Total Marrow Irradiation for Refractory Acute Leukemia

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Masonic Cancer Center, University of Minnesota
Sponsor:
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier:
NCT00686556
First received: May 29, 2008
Last updated: May 15, 2014
Last verified: May 2014
  Purpose

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 that did not respond to previous therapy.


Condition Intervention Phase
Leukemia
Myelodysplastic Syndrome
Drug: cyclophosphamide
Drug: cyclosporine
Drug: Fludarabine
Drug: mycophenolate mofetil
Radiation: total marrow irradiation
Procedure: umbilical cord blood transplantation
Biological: Granulocyte colony-stimulating factor
Biological: HLA-matched related donor bone marrow
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Total Marrow Irradiation and Myeloablative Chemotherapy Followed By Double Umbilical Cord BloodTransplantation In Patients With Refractory Acute Leukemia

Resource links provided by NLM:


Further study details as provided by Masonic Cancer Center, University of Minnesota:

Primary Outcome Measures:
  • Maximum tolerated dose (MTD) of total marrow irradiation (TMI) [ Time Frame: Day 42 and 6 months ] [ Designated as safety issue: Yes ]
    Maximum tolerated dose (MTD) is the highest dose of a drug or treatment that does not cause unacceptable side effects. The MTD of TMI will be determined by using the modified Continual Reassessment Method (CRM). The goal of this CRM will be to identify 1 of the 5 dose levels which corresponds to the desired maximum toxicity rate of <=15%.


Secondary Outcome Measures:
  • Incidence of neutrophil engraftment [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
    Neutrophil engraftment is defined as the first day of three consecutive days where the neutrophil count (absolute neutrophil count) is 500 cells/mm3 (0.5 x 109/L) or greater.

  • Incidence of platelet engraftment [ Time Frame: 6 Months and 1 Year After Transplantation ] [ Designated as safety issue: No ]
    Platelet engraftment is defined as 20,000/mm^3 (20 x 10^9/L) for 3 consecutive days unsupported by a platelet transfusion.

  • Incidence of complete donor chimerism [ Time Frame: Day 100 ] [ Designated as safety issue: No ]
    Defined as a state in bone marrow transplantation in which bone marrow and host cells exist compatibly without signs of graft-versus-host rejection disease.

  • Incidence of transplantation-related mortality [ Time Frame: 6 Months ] [ Designated as safety issue: No ]
    In the field of transplantation, toxicity is high and all deaths without previous relapse or progression are usually considered as related to transplantation.

  • Incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) after transplantation [ Time Frame: Day 100 ] [ Designated as safety issue: No ]
    Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host.

  • Incidence of chronic GVHD after transplantation [ Time Frame: 1 Year ] [ Designated as safety issue: No ]
    Chronic Graft-Versus-Host Disease is a severe long-term complication created by infusion of donor cells into a foreign host.

  • Incidence of relapse after transplantation [ Time Frame: 1 Year ] [ Designated as safety issue: No ]
    The return of disease after its apparent recovery/cessation.

  • Disease-free survival after transplantation [ Time Frame: 1 year and 2 years ] [ Designated as safety issue: No ]
    Disease-free survival (progression-free survival [PFS]) is the length of time during and after medication or treatment during which the disease being treated (usually cancer) does not get worse. It is sometimes used as a metric to study the health of a person with a disease to try to determine how well a new treatment is working.

  • Durability of remission based on presence of rapid early response after transplantation [ Time Frame: Day 21 ] [ Designated as safety issue: No ]
    Remission - a decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer that can be detected with modern technology have disappeared, although cancer still may be in the body.

  • Overall survival after transplantation [ Time Frame: 1 year and 2 years ] [ Designated as safety issue: No ]
    The percentage of people in a study or treatment group who are alive for a certain period of time after they were diagnosed with or treated for a disease, such as cancer.


