- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01824693
Busulfan, Cyclophosphamide, and Melphalan or Busulfan and Fludarabine Phosphate Before Donor Hematopoietic Cell Transplant in Treating Younger Patients With Juvenile Myelomonocytic Leukemia
A Randomized Phase II Study Comparing Two Different Conditioning Regimens Prior to Allogeneic Hematopoietic Cell Transplantation (HCT) for Children With Juvenile Myelomonocytic Leukemia (JMML)
Study Overview
Status
Conditions
Detailed Description
PRIMARY OBJECTIVES:
I. To compare ? in a randomized fashion ? the day 100 treatment related mortality (TRM) incidence for two myeloablative conditioning regimens, busulfan-fludarabine (fludarabine phosphate) (BU-FLU) and busulfan-cyclophosphamide-melphalan (BU-CY-MEL), prior to hematopoietic cell transplant (HCT) for children with juvenile myelomonocytic leukemia (JMML), in order to determine the preferred regimen for future trials.
II. To compare ? in a randomized fashion ? the 18-month event-free survival (EFS) following two different myeloablative conditioning regimens (BU-FLU vs. BU-CY-MEL) prior to HCT for children with JMML, in order to determine the preferred regimen for future trials.
SECONDARY OBJECTIVES:
I. To determine the 18-month relapse incidence (RI) following two different myeloablative conditioning regimens (BU-FLU vs. BU-CY-MEL) prior to HCT for children with JMML.
II. To determine the graft failure rates following two different myeloablative conditioning regimens (BU-FLU vs. BU-CY-MEL) prior to HCT for children with JMML.
TERTIARY OBJECTIVES:
I. To determine the rates of severe toxicities (grade 3/4) at day 100 post-HCT between the two myeloablative conditioning regimens (BU-FLU vs. BU-CY-MEL).
II. To determine the rates of acute and chronic (at 18 months post-HCT) graft-versus-host disease (GVHD) following HCT using two different conditioning regimens (BU-FLU vs. BU-CY-MEL) in children with JMML.
III. To create a JMML-specific pre-HCT index to allow better risk-stratification of future patients.
IV. To determine the feasibility of assessing post-transplant disease burden by donor chimerism measurements and allele-specific polymerase chain reaction (PCR) in mononuclear and sorted cell subsets.
V. To validate gene expression and methylation classifiers predictive of relapse in patients with JMML.
VI. To comprehensively assess genetic and biochemical alterations amongst patients with JMML who are treated on this transplant protocol.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I:
CONDITIONING REGIMEN: Patients receive busulfan intravenously (IV) over 2-3 hours once daily (QD), every 12 hours, or every 6 hours on days -8 to -5, cyclophosphamide IV over 60 minutes QD on days -4 and -3, and melphalan IV over 15-30 minutes on day -1.
TRANSPLANT: Patients undergo allogeneic HCT on day 0.
Patients receive tacrolimus IV or orally (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).
ARM II:
CONDITIONING REGIMEN: Patients receive busulfan as in Arm I and fludarabine phosphate IV over 30-60 minutes 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).
After completion of study treatment, patients are followed up for 5 years.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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Western Australia
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Perth, Western Australia, Australia, 6008
- Princess Margaret Hospital for Children
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British Columbia
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Vancouver, British Columbia, Canada, V6H 3V4
- British Columbia Children's Hospital
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Manitoba
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Winnipeg, Manitoba, Canada, R3E 0V9
- CancerCare Manitoba
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Quebec
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Montreal, Quebec, Canada, H3H 1P3
- The Montreal Children's Hospital of the MUHC
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Montreal, Quebec, Canada, H3T 1C5
- Centre Hospitalier Universitaire Sainte-Justine
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Auckland
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Grafton, Auckland, New Zealand, 1145
- Starship Children's Hospital
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Alabama
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Birmingham, Alabama, United States, 35233
- Children's Hospital of Alabama
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Arizona
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Phoenix, Arizona, United States, 85016
- Phoenix Childrens Hospital
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California
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Duarte, California, United States, 91010
- City of Hope Comprehensive Cancer Center
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Los Angeles, California, United States, 90095
- Mattel Children's Hospital UCLA
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Orange, California, United States, 92868
- Children's Hospital of Orange County
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San Diego, California, United States, 92123
- Rady Children's Hospital - San Diego
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San Francisco, California, United States, 94158
- UCSF Medical Center-Mission Bay
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San Francisco, California, United States, 94143
- UCSF Medical Center-Parnassus
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Delaware
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Wilmington, Delaware, United States, 19803
- Alfred I duPont Hospital for Children
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Florida
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Jacksonville, Florida, United States, 32207
- Nemours Children's Clinic-Jacksonville
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Saint Petersburg, Florida, United States, 33701
- Johns Hopkins All Children's Hospital
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Georgia
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Atlanta, Georgia, United States, 30322
- Children's Healthcare of Atlanta - Egleston
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Illinois
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Chicago, Illinois, United States, 60611
- Lurie Children's Hospital-Chicago
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Indiana
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Indianapolis, Indiana, United States, 46202
- Riley Hospital for Children
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Iowa
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Iowa City, Iowa, United States, 52242
- University of Iowa/Holden Comprehensive Cancer Center
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Kentucky
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Louisville, Kentucky, United States, 40202
- Norton Children's Hospital
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Maryland
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Baltimore, Maryland, United States, 21287
- Johns Hopkins University/Sidney Kimmel Cancer Center
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Massachusetts
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Boston, Massachusetts, United States, 02215
- Dana-Farber Cancer Institute
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Michigan
