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Busulfan, Cyclophosphamide, and Melphalan or Busulfan and Fludarabine Phosphate Before Donor Hematopoietic Cell Transplant in Treating Younger Patients With Juvenile Myelomonocytic Leukemia

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ClinicalTrials.gov Identifier: NCT01824693
Recruitment Status : Completed
First Posted : April 5, 2013
Results First Posted : December 5, 2018
Last Update Posted : December 5, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

Study Description
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Brief Summary:
This randomized phase II trial studies how well giving busulfan, cyclophosphamide, and melphalan or busulfan and fludarabine phosphate before donor hematopoietic cell transplant works in treating younger patients with juvenile myelomonocytic leukemia. Giving chemotherapy before a donor hematopoietic transplant helps stop the growth of cancer cells. It may also 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. It is not yet known whether giving busulfan, cyclophosphamide, and melphalan or busulfan and fludarabine phosphate before a donor stem cell transplant is more effective in treating juvenile myelomonocytic leukemia.

Condition or disease Intervention/treatment Phase
Juvenile Myelomonocytic Leukemia Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Drug: Busulfan Drug: Cyclophosphamide Drug: Fludarabine Phosphate Other: Laboratory Biomarker Analysis Drug: Melphalan Drug: Mycophenolate Mofetil Other: Pharmacological Study Drug: Tacrolimus Phase 2

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Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Phase II Study Comparing Two Different Conditioning Regimens Prior to Allogeneic Hematopoietic Cell Transplantation (HCT) for Children With Juvenile Myelomonocytic Leukemia (JMML)
Actual Study Start Date : June 24, 2013
Actual Primary Completion Date : December 31, 2017
Actual Study Completion Date : December 31, 2017

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Arm I (busulfan, cyclophosphamide, melphalan)

CONDITIONING REGIMEN: Patients receive busulfan IV QD, every 12 hours, or every 6 hours over 2-3 hours on days -8 to -5, cyclophosphamide IV QD over 60 minutes on days -4 and -3, and melphalan IV over 15-30 minutes on day -1.

TRANSPLANT: Patients undergo allogeneic HCT no sooner than 24 hours after the last dose of chemotherapy.

Patients receive tacrolimus IV or PO on days -1 to 98 (related donor) or 180 (unrelated donor) and mycophenolate mofetil IV over 2 hours or PO every 8 hours on days 1-30 (related donor) or 45 (unrelated donor).

 Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic HCT
Other Names:
  • Allogeneic Hematopoietic Cell Transplantation
  • Allogeneic Stem Cell Transplantation
  • HSC
  • HSCT

Drug: Busulfan
Given IV
Other Names:
  • 1, 4-Bis[methanesulfonoxy]butane
  • BUS
  • Bussulfam
  • Busulfanum
  • Busulfex
  • Busulphan
  • CB 2041
  • CB-2041
  • Glyzophrol
  • GT 41
  • GT-41
  • Joacamine
  • Methanesulfonic Acid Tetramethylene Ester
  • Methanesulfonic acid, tetramethylene ester
  • Mielucin
  • Misulban
  • Misulfan
  • Mitosan
  • Myeleukon
  • Myeloleukon
  • Myelosan
  • Mylecytan
  • Myleran
  • Sulfabutin
  • Tetramethylene Bis(methanesulfonate)
  • Tetramethylene bis[methanesulfonate]
  • WR-19508

Drug: Cyclophosphamide
Given IV
Other Names:
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Melphalan
Given IV
Other Names:
  • Alanine Nitrogen Mustard
  • CB-3025
  • L-PAM
  • L-Phenylalanine Mustard
  • L-sarcolysin
  • L-Sarcolysin Phenylalanine mustard
  • L-Sarcolysine
  • Melphalanum
  • Phenylalanine Mustard
  • Phenylalanine nitrogen mustard
  • Sarcoclorin
  • Sarkolysin
  • WR-19813

Drug: Mycophenolate Mofetil
Given IV or PO
Other Names:
  • Cellcept
  • MMF

Other: Pharmacological Study
Correlative studies

Drug: Tacrolimus
Given IV or PO
Other Names:
  • FK 506
  • Fujimycin
  • Hecoria
  • Prograf
  • Protopic
Experimental: Arm II (busulfan, fludarabine phosphate)

CONDITIONING REGIMEN: Patients receive busulfan as in Arm I and fludarabine phosphate IV over 1 hour on days -5 to -2.

TRANSPLANT: Patients undergo allogeneic HCT as in Arm I.

Patients receive tacrolimus IV or PO on days -1 to 98 (related donor) or 180 (unrelated donor) and mycophenolate mofetil IV over 2 hours or PO every 8 hours on days 1-30 (related donor) or 45 (unrelated donor).

 Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic HCT
Other Names:
  • Allogeneic Hematopoietic Cell Transplantation
  • Allogeneic Stem Cell Transplantation
  • HSC
  • HSCT

Drug: Busulfan
Given IV
Other Names:
  • 1, 4-Bis[methanesulfonoxy]butane
  • BUS
  • Bussulfam
  • Busulfanum
  • Busulfex
  • Busulphan
  • CB 2041
  • CB-2041
  • Glyzophrol
  • GT 41
  • GT-41
  • Joacamine
  • Methanesulfonic Acid Tetramethylene Ester
  • Methanesulfonic acid, tetramethylene ester
  • Mielucin
  • Misulban
  • Misulfan
  • Mitosan
  • Myeleukon
  • Myeloleukon
  • Myelosan
  • Mylecytan
  • Myleran
  • Sulfabutin
  • Tetramethylene Bis(methanesulfonate)
  • Tetramethylene bis[methanesulfonate]
  • WR-19508

Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • SH T 586

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Mycophenolate Mofetil
Given IV or PO
Other Names:
  • Cellcept
  • MMF

Other: Pharmacological Study
Correlative studies

Drug: Tacrolimus
Given IV or PO
Other Names:
  • FK 506
  • Fujimycin
  • Hecoria
  • Prograf
  • Protopic


Outcome Measures
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Primary Outcome Measures :
  1. Percent Probability of Event-free Survival (EFS) [ Time Frame: From transplant up to 18 months ]
    Probability of Event-free Survival (EFS) for Patients after 18 months. An event is either treatment related mortality (TRM), primary or secondary graft failure, or relapse/non-response (as defined in protocol section 10). Time to event is time from transplant with patients who die between the start of the conditioning regimen and transplant given a time to event of zero.

  2. Number of Participants Who Experience Treatment-Related Mortality (TRM) by Day 100 [ Time Frame: From transplant up to 100 days ]
    The number of patients who experience TRM on day 100. Treatment-Related Mortality (TRM) an event defined as a death prior to relapse or non-response. Time to TRM is defined as time from transplants to TRM. Patients who die between the start of the conditioning regimen and transplant will be considered a TRM with time to TRM of zero.


Secondary Outcome Measures :
  1. Percentage of Participants Who Experience Primary Graft Failure Event Between Arms [ Time Frame: Day 0 - day 540 (18 months) following completion of stem cell transplant ]
    Primary Graft failure is defined as the failure to achieve an ANC >= 500/uL after 42 days, determined by 3 consecutive measurements on different days; OR < 5% donor cells in blood or bone marrow by day +42 (as demonstrated by a chimerism assay), without evidence of Juvenile Myelomonocytic Leukemia (JMML).

  2. Percent Probability of 18 Months-relapse Event Between Arms [ Time Frame: From transplant up to 18 months ]
    Probability of patients relapsing at 18 months. A relapse event is defined in protocol section 10.2.3. Time to relapse/non-response is defined as time from transplant to when all criteria of section 10.2.3 are met.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   3 Months to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have a strong clinical suspicion of JMML, based on a modified category 1 of the revised diagnostic criteria; specifically, eligible patients must have all of the following:

    • Splenomegaly
    • Absolute monocyte count (AMC) > 1000/uL
    • Blasts in peripheral blood (PB)/bone marrow (BM) < 20%

  • For the 7-10% of patients without splenomegaly, the diagnostic entry criteria must include all other features described above and at least 2 of the following criteria:

    • Circulating myeloid precursors
    • White blood cell (WBC) > 10,000/uL
    • Increased fetal hemoglobin (HgbF) for age
    • Sargramostim (GM-CSF) hypersensitivity OR, patients must have been previously diagnosed with JMML
  • Patients must be previously untreated with HCT
  • All patients and/or their parents or legal guardians must sign a written informed consent
  • All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria:

  • Patients with a known germline mutation of PTPN11 (Noonan?s Syndrome) are not eligible

  • Patients with a known history of NF1 (Neurofibromatosis Type 1) and either

    • A history of a tumor of the central nervous system (astrocytoma or optic glioma), or
    • A malignant peripheral nerve sheath tumor with a complete remission of < 1 year are not eligible
  • Human immunodeficiency virus (HIV) positive patients are not eligible
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): NCT01824693


Locations
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Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Christopher Dvorak Children's Oncology Group
  Study Documents (Full-Text)

Documents provided by Children's Oncology Group:
Study Protocol and Statistical Analysis Plan  [PDF] June 5, 2014

More Information
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Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT01824693    
Other Study ID Numbers: ASCT1221
NCI-2013-00738 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
COG-ASCT1221
ASCT1221
ASCT1221 ( Other Identifier: Childrens Oncology Group )
ASCT1221 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
U10CA098543 ( U.S. NIH Grant/Contract )
First Posted: April 5, 2013    Key Record Dates
Results First Posted: December 5, 2018
Last Update Posted: December 5, 2018
Last Verified: November 2018
Additional relevant MeSH terms:
Layout table for MeSH terms
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
Mycophenolic Acid
Cyclophosphamide
Melphalan
Busulfan
Mechlorethamine
 Nitrogen Mustard Compounds
Fludarabine
Fludarabine phosphate
Tacrolimus
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