Estimated Enrollment: 20
Study Start Date: August 2012
Estimated Study Completion Date: September 2017
Estimated Primary Completion Date: September 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort -1
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.
Drug: cyclophosphamide
60 mg/kg/day intravenous x 2 days pre-transplant, total dose 120 mg/kg
Other Name: Cytoxan
Drug: cyclosporine
Beginning on Day -3 pre-transplant maintaining a level of >200 ng/mL. CSA dosing will be monitored and altered as clinically appropriate by Pharm D or physician, and discontinue at approximately day + 180 post-transplant.
Other Name: CSA
Drug: Fludarabine
25 mg/m2/day intravenous as a 1 hour infusion for consecutive 3 days pre-transplant, total dose 75 mg/m2
Other Name: Fludara
Drug: mycophenolate mofetil
Beginning on day -3, use intravenous route between days -3 and +5, followed by oral administration on Day +6 through +30, if tolerated. 15mg/kg/dose for patients <40 kg, 3 gm/day for patients >40 kg.
Other Name: MMF
Radiation: total marrow irradiation
Dose escalating schedule per Cohort (TMI: 300 cGy) once daily.
Other Name: TMI
Procedure: umbilical cord blood transplantation
product will be infused via intravenous drip on Day 0 according to current University of Minnesota guidelines for Umbilical Cord Blood Grafts
Other Names:
  • umbilical cord blood
  • allogeneic hematopoietic stem cell transplantation
Biological: Granulocyte colony-stimulating factor
5 mcg/kg/day intravenous or subcutaneous based on body weight beginning on Day +1 after umbilical cord blood infusion until absolute neutrophil count exceeds 2.5 x 10^9/L for 3 consecutive days.
Other Name: G-CSF
Biological: HLA-matched related donor bone marrow
Related donor bone marrow or mobilized stem cells 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 according to University of Minnesota Blood and Marrow Transplant Program guidelines.
Other Name: mobilized peripheral blood stem cells
Experimental: Cohort 1
Patient receives preparative therapy including Fludarabine, cyclophosphamide, and total marrow irradiation of 15 Gy on Days -5 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.
Drug: cyclophosphamide
60 mg/kg/day intravenous x 2 days pre-transplant, total dose 120 mg/kg
Other Name: Cytoxan
Drug: cyclosporine
Beginning on Day -3 pre-transplant maintaining a level of >200 ng/mL. CSA dosing will be monitored and altered as clinically appropriate by Pharm D or physician, and discontinue at approximately day + 180 post-transplant.
Other Name: CSA
Drug: Fludarabine
25 mg/m2/day intravenous as a 1 hour infusion for consecutive 3 days pre-transplant, total dose 75 mg/m2
Other Name: Fludara
Drug: mycophenolate mofetil
Beginning on day -3, use intravenous route between days -3 and +5, followed by oral administration on Day +6 through +30, if tolerated. 15mg/kg/dose for patients <40 kg, 3 gm/day for patients >40 kg.
Other Name: MMF
Radiation: total marrow irradiation
Dose escalating schedule per Cohort (TMI: 300 cGy) once daily.
Other Name: TMI
Procedure: umbilical cord blood transplantation
product will be infused via intravenous drip on Day 0 according to current University of Minnesota guidelines for Umbilical Cord Blood Grafts
Other Names:
  • umbilical cord blood
  • allogeneic hematopoietic stem cell transplantation
Biological: Granulocyte colony-stimulating factor
5 mcg/kg/day intravenous or subcutaneous based on body weight beginning on Day +1 after umbilical cord blood infusion until absolute neutrophil count exceeds 2.5 x 10^9/L for 3 consecutive days.
Other Name: G-CSF
Biological: HLA-matched related donor bone marrow
Related donor bone marrow or mobilized stem cells 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 according to University of Minnesota Blood and Marrow Transplant Program guidelines.
Other Name: mobilized peripheral blood stem cells
Experimental: Cohort 2
Patient receives preparative therapy including Fludarabine, cyclophosphamide, and total marrow irradiation of 18 Gy on Days -6 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.
Drug: cyclophosphamide
60 mg/kg/day intravenous x 2 days pre-transplant, total dose 120 mg/kg
Other Name: Cytoxan
Drug: cyclosporine
Beginning on Day -3 pre-transplant maintaining a level of >200 ng/mL. CSA dosing will be monitored and altered as clinically appropriate by Pharm D or physician, and discontinue at approximately day + 180 post-transplant.
Other Name: CSA
Drug: Fludarabine
25 mg/m2/day intravenous as a 1 hour infusion for consecutive 3 days pre-transplant, total dose 75 mg/m2
Other Name: Fludara
Drug: mycophenolate mofetil
Beginning on day -3, use intravenous route between days -3 and +5, followed by oral administration on Day +6 through +30, if tolerated. 15mg/kg/dose for patients <40 kg, 3 gm/day for patients >40 kg.
Other Name: MMF
Radiation: total marrow irradiation
Dose escalating schedule per Cohort (TMI: 300 cGy) once daily.
Other Name: TMI
Procedure: umbilical cord blood transplantation
product will be infused via intravenous drip on Day 0 according to current University of Minnesota guidelines for Umbilical Cord Blood Grafts
Other Names:
  • umbilical cord blood
  • allogeneic hematopoietic stem cell transplantation
Biological: Granulocyte colony-stimulating factor
5 mcg/kg/day intravenous or subcutaneous based on body weight beginning on Day +1 after umbilical cord blood infusion until absolute neutrophil count exceeds 2.5 x 10^9/L for 3 consecutive days.
Other Name: G-CSF
Biological: HLA-matched related donor bone marrow
Related donor bone marrow or mobilized stem cells 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 according to University of Minnesota Blood and Marrow Transplant Program guidelines.
Other Name: mobilized peripheral blood stem cells
Experimental: Cohort 3
Patient receives preparative therapy including Fludarabine, cyclophosphamide, and total marrow irradiation of 21 Gy on Days -7 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.
Drug: cyclophosphamide
60 mg/kg/day intravenous x 2 days pre-transplant, total dose 120 mg/kg
Other Name: Cytoxan
Drug: cyclosporine
Beginning on Day -3 pre-transplant maintaining a level of >200 ng/mL. CSA dosing will be monitored and altered as clinically appropriate by Pharm D or physician, and discontinue at approximately day + 180 post-transplant.
Other Name: CSA
Drug: Fludarabine
25 mg/m2/day intravenous as a 1 hour infusion for consecutive 3 days pre-transplant, total dose 75 mg/m2
Other Name: Fludara
Drug: mycophenolate mofetil
Beginning on day -3, use intravenous route between days -3 and +5, followed by oral administration on Day +6 through +30, if tolerated. 15mg/kg/dose for patients <40 kg, 3 gm/day for patients >40 kg.
Other Name: MMF
Radiation: total marrow irradiation
Dose escalating schedule per Cohort (TMI: 300 cGy) once daily.
Other Name: TMI
Procedure: umbilical cord blood transplantation
product will be infused via intravenous drip on Day 0 according to current University of Minnesota guidelines for Umbilical Cord Blood Grafts
Other Names:
  • umbilical cord blood
  • allogeneic hematopoietic stem cell transplantation
Biological: Granulocyte colony-stimulating factor
5 mcg/kg/day intravenous or subcutaneous based on body weight beginning on Day +1 after umbilical cord blood infusion until absolute neutrophil count exceeds 2.5 x 10^9/L for 3 consecutive days.
Other Name: G-CSF
Biological: HLA-matched related donor bone marrow
Related donor bone marrow or mobilized stem cells 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 according to University of Minnesota Blood and Marrow Transplant Program guidelines.
Other Name: mobilized peripheral blood stem cells
Experimental: Cohort 4
Patient receives preparative therapy including Fludarabine, cyclophosphamide, and total marrow irradiation of 24 Gy on Days -8 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.
Drug: cyclophosphamide
60 mg/kg/day intravenous x 2 days pre-transplant, total dose 120 mg/kg
Other Name: Cytoxan
Drug: cyclosporine
Beginning on Day -3 pre-transplant maintaining a level of >200 ng/mL. CSA dosing will be monitored and altered as clinically appropriate by Pharm D or physician, and discontinue at approximately day + 180 post-transplant.
Other Name: CSA
Drug: Fludarabine
25 mg/m2/day intravenous as a 1 hour infusion for consecutive 3 days pre-transplant, total dose 75 mg/m2
Other Name: Fludara
Drug: mycophenolate mofetil
Beginning on day -3, use intravenous route between days -3 and +5, followed by oral administration on Day +6 through +30, if tolerated. 15mg/kg/dose for patients <40 kg, 3 gm/day for patients >40 kg.
Other Name: MMF
Radiation: total marrow irradiation
Dose escalating schedule per Cohort (TMI: 300 cGy) once daily.
Other Name: TMI
Procedure: umbilical cord blood transplantation
product will be infused via intravenous drip on Day 0 according to current University of Minnesota guidelines for Umbilical Cord Blood Grafts
Other Names:
  • umbilical cord blood
  • allogeneic hematopoietic stem cell transplantation
Biological: Granulocyte colony-stimulating factor
5 mcg/kg/day intravenous or subcutaneous based on body weight beginning on Day +1 after umbilical cord blood infusion until absolute neutrophil count exceeds 2.5 x 10^9/L for 3 consecutive days.
Other Name: G-CSF
Biological: HLA-matched related donor bone marrow
Related donor bone marrow or mobilized stem cells 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 according to University of Minnesota Blood and Marrow Transplant Program guidelines.
Other Name: mobilized peripheral blood stem cells

