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.
Brief Title
Busulfan, Cyclophosphamide, and Melphalan or Busulfan and Fludarabine Phosphate Before Donor Hematopoietic Cell Transplant in Treating Younger Patients With Juvenile Myelomonocytic Leukemia
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.
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.
Completion Date
Completion Date Type
Actual
Conditions
Juvenile Myelomonocytic Leukemia
Eligibility 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
* 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
Inclusion 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
* 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
Gender
All
Gender Based
false
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Maximum Age
18 Years
Minimum Age
3 Months
NCT Id
NCT01824693
Org Class
Network
Org Full Name
Children's Oncology Group
Org Study Id
ASCT1221
Overall Status
Completed
Phases
Phase 2
Primary Completion Date
Primary Completion Date Type
Actual
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)
Primary Outcomes
Outcome Description
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.
Outcome Measure
Percent Probability of Event-free Survival (EFS)
Outcome Time Frame
From transplant up to 18 months
Outcome Description
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.
Outcome Measure
Number of Participants Who Experience Treatment-Related Mortality (TRM) by Day 100
Outcome Time Frame
From transplant up to 100 days
Secondary Ids
Secondary Id
NCI-2013-00738
Secondary Id
COG-ASCT1221
Secondary Id
ASCT1221
Secondary Id
ASCT1221
Secondary Id
ASCT1221
Secondary Id
U10CA180886
Secondary Id
U10CA098543
Secondary Outcomes
Outcome Description
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).
Outcome Time Frame
Day 0 - day 540 (18 months) following completion of stem cell transplant
Outcome Measure
Percentage of Participants Who Experience Primary Graft Failure Event Between Arms
Outcome Description
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.
Outcome Time Frame
From transplant up to 18 months
Outcome Measure
Percent Probability of 18 Months-relapse Event Between Arms
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Child
Adult
Maximum Age Number (converted to Years and rounded down)
18
Minimum Age Number (converted to Years and rounded down)
0
Investigators
Investigator Type
Principal Investigator
Investigator Name
Jonathan Gill
Investigator Email
jgill@montefiore.org
Investigator Phone
718-741-2331
Categories Mesh Debug
Blood & Bone Marrow Cancers --- LEUKEMIA, MYELOMONOCYTIC, JUVENILE
Blood & Bone Marrow Cancers --- LEUKEMIA, MYELOID
Cancer --- LEUKEMIA
Blood & Bone Marrow Cancers --- LEUKEMIA
Cancer --- NEOPLASMS
Blood & Bone Marrow Cancers --- MYELODYSPLASTIC-MYELOPROLIFERATIVE DISEASES
Blood & Bone Marrow Cancers --- BONE MARROW DISEASES
Blood Disorders --- HEMATOLOGIC DISEASES
Blood & Bone Marrow Cancers --- HEMATOLOGIC DISEASES
MeSH Terms
LEUKEMIA, MYELOMONOCYTIC, JUVENILE
LEUKEMIA, MYELOID
LEUKEMIA
NEOPLASMS BY HISTOLOGIC TYPE
NEOPLASMS
MYELODYSPLASTIC-MYELOPROLIFERATIVE DISEASES
BONE MARROW DISEASES
HEMATOLOGIC DISEASES
HEMIC AND LYMPHATIC DISEASES
BUSULFAN
CYCLOPHOSPHAMIDE
FLUDARABINE PHOSPHATE
MELPHALAN
MYCOPHENOLIC ACID
TACROLIMUS
BUTYLENE GLYCOLS
GLYCOLS
ALCOHOLS
ORGANIC CHEMICALS
MESYLATES
ALKANESULFONATES
ALKANESULFONIC ACIDS
ALKANES
HYDROCARBONS, ACYCLIC
HYDROCARBONS
SULFONIC ACIDS
SULFUR ACIDS
SULFUR COMPOUNDS
PHOSPHORAMIDE MUSTARDS
NITROGEN MUSTARD COMPOUNDS
MUSTARD COMPOUNDS
HYDROCARBONS, HALOGENATED
PHOSPHORAMIDES
ORGANOPHOSPHORUS COMPOUNDS
PHENYLALANINE
AMINO ACIDS, AROMATIC
AMINO ACIDS, CYCLIC
AMINO ACIDS
AMINO ACIDS, PEPTIDES, AND PROTEINS
CAPROATES
ACIDS, ACYCLIC
CARBOXYLIC ACIDS
FATTY ACIDS
LIPIDS
MACROLIDES
LACTONES