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A Phase I Trial and Pharmacokinetic Study of R115777 in Pediatric Patients With Refractory Leukemia

Phase 1
21 Years
Not Enrolling

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Trial Information

A Phase I Trial and Pharmacokinetic Study of R115777 in Pediatric Patients With Refractory Leukemia



- Determine the maximum tolerated dose and toxicity profile of tipifarnib in pediatric
patients with refractory leukemia.

- Determine the pharmacokinetics of this drug in these patients.

- Determine the toxicity profile of this drug in these patients.


- Analyze the gene expression profile of leukemic blasts from these patients before and
after treatment with this drug.

- Determine circulating levels of nerve growth factor and correlate these levels with
clinical neurotoxicity from this drug in these patients.

OUTLINE: This is an open-label, dose-escalation study.

Patients receive oral tipifarnib every 12 hours on days 1-21. Courses repeat every 28 days
in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of tipifarnib until the maximum tolerated
dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2
of 6 patients experience dose-limiting toxicity. At least 9 additional patients are treated
at the MTD.

PROJECTED ACCRUAL: A total of 12-34 patients will be accrued for this study within 1-2

Inclusion Criteria


- Histologically confirmed acute lymphoblastic leukemia, acute nonlymphoblastic
leukemia, juvenile myelomonocytic leukemia (JMML), or chronic myelogenous leukemia
(CML) in blast crisis

- Refractory to standard curative therapy

- Acute promyelocytic leukemia refractory to tretinoin and arsenic trioxide

- Philadelphia chromosome-positive CML refractory to imatinib mesylate

- Greater than 25% blasts in bone marrow (M3 bone marrow) except for patients with JMML

- Active extramedullary disease allowed

- No active leptomeningeal leukemia



- 21 and under

Performance status:

- Karnofsky 50-100% (over 10 years of age)

- Lansky 50-100% (10 years of age and under)

Life expectancy:

- Not specified


- Not required to be normal


- Bilirubin normal

- SGPT and SGOT normal

- No significant hepatic dysfunction

- No grade 3 or 4 liver function test results within the past month


- Creatinine normal OR

- Creatinine clearance at least 60 mL/min

- No significant renal dysfunction


- No significant cardiac dysfunction


- No significant pulmonary dysfunction


- No history of grand mal seizures grade 3 or greater except febrile seizures

- No persistent sensory or motor neuropathy greater than grade 2


- No clinically significant unrelated systemic illness

- No serious infection

- No organ dysfunction that would preclude study participation

- No requirement for total parenteral nutrition

- No known allergy to azoles (e.g., clotrimazole, fluconazole, ketoconazole,

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception


Biologic therapy:

- At least 1 week since prior colony-stimulating factor therapy (e.g., filgrastim
[G-CSF] or sargramostim [GM-CSF]) except epoetin alfa

- At least 3 months since prior myeloablative therapy followed by bone marrow or stem
cell transplantation

- No concurrent immunotherapy

- No concurrent GM-CSF or interleukin-11


- At least 2 weeks since prior chemotherapy

- No concurrent intrathecal chemotherapy

- No other concurrent chemotherapy

Endocrine therapy:

- At least 1 week since prior corticosteroids

- No concurrent corticosteroids (except for acute allergic reaction)


- At least 4 weeks since prior radiotherapy

- No concurrent radiotherapy


- Not specified


- Recovered from nonhematologic toxicity of all prior therapy

- At least 1 week since prior retinoids

- No antacids (magnesium- or aluminum-containing formulations) within 2 hours of study

- No other concurrent investigational agents

- No concurrent retinoids

- No concurrent anticonvulsants

Type of Study:


Study Design:

Masking: Open Label, Primary Purpose: Treatment

Principal Investigator

Brigitte C. Widemann, MD

Investigator Role:

Study Chair

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Federal Government

Study ID:




Start Date:

June 2001

Completion Date:

March 2005

Related Keywords:

  • Leukemia
  • recurrent childhood acute lymphoblastic leukemia
  • recurrent childhood acute myeloid leukemia
  • relapsing chronic myelogenous leukemia
  • blastic phase chronic myelogenous leukemia
  • chronic myelogenous leukemia, BCR-ABL1 positive
  • childhood acute promyelocytic leukemia (M3)
  • acute undifferentiated leukemia
  • juvenile myelomonocytic leukemia
  • childhood chronic myelogenous leukemia
  • Leukemia



Memorial Sloan-Kettering Cancer CenterNew York, New York  10021
University of Texas - MD Anderson Cancer CenterHouston, Texas  77030-4009
University of Michigan Comprehensive Cancer CenterAnn Arbor, Michigan  48109-0752
Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
Mayo Clinic Cancer CenterRochester, Minnesota  55905
Jonsson Comprehensive Cancer Center, UCLALos Angeles, California  90095-1781
University of Minnesota Cancer CenterMinneapolis, Minnesota  55455
University of Mississippi Medical CenterJackson, Mississippi  39216-4505
Duke Comprehensive Cancer CenterDurham, North Carolina  27710
Children's Hospital of MichiganDetroit, Michigan  48201
University of Texas Health Science Center at San AntonioSan Antonio, Texas  78284-7811
Midwest Children's Cancer CenterMilwaukee, Wisconsin  53226
NYU School of Medicine's Kaplan Comprehensive Cancer CenterNew York, New York  10016
Huntsman Cancer InstituteSalt Lake City, Utah  84112
University of Wisconsin Comprehensive Cancer CenterMadison, Wisconsin  53792
CCOP - Columbia River Oncology ProgramPortland, Oregon  97225
CCOP - Scott and White HospitalTemple, Texas  76508
Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimore, Maryland  21231-2410
MBCCOP - LSU Health Sciences CenterNew Orleans, Louisiana  70112
Children's Hospital Los AngelesLos Angeles, California  90027-0700
Children's Hospital of Orange CountyOrange, California  92668
Children's National Medical CenterWashington, District of Columbia  20010-2970
Children's Mercy HospitalKansas City, Missouri  64108
Children's Hospital of PittsburghPittsburgh, Pennsylvania  15213
Children's Hospital and Regional Medical Center - SeattleSeattle, Washington  98105
Rebecca and John Moores UCSD Cancer CenterLa Jolla, California  92093-0658
Children's Memorial Hospital - ChicagoChicago, Illinois  60614
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer InstituteBoston, Massachusetts  02115
Floating Hospital for ChildrenBoston, Massachusetts  02111
Cardinal Glennon Children's HospitalSaint Louis, Missouri  63104
St. Jude Children's Research HospitalMemphis, Tennessee  38105-2794
Cook Children's Medical Center - Fort WorthFort Worth, Texas  76104
Texas Children's Cancer CenterHouston, Texas  77030-2399
City of Hope Comprehensive Cancer CenterDuarte, California  91010
UCSF Comprehensive Cancer CenterSan Francisco, California  94115
St. Louis Children's HospitalSaint Louis, Missouri  63110
Arkansas Cancer Research Center at University of Arkansas for Medical SciencesLittle Rock, Arkansas  72205
Kansas Masonic Cancer Research Institute at the University of Kansas Medical CenterKansas City, Kansas  66160-7353
Herbert Irving Comprehensive Cancer Center at Columbia UniversityNew York, New York  10032
Oklahoma University Medical CenterOklahoma City, Oklahoma  73104
Stanford Cancer Center at Stanford University Medical CenterStanford, California  94305
SUNY Upstate Medical University HospitalSyracuse, New York  13210
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
Hollings Cancer Center at Medical University of South CarolinaCharleston, South Carolina  29425
CCOP - Marshfield Clinic Research FoundationMarshfield, Wisconsin  54449
AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Scottish Rite CampusAtlanta, Georgia  30342
Shands Cancer Center at the University of Florida Health Science CenterGainesville, Florida  32610-0296
MBCCOP-Medical College of Georgia Cancer CenterAugusta, Georgia  30912-4000
Riley Children Cancer Center at Riley Hospital for ChildrenIndianapolis, Indiana  46202-5225
Cancer Center at Hackensack University Medical CenterHackensack, New Jersey  07601
Cancer Institute of New Jersey at Robert Wood Johnson University HospitalNew Brunswick, New Jersey  08903
Vanderbilt Children's HospitalNashville, Tennessee  37232-6310
Simmons Cancer Center at University of Texas Southwestern Medical Center - DallasDallas, Texas  75390-9063
MBCCOP - South Texas PediatricsSan Antonio, Texas  78229-3900
Columbus Children's HospitalColumbus, Ohio  43205-2696
Warren Grant Magnuson Clinical Center - NCI Clinical Studies SupportBethesda, Maryland  20892-1182