Clinical trial NCT00025038: Combination Chemotherapy Followed By Donor Bone Marrow or Umbilical Cord Blood Transplant in Treating Children With Newly Diagnosed Juvenile Myelomonocytic Leukemia
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Juvenile Myelomonocytic Leukemia
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2003-01-27
Enrollment: 100
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Giving chemotherapy drugs, such as R115777, isotretinoin, cytarabine, and fludarabine, before a donor bone marrow transplant or an umbilical cord transplant helps stop the growth of cancer cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. This phase II trial is studying how well giving combination chemotherapy together with donor bone marrow or umbilical cord blood transplant works in treating children with newly diagnosed juvenile myelomonocytic leukemia

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Newly diagnosed, previously untreated juvenile myelomonocytic leukemia
* Presenting with all of the following:

  * Absence of t(9;22) or bcr/abl by PCR
  * Absolute monocyte count greater than 1,000/mm\^3
  * Less than 20% bone marrow blasts
* Presenting with at least 2 of the following:

  * Elevated F hemoglobin
  * Myeloid precursors in peripheral blood
  * WBC greater than 10,000/mm\^3
  * Sargramostim (GM-CSF) hypersensitivity
* See Disease Characteristics
* Bilirubin no greater than 2.0 mg/dL
* ALT no greater than 3 times normal
* Creatinine no greater than 2 times normal
* No concurrent sargramostim (GM-CSF)
* No concurrent proton pump inhibitors

Primary outcomes:
measure: Response rate (CR or PR)
timeFrame: Up to 6 years
measure: Duration of response
timeFrame: Up to 6 years
measure: Progression-free survival
timeFrame: 2 years
measure: Evaluation of prognostic importance of genetic marker
timeFrame: Up to 6 years
measure: Grade 3 or greater toxicities assessed using CTC version 2.0
timeFrame: Up to 6 years
Secondary outcomes:
measure: Survival of patients receiving the window vs. not
timeFrame: Up to 6 years
measure: Response status on end of course reports (pre vs.post)
timeFrame: Up to 6 years
Other outcomes:
Locations:
city: Arcadia
country: United States
facility: Children's Oncology Group
state: California
Study officials:
affiliation: Children's Oncology Group
name: Robert Castleberry
role: PRINCIPAL_INVESTIGATOR
References: