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
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Juvenile Myelomonocytic Leukemia
Lead sponsor: Children's Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2013-04-05
Enrollment: 30
Sex: ALL
Minimum age (years): 3
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

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

Primary outcomes:
measure: Percent Probability of Event-free Survival (EFS)
timeFrame: From transplant up to 18 months
measure: Number of Participants Who Experience Treatment-Related Mortality (TRM) by Day 100
timeFrame: From transplant up to 100 days
Secondary outcomes:
measure: Percentage of Participants Who Experience Primary Graft Failure Event Between Arms
timeFrame: Day 0 - day 540 (18 months) following completion of stem cell transplant
measure: Percent Probability of 18 Months-relapse Event Between Arms
timeFrame: From transplant up to 18 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Children's Hospital of Alabama
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Childrens Hospital
state: Arizona
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: Mattel Children's Hospital UCLA
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital - San Diego
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center-Parnassus
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center-Mission Bay
state: California
city: Wilmington
country: United States
facility: Alfred I duPont Hospital for Children
state: Delaware
city: Jacksonville
country: United States
facility: Nemours Children's Clinic-Jacksonville
state: Florida
city: Saint Petersburg
country: United States
facility: Johns Hopkins All Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta - Egleston
state: Georgia
city: Chicago
country: United States
facility: Lurie Children's Hospital-Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Riley Hospital for Children
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa/Holden Comprehensive Cancer Center
state: Iowa
city: Louisville
country: United States
facility: Norton Children's Hospital
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins University/Sidney Kimmel Cancer Center
state: Maryland
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State University/Karmanos Cancer Institute
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota/Masonic Cancer Center
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Kansas City
country: United States
facility: The Childrens Mercy Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Cardinal Glennon Children's Medical Center
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center - Moses Campus
state: New York
city: New York
country: United States
facility: Columbia University/Herbert Irving Cancer Center
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Valhalla
country: United States
facility: New York Medical College
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Rainbow Babies and Childrens Hospital
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Dallas
country: United States
facility: Medical City Dallas Hospital
state: Texas
city: Dallas
country: United States
facility: UT Southwestern/Simmons Cancer Center-Dallas
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: San Antonio
country: United States
facility: Methodist Children's Hospital of South Texas
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Hospital
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
city: Perth
country: Australia
facility: Princess Margaret Hospital for Children
state: Western Australia
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital
state: British Columbia
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Montreal
country: Canada
facility: The Montreal Children's Hospital of the MUHC
state: Quebec
city: Montreal
country: Canada
facility: Centre Hospitalier Universitaire Sainte-Justine
state: Quebec
city: Grafton
country: New Zealand
facility: Starship Children's Hospital
state: Auckland
Study officials:
affiliation: Children's Oncology Group
name: Christopher Dvorak
role: PRINCIPAL_INVESTIGATOR
References: