Trial Information

Phase II Window Evaluation of the Farnesyl Transferase Inhibitor (R115777) Followed by 13-CIS Retinoic Acid, Cytosine Arabinoside and Fludarabine Plus Hematopoietic Stem Cell Transplantation in Children With Juvenile Myelomonocytic Leukemia

PRIMARY OBJECTIVES:

I. Determine the response rate of children with newly diagnosed juvenile myelomonocytic
leukemia treated with R115777, isotretinoin, cytarabine, and fludarabine followed by
allogeneic bone marrow or umbilical cord blood transplantation.

II. Determine the safety and toxicity of this regimen in these patients. III. Determine the
tolerability of this regimen in these patients. IV. Determine the rate of 2-year event-free
survival of patients treated with this regimen.

V. Determine whether prognostic subsets of these patients can be identified based on
expression of clinical, genetic (NFI, monosomy 7, RAS gene), or hematopoietic
characteristics.

OUTLINE: This is a multicenter study.

Patients may choose to receive upfront window induction therapy with oral R115777 twice
daily on days 1-21. Treatment repeats every 28 days for 2 courses in the absence of disease
progression or unacceptable toxicity.

Patients with progressive disease or stable disease with unacceptable hematopoietic recovery
after 1 course proceed to induction chemotherapy. (R11577 portion of the study closed to
accrual as of 08/2005)

All patients receive induction chemotherapy comprising oral isotretinoin once daily
beginning on day 1 and fludarabine IV over 30 minutes and cytarabine IV over 4 hours on days
1-5. Treatment with fludarabine and cytarabine repeats every 28 days for 2 courses.
Treatment with isotretinoin continues until allogeneic bone marrow or umbilical cord blood
transplantation. Patients with progressive disease after 1 course proceed to
transplantation.

After completion of isotretinoin, patients receive a preparative regimen comprising total
body irradiation twice daily on days -7 to -4, cyclophosphamide IV over 2 hours on days -3
and -2, and anti-thymocyte globulin IV over 4-6 hours every 12 hours on days -3 to -1.
Patients undergo allogeneic bone marrow or umbilical cord blood transplantation on day 0.
Patients receive oral isotretinoin daily beginning on approximately day 60 and continuing
for 1 year.

Patients are followed every 6 months for 5 years and then annually thereafter.

PROJECTED ACCRUAL: A maximum of 100 patients (18-46 receiving R115777 with induction
chemotherapy [R11577 portion of the study closed to accrual as of 08/2005] and 27-54
receiving induction chemotherapy only) will be accrued for this study within 3.2 years.