Brief Title
Total Marrow Irradiation for Refractory Acute Leukemia
Official Title
Total Marrow Irradiation and Myeloablative Chemotherapy Followed By Double Umbilical Cord BloodTransplantation In Patients With Refractory Acute Leukemia
Brief Summary
RATIONALE: Giving chemotherapy and total marrow irradiation before a donor umbilical cord
blood or hematopoietic stem cell 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. Sometimes the
transplanted cells from a donor can make an immune response against the body's normal cells.
Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from
happening.
PURPOSE: This phase I trial is studying the side effects and best dose of total marrow
irradiation when given together with combination chemotherapy and umbilical cord blood
hematopoietic stem cell transplant in treating patients with acute leukemia, acute myeloid
leukemia or multiple myeloma that did not respond to previous therapy.
Detailed Description
OBJECTIVES:
Primary
- Determine the maximum tolerated dose of total marrow irradiation (TMI) delivered by
image-guided tomographic intensity-modulated radiotherapy when administered in
combination with myeloablative chemotherapy in patients undergoing double umbilical cord
blood (UCB) transplantation or hematopoietic stem cell for refractory acute leukemia.
Secondary
- Determine the incidence of engraftment (defined as achievement of neutrophil count >
500/uL at 42 days after transplantation).
- Determine the incidence of platelet engraftment at 6 months and at 1 year after
transplantation.
- Evaluate the incidence of complete donor chimerism and the relative contribution of each
UCB unit to donor engraftment within the first 100 days after transplantation.
- Determine the incidence of transplantation-related mortality (TRM) at 6 months after
treatment with a TMI-containing myeloablative conditioning regimen.
- Determine the incidence of grade II-IV and grade III-IV acute graft-versus-host disease
(GVHD) at 100 days after transplantation.
- Determine the incidence of chronic GVHD at 1 year after transplantation.
- Determine the incidence of relapse at 1 year after transplantation.
- Determine the survival and disease-free survival at 1 and 2 years after transplantation.
- Assess the durability of remission based on presence of rapid early response (defined by
clearance of leukemic blasts from the bone marrow at 21 days after transplantation).
OUTLINE: This is a dose-escalation study of total marrow irradiation (TMI).
- Myeloablative conditioning regimen: Patients receive fludarabine phosphate IV over 1
hour once daily for 3 days between days -12 and -6 and cyclophosphamide IV once daily
for 2 days between days -11 and -6. Patients undergo TMI once daily for 4-8 days between
days -8 and -1.
- Donor umbilical cord blood (UCB) transplantation: Patients undergo single-unit or
double-unit donor UCB transplantation on day 0. Patients receive filgrastim (G-CSF) IV
or subcutaneously once daily beginning on day 1 and continuing until blood counts
recover.
- Related Donor: Related donor bone marrow will be collected (target cell dose 5x10^8
nucleated cells/kg recipient weight, minimum 3x10^8 nucleated cells/kg recipient weight)
and infused without processing on day 0.
- Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV over 2
hours or orally 2-3 times daily beginning on day -3 and continuing until day 100,
followed by a taper until day 180, in the absence of GVHD. Patients also receive
mycophenolate mofetil IV or orally 2-3 times daily beginning on day -3 and continuing
until day 30 (or 7 days after engraftment), in the absence of acute GVHD.
Patients are followed periodically for up to 2 years after transplantation.
Study Phase
Phase 1
Study Type
Interventional
Primary Outcome
Maximum tolerated dose (MTD) of total marrow irradiation (TMI)
Secondary Outcome
Incidence of neutrophil engraftment
Condition
Acute Lymphoblastic Leukemia
Intervention
cyclophosphamide
Study Arms / Comparison Groups
Cohort -1
Description: Patient receives preparative therapy including Fludarabine, cyclophosphamide, and total marrow irradiation of 12 Gy on Days -4 through -1, and starts immunosuppressive therapy using cyclosporine, Mycophenolate Mofetil, followed by umbilical cord blood transplantation, or HLA-matched related donor bone marrow transplantation and granulocyte colony-stimulating factor administration.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
12
Start Date
August 2012
Completion Date
December 2016
Primary Completion Date
November 2016
Eligibility Criteria
Inclusion Criteria:
- Acute lymphoblastic leukemia
- ≥ Complete remission 2 (CR2) (adults ≥ 18 years and ≤ 55 years)
- CR2 in pediatrics (defined as <18 years) and <12 months duration of first
remission
- ≥ CR3 or not in remission (pediatric patients <18 years)
- T cell leukemia ≥ CR2
- Evidence of pre-transplant minimal residual disease (MRD) by flow cytometry, FISH
or cytogenetics
- Myelodysplastic syndrome
- ≤ 55 years of age and ≥ 10% blasts, not responsive to hypomethylating agents
and/or conventional therapy
- Acute myeloid leukemia
- Not in remission (pediatric patients <18 years)
- Not in remission (10-30% blasts in the bone marrow for adult patients ≥18 years
and ≤ 55 years)
- Evidence of pre-transplant minimal residual disease (MRD) by flow cytometry, FISH
or cytogenetics
- Multiple myeloma
- No prior autologous transplant and fitting into one of the following disease
categories:
- Early disease stage (CR1/PR1) with high-risk molecular features
- Early disease stage (CR1/PR1) with high-risk clinical features
- Late disease stage (CR2/PR2+) with high-risk clinical features
- Other high risk hematologic malignancies - to be approved by 2 or more
hematology/oncology and BMT physicians
- Patients with prior CNS involvement are eligible provided that it has been treated and
is in remission. CNS therapy (chemotherapy or radiation) should continue as medically
indicated during the protocol.
- Have acceptable organ function within 14 days of study registration defined as:
- Renal: glomerular filtration rate > 60ml/min/1.73m2
- Hepatic: bilirubin, aspartate aminotransferase (AST), alanine aminotransferase
(ALT), Alkaline phosphatase (ALP) < 5 x upper limit of normal (ULN)
- Pulmonary function: Carbon Monoxide Diffusing Capacity corrected (DLCOcorr) > 50%
of normal, (oxygen saturation [>92%] can be used in child where pulmonary
function tests (PFT's) cannot be obtained)
- Cardiac: left ventricular ejection fraction ≥ 45% by echocardiogram (ECHO) or
multi gated acquisition scan (MUGA)
- Karnofsky performance status (PS) >80% for ages 16 years and older or Lansky Play
Score >50 for < 16 years
- An acceptable source of stem cells according to current University of Minnesota BMT
program guidelines:
- UCB graft will be composed of two partially HLA matched units. Each unit must be
matched at 4-6 HLA loci to the recipient and to each other. If two matched units
are not available, then a single HLA 4-6 matched unit may be used if of adequate
cell dose - total graft dose must be >3 x 107 MNC/kg
- HLA-matched related donor (6/6 or 5/6 antigen match)
- HLA-matched unrelated adult donor (if previously identified)
- Women of childbearing potential must agree to use adequate contraception (diaphragm,
birth control pills, injections, intrauterine device [IUD], surgical sterilization,
subcutaneous implants, or abstinence, etc.) for the duration of treatment.
- Voluntary written consent
Exclusion Criteria:
- Active uncontrolled infection at time of enrollment or documented fungal infection
within 3 months.
- Evidence of Human immunodeficiency virus (HIV) infection
- Pregnant or breast feeding. The agents used in this study may be teratogenic to a
fetus and there is no information on the excretion of agents into breast milk. All
females of childbearing potential must have a blood test or urine study within 2 weeks
prior to registration to rule out pregnancy.
- Prior myeloablative transplant within the last 6 months
- Prior total body irradiation (TBI) making total marrow irradiation (TMI) not feasible
Gender
All
Ages
N/A - 55 Years
Accepts Healthy Volunteers
No
Contacts
John Wagner, MD, ,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT00686556
Organization ID
2007LS024
Secondary IDs
MT2006-24
Responsible Party
Sponsor
Study Sponsor
Masonic Cancer Center, University of Minnesota
Study Sponsor
John Wagner, MD, Principal Investigator, Masonic Cancer Center, University of Minnesota
Verification Date
December 2017