Skip to main content

Advertisement

SpringerLink
Log in

Phase I trial of lestaurtinib for children with refractory neuroblastoma: a new approaches to neuroblastoma therapy consortium study

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

TrkB acts as an oncogenic kinase in a subset of human neuroblastomas. Lestaurtinib, a multi-kinase inhibitor with potent activity against Trk kinases, has demonstrated activity in preclinical models of neuroblastoma.

Methods

Patients with refractory high-risk neuroblastoma received lestaurtinib twice daily for 5 days out of seven in 28-day cycles, starting at 70% of the adult recommended Phase 2 dose. Lestaurtinib dose was escalated using a 3 + 3 design. Pharmacokinetics and plasma phospho-TrkB inhibitory activity were evaluated in the first cycle.

Results

Forty-seven subjects were enrolled, and 10 dose levels explored starting at 25 mg/M2/dose BID. Forty-six subjects were evaluable for response, and 42 subjects were fully evaluable for determination of dose escalation. Asymptomatic and reversible grade 3–4 transaminase elevation was dose limiting in 4 subjects. Reversible pancreatitis (grade 2) was observed in 3 subjects after prolonged treatment at higher dose levels. Other toxicities were mild and reversible. Pharmacokinetic analyses revealed rapid drug absorption, however inter-patient variability was large. Plasma inhibition of phospho-TrkB activity was observed 1 h post-dosing at 85 mg/M2 with uniform inhibition at 120 mg/M2. There were two partial responses and nine subjects had prolonged stable disease at dose levels ≥ 5, (median: 6 cycles). A biologically effective and recommended phase 2 dose of 120 mg/M2/dose BID was established.

Conclusions

Lestaurtinib was well tolerated in patients with refractory neuroblastoma, and a dose level sufficient to inhibit TrkB activity was established. Safety and signs of activity at the higher dose levels warrant further evaluation in neuroblastoma.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Acheson A, Conover JC, Fandl JP, DeChiara TM, Russell M, Thadani A, Squinto SP, Yancopoulos GD, Lindsay RM (1995) A BDNF autocrine loop in adult sensory neurons prevents cell death. Nature 374:450–453

    Article  PubMed  CAS  Google Scholar 

  2. Ady N, Zucker JM, Asselain B, Edeline V, Bonnin F, Michon J, Gongora R, Manil L (1995) A new 123I-MIBG whole body scan scoring method–application to the prediction of the response of metastases to induction chemotherapy in stage IV neuroblastoma. Eur J Cancer 31A:256–261

    Article  PubMed  CAS  Google Scholar 

  3. Asgharzadeh S, Pique-Regi R, Sposto R, Wang H, Yang Y, Shimada H, Matthay K, Buckley J, Ortega A, Seeger RC (2006) Prognostic significance of gene expression profiles of metastatic neuroblastomas lacking MYCN gene amplification. J Natl Cancer Inst 98:1193–1203

    Article  PubMed  CAS  Google Scholar 

  4. Brodeur GM, Maris JM, Yamashiro DJ, Hogarty MD, White PS (1997) Biology and genetics of human neuroblastomas. J Pediatr Hematol Oncol 19:93–101

    Article  PubMed  CAS  Google Scholar 

  5. Brodeur GM, Minturn JE, Ho R, Simpson AM, Iyer R, Varela CR, Light JE, Kolla V, Evans AE (2009) Trk receptor expression and inhibition in neuroblastomas. Clin Cancer Res 15:3244–3250

    Article  PubMed  CAS  Google Scholar 

  6. Brodeur GM, Pritchard J, Berthold F, Carlsen NL, Castel V, Castelberry RP, De Bernardi B, Evans AE, Favrot M, Hedborg F et al (1993) Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 11:1466–1477

    PubMed  CAS  Google Scholar 

  7. Evans AE, Kisselbach KD, Liu X, Eggert A, Ikegaki N, Camoratto AM, Dionne C, Brodeur GM (2001) Effect of CEP-751 (KT-6587) on neuroblastoma xenografts expressing TrkB. Med Pediatr Oncol 36:181–184

