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

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ClinicalTrials.gov Identifier: NCT00025038
Recruitment Status : Completed
First Posted : January 27, 2003
Last Update Posted : April 11, 2013
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Description
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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

Condition or disease Intervention/treatment Phase
Juvenile Myelomonocytic Leukemia Drug: tipifarnib Drug: isotretinoin Drug: fludarabine phosphate Drug: cytarabine Radiation: radiation therapy Drug: cyclophosphamide Biological: anti-thymocyte globulin Procedure: allogeneic bone marrow transplantation Procedure: double-unit umbilical cord blood transplantation Procedure: umbilical cord blood transplantation Other: laboratory biomarker analysis Phase 2

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 100 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : June 2001
Actual Primary Completion Date : October 2007

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Leukemia

Arms and Interventions
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Arm Intervention/treatment
Experimental: Treatment (tipifarnib, bone marrow/umbilical cord transplant)
See detailed description.
 Drug: tipifarnib
Given orally
Other Names:
  • R115777
  • Zarnestra

Drug: isotretinoin
Given orally
Other Names:
  • 13-CRA
  • Amnesteem
  • Cistane
  • Claravis
  • Sotret

Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara

Drug: cytarabine
Given IV
Other Names:
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside

Radiation: radiation therapy
Undergo total body irradiation
Other Names:
  • irradiation
  • radiotherapy
  • therapy, radiation

Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana

Biological: anti-thymocyte globulin
Given IV
Other Names:
  • ATG
  • ATGAM
  • lymphocyte immune globulin
  • Thymoglobulin

Procedure: allogeneic bone marrow transplantation
Undergo allogeneic bone marrow transplant
Other Names:
  • bone marrow therapy, allogeneic
  • bone marrow therapy, allogenic
  • transplantation, allogeneic bone marrow
  • transplantation, allogenic bone marrow

Procedure: double-unit umbilical cord blood transplantation
Procedure: umbilical cord blood transplantation
Undergo allogeneic cord blood transplant
Other Names:
  • cord blood transplantation
  • transplantation, umbilical cord blood
  • UCB transplantation

Other: laboratory biomarker analysis
Correlative studies


Outcome Measures
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Primary Outcome Measures :
  1. Response rate (CR or PR) [ Time Frame: Up to 6 years ]
    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.

  2. Duration of response [ Time Frame: Up to 6 years ]
    Will be estimated by Kaplan-Meier method.

  3. Progression-free survival [ Time Frame: 2 years ]
    Will be estimated by Kaplan-Meier method.

  4. Evaluation of prognostic importance of genetic marker [ Time Frame: Up to 6 years ]
    Logrank test and Cox proportional hazards model will be applied.

  5. Grade 3 or greater toxicities assessed using CTC version 2.0 [ Time Frame: Up to 6 years ]

Secondary Outcome Measures :
  1. Survival of patients receiving the window vs. not [ Time Frame: Up to 6 years ]
  2. Response status on end of course reports (pre vs.post) [ Time Frame: Up to 6 years ]
    Signed-rank comparison of components of therapy will be done.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00025038


Locations
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United States, California
Children's Oncology Group
Arcadia, California, United States, 91006-3776
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Robert Castleberry Children's Oncology Group
More Information
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00025038    
Other Study ID Numbers: NCI-2012-01861
AAML0122
U10CA098543 ( U.S. NIH Grant/Contract )
CDR0000068788 ( Registry Identifier: PDQ (Physician Data Query) )
First Posted: January 27, 2003    Key Record Dates
Last Update Posted: April 11, 2013
Last Verified: January 2013
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Neoplasms by Histologic Type
Neoplasms
Leukemia, Myeloid
Myelodysplastic-Myeloproliferative Diseases
Bone Marrow Diseases
Hematologic Diseases
Cytarabine
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Tipifarnib
 Isotretinoin
Thymoglobulin
Antilymphocyte Serum
Immunoglobulins
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites