Combination Chemotherapy Followed By Donor Bone Marrow or Umbilical Cord Blood Transplant in Treating Children With Newly Diagnosed Juvenile Myelomonocytic Leukemia

Juvenile Myelomonocytic Leukemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00025038
• Other study ID #: NCI-2012-01861
• Secondary ID: AAML0122U10CA098
• Status: Completed
• Phase: Phase 2
• First received: October 11, 2001
• Last updated: April 10, 2013
• Start date: June 2001

Study information

• Verified date: January 2013
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 100
• Est. primary completion date: October 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 18 Years

Eligibility

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

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Juvenile Myelomonocytic Leukemia
• Leukemia
• Leukemia, Myelomonocytic, Acute
• Leukemia, Myelomonocytic, Chronic
• Leukemia, Myelomonocytic, Juvenile

Intervention

Drug:
• tipifarnib
Given orally
• isotretinoin
Given orally
• fludarabine phosphate
Given IV
• cytarabine
Given IV

Radiation:
• radiation therapy
Undergo total body irradiation

Drug:
• cyclophosphamide
Given IV

Biological:
• anti-thymocyte globulin
Given IV

Procedure:
• allogeneic bone marrow transplantation
Undergo allogeneic bone marrow transplant
• double-unit umbilical cord blood transplantation

• umbilical cord blood transplantation
Undergo allogeneic cord blood transplant

Other:
• laboratory biomarker analysis
Correlative studies

Locations

Country	Name	City	State
United States	Children's Oncology Group	Arcadia	California

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Response rate (CR or PR)	The response rates in the up-front window with respect to whether or not patients had vas activating mutations will also be estimated by proportions.	Up to 6 years	No
Primary	Duration of response	Will be estimated by Kaplan-Meier method.	Up to 6 years	No
Primary	Progression-free survival	Will be estimated by Kaplan-Meier method.	2 years	No
Primary	Evaluation of prognostic importance of genetic marker	Logrank test and Cox proportional hazards model will be applied.	Up to 6 years	No
Primary	Grade 3 or greater toxicities assessed using CTC version 2.0		Up to 6 years	Yes
Secondary	Survival of patients receiving the window vs. not		Up to 6 years	No
Secondary	Response status on end of course reports (pre vs.post)	Signed-rank comparison of components of therapy will be done.	Up to 6 years	No