    Article  PubMed  CAS  Google Scholar 

  8. Evans AE, Kisselbach KD, Yamashiro DJ, Ikegaki N, Camoratto AM, Dionne CA, Brodeur GM (1999) Antitumor activity of CEP-751 (KT-6587) on human neuroblastoma and medulloblastoma xenografts. Clin Cancer Res 5:3594–3602

    PubMed  CAS  Google Scholar 

  9. George RE, Li S, Medeiros-Nancarrow C, Neuberg D, Marcus K, Shamberger RC, Pulsipher M, Grupp SA, Diller L (2006) High-risk neuroblastoma treated with tandem autologous peripheral-blood stem cell-supported transplantation: long-term survival update. J Clin Oncol 24:2891–2896

    Article  PubMed  Google Scholar 

  10. Iyer R, Evans AE, Qi X, Ho R, Minturn JE, Zhao H, Balamuth N, Maris JM, Brodeur GM (2010) Lestaurtinib enhances the anti-tumor efficacy of chemotherapy in murine xenograft models of neuroblastoma. Clin Cancer Res 16:1478–1485

    Article  PubMed  CAS  Google Scholar 

  11. Knapper S, Burnett AK, Littlewood T, Kell WJ, Agrawal S, Chopra R, Clark R, Levis MJ, Small D (2006) A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy. Blood 108:3262–3270

    Article  PubMed  CAS  Google Scholar 

  12. Levis M, Brown P, Smith BD, Stine A, Pham R, Stone R, Deangelo D, Galinsky I, Giles F, Estey E, Kantarjian H, Cohen P, Wang Y, Roesel J, Karp JE, Small D (2006) Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors. Blood 108:3477–3483

    Article  PubMed  CAS  Google Scholar 

  13. Maris JM, Hogarty MD, Bagatell R, Cohn SL (2007) Neuroblastoma. Lancet 369:2106–2120

    Article  PubMed  CAS  Google Scholar 

  14. Marshall JL, Kindler H, Deeken J, Bhargava P, Vogelzang NJ, Rizvi N, Luhtala T, Boylan S, Dordal M, Robertson P, Hawkins MJ, Ratain MJ (2005) Phase I trial of orally administered CEP-701, a novel neurotrophin receptor-linked tyrosine kinase inhibitor. Invest New Drugs 23:31–37

    Article  PubMed  CAS  Google Scholar 

  15. Matsumoto K, Wada RK, Yamashiro JM, Kaplan DR, Thiele CJ (1995) Expression of brain-derived neurotrophic factor and p145TrkB affects survival, differentiation, and invasiveness of human neuroblastoma cells. Cancer Res 55:1798–1806

    PubMed  CAS  Google Scholar 

  16. Matthay KK, Villablanca JG, Seeger RC, Stram DO, Harris RE, Ramsay NK, Swift P, Shimada H, Black CT, Brodeur GM, Gerbing RB, Reynolds CP (1999) Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children’s Cancer Group. N Engl J Med 341:1165–1173

    Article  PubMed  CAS  Google Scholar 

  17. Miknyoczki SJ, Dionne CA, Klein-Szanto AJ, Ruggeri BA (1999) The novel Trk receptor tyrosine kinase inhibitor CEP-701 (KT-5555) exhibits antitumor efficacy against human pancreatic carcinoma (Panc1) xenograft growth and in vivo invasiveness. Ann N Y Acad Sci 880:252–262

    Article  PubMed  CAS  Google Scholar 

  18. Nakagawara A (2001) Trk receptor tyrosine kinases: a bridge between cancer and neural development. Cancer Lett 169:107–114

    Article  PubMed  CAS  Google Scholar 

  19. Nakagawara A, Arima-Nakagawara M, Scavarda NJ, Azar CG, Cantor AB, Brodeur GM (1993) Association between high levels of expression of the TRK gene and favorable outcome in human neuroblastoma. N Engl J Med 328:847–854

    Article  PubMed  CAS  Google Scholar 

  20. Nakagawara A, Azar CG, Scavarda NJ, Brodeur GM (1994) Expression and function of TRK-B and BDNF in human neuroblastomas. Mol Cell Biol 14:759–767

    PubMed  CAS  Google Scholar 

  21. Santos FP, Kantarjian HM, Jain N, Manshouri T, Thomas DA, Garcia-Manero G, Kennedy D, Estrov Z, Cortes J, Verstovsek S (2009) Phase II study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post polycythemia vera/essential thrombocythemia myelofibrosis. Blood 115:1131–1136

