Research Article

Phase 1 trial and pharmacokinetic study of the farnesyl transferase inhibitor tipifarnib in children and adolescents with refractory leukemias: A report from the Children's Oncology Group†‡

  1. Brigitte C. Widemann MD1,*,
  2. Robert J. Arceci MD, PhD2,
  3. Nalini Jayaprakash MS1,
  4. Elizabeth Fox MD1,
  5. Peter Zannikos PhD3,
  6. Wendy Goodspeed RN1,
  7. Anne Goodwin RN1,
  8. John J. Wright MD, PhD4,
  9. Susan M. Blaney MD5,
  10. Peter C. Adamson MD6,
  11. Frank M. Balis MD1

Article first published online: 21 SEP 2010

DOI: 10.1002/pbc.22775

Issue

Pediatric Blood & Cancer

Pediatric Blood & Cancer

Volume 56, Issue 2, pages 226–233, February 2011

Additional Information

How to Cite

Widemann, B. C., Arceci, R. J., Jayaprakash, N., Fox, E., Zannikos, P., Goodspeed, W., Goodwin, A., Wright, J. J., Blaney, S. M., Adamson, P. C. and Balis, F. M. (2011), Phase 1 trial and pharmacokinetic study of the farnesyl transferase inhibitor tipifarnib in children and adolescents with refractory leukemias: A report from the Children's Oncology Group. Pediatr. Blood Cancer, 56: 226–233. doi: 10.1002/pbc.22775

Author Information

  1. 1

    Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland

  2. 2

    Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins, Baltimore, Maryland

  3. 3

    Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Titusville, New Jersey

  4. 4

    Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland

  5. 5

    Texas Children's Cancer Center, Houston, Texas

  6. 6

    Children's Hospital of Philadelphia, Philadelphia, Pennsylvania

*NCI, POB, 10 Center Drive, Bldg. 10 CRC/Rm. 1-5750, Bethesda, MD 20892.

  1. †

    Conflict of interest: Nothing to declare.

  2. ‡

    Peter Zannikos is employed by Johnson & Johnson Pharmaceutical Research & Development and has stock in the company.

Publication History

  1. Issue published online: 14 DEC 2010
  2. Article first published online: 21 SEP 2010
  3. Manuscript Accepted: 12 JUL 2010
  4. Manuscript Received: 25 JAN 2010

Funded by

  • NIH, National Cancer Institute, Center for Cancer Research
  • Phase I/Pilot Consortium Grant. Grant Number: U01 CA97452

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Keywords:

  • pharmacodynamics;
  • pharmacokinetics;
  • phase I trial;
  • refractory childhood leukemia;
  • toxicity

Abstract

Background

The objectives of this trial were to define the toxicity profile, dose, pharmacokinetics, and pharmacodynamics of the farnesyl transferase (FTase) inhibitor, tipifarnib, in children and adolescents with hematological malignancies.

Procedure

Tipifarnib was administered twice daily for 21 days, repeated every 28 days starting at a dose of 300 mg/m2/dose. Pharmacokinetic sampling was performed for 36 hr after the first dose and leukemic blasts were collected pre-treatment and at steady state for determination of FTase activity.

Results

Of 29 patients enrolled, 18 were fully evaluable for toxicity, and 23 for response; 26 had pharmacokinetic and pharmacodynamic sampling. The recommended dose is 300 mg/m2/dose and toxicities included skin rash, mucositis, nausea, vomiting, and diarrhea. Neurotoxicity, which was dose-limiting in adults at doses exceeding 600 mg/dose, was infrequent and mild. The plasma pharmacokinetics of tipifarnib were highly variable but comparable to adults with acute leukemia and children with solid tumors. The median apparent clearance of tipifarnib was 630 ml/min/m2 and the median half-life was 4.7 hr. At steady state on 300 mg/m2/dose, FTase activity was inhibited by 82% in leukemic blasts. No objective responses were observed.

Conclusions

Oral tipifarnib is well tolerated in children with leukemia on a twice daily for 21days schedule at 300 mg/m2/dose. Pediatr Blood Cancer 2011;56:226–233. © 2010 Wiley-Liss, Inc.

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