarabine triphosphate by clofarabine. Cancer Chemother Pharmacol, 2005. 55(4): pp. 361–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Faderl, S., et al., Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. Blood, 2005. 105(3): pp. 940–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Eng, W.K., et al., Evidence that DNA topoisomerase I is necessary for the cytotoxic effects of camptothecin. Mol Pharmacol, 1988. 34(6): pp. 755–60.PubMedGoogle Scholar
  42. 42.
    Hsiang, Y.H. and L.F. Liu, Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res, 1988. 48(7): pp. 1722–6.PubMedGoogle Scholar
  43. 43.
    Pratt, C.B., et al., Phase I study of topotecan for pediatric patients with malignant solid tumors. J Clin Oncol, 1994. 12(3): pp. 539–43.PubMedGoogle Scholar
  44. 44.
    Langler, A., et al., Topotecan in the treatment of refractory neuroblastoma and other malignant tumors in childhood – a phase-II-study. Klin Padiatr, 2002. 214(4): pp. 153–6.PubMedCrossRefGoogle Scholar
  45. 45.
    Blaney, S.M., et al., Phase II trial of topotecan administered as 72-hour continuous infusion in children with refractory solid tumors: a collaborative Pediatric Branch, National Cancer Institute, and Children’s Cancer Group Study. Clin Cancer Res, 1998. 4(2): pp. 357–60.PubMedGoogle Scholar
  46. 46.
    Hawkins, D.S., et al., Topotecan by 21-day continuous infusion in children with relapsed or refractory solid tumors: a Children’s Oncology Group study. Pediatr Blood Cancer, 2006. 47(6): pp. 790–4.PubMedCrossRefGoogle Scholar
  47. 47.
    Coggins, C.A., et al., Enhancement of irinotecan (CPT-11) activity against central nervous system tumor xenografts by alkylating agents. Cancer Chemother Pharmacol, 1998. 41(6): pp. 485–90.PubMedCrossRefGoogle Scholar
  48. 48.
    Mattern, M.R., et al., Synergistic cell killing by ionizing radiation and topoisomerase I inhibitor topotecan (SK&F 104864). Cancer Res, 1991. 51(21): pp. 5813–6.PubMedGoogle Scholar
  49. 49.
    Kushner, B.H., et al., Pilot study of topotecan and high-dose cyclophosphamide for resistant pediatric solid tumors. Med Pediatr Oncol, 2000. 35(5): pp. 468–74.PubMedCrossRefGoogle Scholar
  50. 50.
    Saylors, R.L., III, et al., Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol, 2001. 19(15): pp. 3463–9.PubMedGoogle Scholar
  51. 51.
    Vassal, G., et al., Therapeutic activity of CPT-11, a DNA-topoisomerase I inhibitor, against peripheral primitive neuroectodermal tumour and neuroblastoma xenografts. Br J Cancer, 1996. 74(4): pp. 537–45.PubMedCrossRefGoogle Scholar
  52. 52.
    Houghton, P.J., et al., Therapeutic efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptothecin against human tumor xenografts: lack of cross-resistance in vivo in tumors with acquired resistance to the topoisomerase I inhibitor 9-dimethylaminomethyl-10-hydroxycamptothecin. Cancer Res, 1993. 53(12): pp. 2823–9.PubMedGoogle Scholar
  53. 53.
    Vassal, G., et al., Potent therapeutic activity of irinotecan (CPT-11) and its schedule dependency in medulloblastoma xenografts in nude mice. Int J Cancer, 1997. 73(1): pp. 156–63.PubMedCrossRefGoogle Scholar
  54. 54.
    Hare, C.B., et al., Therapeutic efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptothecin against pediatric and adult central nervous system tumor xenografts. Cancer Chemother Pharmacol, 1997. 39(3): pp. 187–91.PubMedCrossRefGoogle Scholar
  55. 55.
    Bisogno, G., et al., Phase II study of a protracted irinotecan schedule in children with refractory or recurrent soft tissue sarcoma. Cancer, 2006. 106(3): pp. 703–7.PubMedCrossRefGoogle Scholar
  56. 56.
    Cosetti, M., et al., Irinotecan for pediatric solid tumors: the Memorial Sloan-Kettering experience. J Pediatr Hematol Oncol, 2002. 24(2): pp. 101–5.PubMedCrossRefGoogle Scholar
  57. 57.
    Vassal, G., et al., Phase II trial of irinotecan in children with relapsed or refractory rhabdomyosarcoma: a joint study of the French Society of Pediatric Oncology and the United Kingdom Children’s Cancer Study Group. J Clin Oncol, 2007. 25(4): pp. 356–61.PubMedCrossRefGoogle Scholar
  58. 58.
    Kushner, B.H., et al., Irinotecan plus temozolomide for relapsed or refractory neuroblastoma. J Clin Oncol, 2006. 24(33): pp. 5271–6.PubMedCrossRefGoogle Scholar
  59. 59.
    Wagner, L.M., et al., Phase I trial of temozolomide and protracted irinotecan in pediatric patients with refractory solid tumors. Clin Cancer Res, 2004. 10(3): pp. 840–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Wagner, L.M., et al., Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Pediatr Blood Cancer, 2007. 48(2): pp. 132–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Dickson, P.V., et al., Bevacizumab-induced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy. Clin Cancer Res, 2007. 13(13): pp. 3942–50.PubMedCrossRefGoogle Scholar
  62. 62.
    Tong, R.T., et al., Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res, 2004. 64(11): pp. 3731–6.PubMedCrossRefGoogle Scholar
  63. 63.
    Wildiers, H., et al., Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11. Br J Cancer, 2003. 88(12): pp. 1979–86.PubMedCrossRefGoogle Scholar
  64. 64.
    Andersson, M.K. and P. Aman, Proliferation of Ewing sarcoma cell lines is suppressed by the receptor tyrosine kinase inhibitors gefitinib and vandetanib. Cancer Cell Int, 2008. 8: p. 1.PubMedCrossRefGoogle Scholar
  65. 65.
    Rowe, D.H., et al., Anti-VEGF antibody suppresses primary tumor growth and metastasis in an experimental model of Wilms’ tumor. J Pediatr Surg, 2000. 35(1): pp. 30–2; discussion 32–3.PubMedCrossRefGoogle Scholar
  66. 66.
    Raetz, E.A., et al., Outcomes of children with first marrow relapse: results from Children’s Oncology Group (COG) study AALL01P2. ASH Annual Meeting Abstracts, 2006. 108(11): p. 1871.Google Scholar
  67. 67.
    Schultz, K.R., et al., Improved early event free survival (EFS) in children with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) with intensive imatinib in combination with high dose chemotherapy: Children’s Oncology Group (COG) study AALL0031. ASH Annual Meeting Abstracts, 2007. 110(11): p. 9a.Google Scholar
  68. 68.
    Lievre, A., et al., KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol, 2008. 26(3): pp. 374–9.PubMedCrossRefGoogle Scholar
  69. 69.
    Lievre, A., et al., KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res, 2006. 66(8): pp. 3992–5.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.The Children’s HospitalCenter for Cancer and Blood DisordersAuroraUSA

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