    Article  PubMed  Google Scholar 

  22. Smith BD, Levis M, Beran M, Giles F, Kantarjian H, Berg K, Murphy KM, Dauses T, Allebach J, Small D (2004) Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood 103:3669–3676

    Article  PubMed  CAS  Google Scholar 

  23. Tacconelli A, Farina AR, Cappabianca L, Desantis G, Tessitore A, Vetuschi A, Sferra R, Rucci N, Argenti B, Screpanti I, Gulino A, Mackay AR (2004) TrkA alternative splicing: a regulated tumor-promoting switch in human neuroblastoma. Cancer Cell 6:347–360

    Article  PubMed  CAS  Google Scholar 

  24. Tacconelli A, Farina AR, Cappabianca L, Gulino A, Mackay AR (2005) TrkAIII. A novel hypoxia-regulated alternative TrkA splice variant of potential physiological and pathological importance. Cell Cycle 4:8–9

    Article  PubMed  CAS  Google Scholar 

  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 92:205–216

    Article  PubMed  CAS  Google Scholar 

  26. Thiele CJ, Li Z, McKee AE (2009) On Trk–the TrkB signal transduction pathway is an increasingly important target in cancer biology. Clin Cancer Res 15:5962–5967

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by NIH Program Project Grants P01-CA81403 (Childrens Hospital Los Angeles, PI:Seeger) and P01-CA97323 (Brodeur), R01-CA-094194 (Brodeur), and the Giulio D’Angio Endowed Chair in Neuroblastoma Research (Maris), NIH/NCRR UCSF-CTSI Grant UL1 RR024131, Alex’s Lemonade Stand Foundation, Children’s Neuroblastoma Cancer Foundation, Dougherty Family Foundation, Evan T.J. Dunbar Memorial Foundation, Neuroblastoma Children’s Cancer Society.

Author information

Authors and Affiliations

  1. Department of Pediatrics and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA

    Jane E. Minturn, Audrey E. Evans, Garrett M. Brodeur & John M. Maris

  2. Departments of Pediatrics and Biostatistics, Keck School of Medicine, University of Southern California and Childrens Hospital Los Angeles, Los Angeles, CA, USA

    Judith G. Villablanca & Susan Groshen

  3. University of Michigan and C.S. Mott Children’s Hospital, Ann Arbor, MI, USA

    Gregory A. Yanik

  4. Department of Pediatrics, Seattle Children’s Hospital and University of Washington, Seattle, WA, USA

    Julie R. Park

  5. Department of Pediatrics, Children’s Hospital Boston and Dana-Farber Cancer Institute, Boston, MA, USA

    Suzanne Shusterman

  6. Departments of Drug Safety and Disposition and Clinical Research, Oncology, Cephalon, Inc., Frazer, PA, USA

    Edward T. Hellriegel & Debra Bensen-Kennedy

  7. Department of Pediatrics, University of California San Francisco School of Medicine, San Francisco, CA, USA

    Katherine K. Matthay

  8. Division of Oncology, The Children’s Hospital of Philadelphia, 3501 Civic Center Blvd., CTRB 3060, Philadelphia, PA, 19104, USA

    John M. Maris

  9. Division of Oncology, The Children’s Hospital of Philadelphia, 3501 Civic Center Blvd., CTRB 3018, Philadelphia, PA, 19104, USA

    Garrett M. Brodeur

Authors
  1. Jane E. Minturn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Audrey E. Evans
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Judith G. Villablanca
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gregory A. Yanik
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Julie R. Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Suzanne Shusterman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Susan Groshen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Edward T. Hellriegel
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Debra Bensen-Kennedy
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Katherine K. Matthay
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Garrett M. Brodeur
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. John M. Maris
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Garrett M. Brodeur or John M. Maris.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Minturn, J.E., Evans, A.E., Villablanca, J.G. et al. Phase I trial of lestaurtinib for children with refractory neuroblastoma: a new approaches to neuroblastoma therapy consortium study. Cancer Chemother Pharmacol 68, 1057–1065 (2011). https://doi.org/10.1007/s00280-011-1581-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-011-1581-4

Keywords

Search

Navigation