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Detroit, Michigan, United States, 48201
- Wayne State University/Karmanos Cancer Institute
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Minnesota
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Minneapolis, Minnesota, United States, 55455
- University of Minnesota/Masonic Cancer Center
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Mississippi
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Jackson, Mississippi, United States, 39216
- University of Mississippi Medical Center
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Missouri
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Kansas City, Missouri, United States, 64108
- The Childrens Mercy Hospital
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Saint Louis, Missouri, United States, 63104
- Cardinal Glennon Children's Medical Center
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Nebraska
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Omaha, Nebraska, United States, 68198
- University of Nebraska Medical Center
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New Jersey
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Hackensack, New Jersey, United States, 07601
- Hackensack University Medical Center
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New York
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Bronx, New York, United States, 10467
- Montefiore Medical Center - Moses Campus
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New York, New York, United States, 10032
- Columbia University/Herbert Irving Cancer Center
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Rochester, New York, United States, 14642
- University of Rochester
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Valhalla, New York, United States, 10595
- New York Medical College
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Ohio
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Cincinnati, Ohio, United States, 45229
- Cincinnati Children's Hospital Medical Center
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Cleveland, Ohio, United States, 44106
- Rainbow Babies and Childrens Hospital
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Columbus, Ohio, United States, 43205
- Nationwide Children's Hospital
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Oklahoma
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Oklahoma City, Oklahoma, United States, 73104
- University of Oklahoma Health Sciences Center
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Oregon
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Portland, Oregon, United States, 97239
- Oregon Health and Science University
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Pennsylvania
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Philadelphia, Pennsylvania, United States, 19104
- Children's Hospital of Philadelphia
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Pittsburgh, Pennsylvania, United States, 15224
- Children's Hospital of Pittsburgh of UPMC
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South Carolina
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Charleston, South Carolina, United States, 29425
- Medical University of South Carolina
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Texas
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Dallas, Texas, United States, 75390
- UT Southwestern/Simmons Cancer Center-Dallas
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Dallas, Texas, United States, 75230
- Medical City Dallas Hospital
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Fort Worth, Texas, United States, 76104
- Cook Children's Medical Center
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San Antonio, Texas, United States, 78229
- Methodist Children's Hospital of South Texas
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Utah
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Salt Lake City, Utah, United States, 84113
- Primary Children's Hospital
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Washington
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Seattle, Washington, United States, 98105
- Seattle Children's Hospital
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Wisconsin
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Madison, Wisconsin, United States, 53792
- University of Wisconsin Hospital and Clinics
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / 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). |
Correlative studies
Correlative studies
Given IV
Other Names:
Given IV
Other Names:
Given IV or PO
Other Names:
Given IV
Other Names:
Undergo allogeneic HCT
Other Names:
Given IV or PO
Other Names:
|
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). |
Correlative studies
Correlative studies
Given IV
Other Names:
Given IV or PO
Other Names:
Given IV
Other Names:
Undergo allogeneic HCT
Other Names:
Given IV or PO
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Percent Probability of Event-free Survival (EFS)
Time Frame: From transplant up to 18 months
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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.
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From transplant up to 18 months
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Number of Participants Who Experience Treatment-Related Mortality (TRM) by Day 100
Time Frame: From transplant up to 100 days
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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.
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From transplant up to 100 days
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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
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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).
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Day 0 - day 540 (18 months) following completion of stem cell transplant
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Percent Probability of 18 Months-relapse Event Between Arms
Time Frame: From transplant up to 18 months
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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.
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From transplant up to 18 months
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Christopher Dvorak, Children's Oncology Group
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms by Histologic Type
- Neoplasms
- Bone Marrow Diseases
- Hematologic Diseases
- Myelodysplastic-Myeloproliferative Diseases
- Leukemia, Myeloid
- Leukemia
- Leukemia, Myelomonocytic, Acute
- Leukemia, Myelomonocytic, Chronic
- Leukemia, Myelomonocytic, Juvenile
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Enzyme Inhibitors
- Antirheumatic Agents
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Antineoplastic Agents, Alkylating
- Alkylating Agents
- Myeloablative Agonists
- Anti-Bacterial Agents
- Antibiotics, Antineoplastic
- Antitubercular Agents
- Antibiotics, Antitubercular
- Calcineurin Inhibitors
- Cyclophosphamide
- Melphalan
- Fludarabine
- Fludarabine phosphate
- Tacrolimus
- Mycophenolic Acid
- Busulfan
- Mechlorethamine
- Nitrogen Mustard Compounds
Other Study ID Numbers
- ASCT1221 (Other Identifier: CTEP)
- U10CA180886 (U.S. NIH Grant/Contract)
- U10CA098543 (U.S. NIH Grant/Contract)
- NCI-2013-00738 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
- COG-ASCT1221
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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