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.

  Eligibility

Ages Eligible for Study:   up to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  • 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
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00686556

Contacts
Contact: Michael Verneris, MD 612-626-2961 verneris@umn.edu
Contact: Timothy Krepski 612-273-2800 tkrepsk1@fairview.org

Locations
United States, Minnesota
Masonic Cancer Center at University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Clinical Trials Office - Masonic Cancer Center at University o    612-624-2620      
Sponsors and Collaborators
Masonic Cancer Center, University of Minnesota
Investigators
Principal Investigator: Michael R. Verneris, MD Masonic Cancer Center, University of Minnesota
  More Information

Additional Information:
No publications provided

Responsible Party: Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier: NCT00686556     History of Changes
Other Study ID Numbers: 2007LS024, MT2006-24, 0708M14041
Study First Received: May 29, 2008
Last Updated: May 15, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Masonic Cancer Center, University of Minnesota:
recurrent adult acute lymphoblastic leukemia
recurrent childhood acute lymphoblastic leukemia
recurrent adult acute myeloid leukemia
recurrent childhood acute myeloid leukemia
adult acute myeloid leukemia with 11q23 (MLL) abnormalities
adult acute myeloid leukemia with inv(16)(p13;q22)
adult acute myeloid leukemia with t(15;17)(q22;q12)
adult acute myeloid leukemia with t(16;16)(p13;q22)
adult acute myeloid leukemia with t(8;21)(q22;q22)

Additional relevant MeSH terms:
Leukemia
Myelodysplastic Syndromes
Preleukemia
Bone Marrow Diseases
Hematologic Diseases
Neoplasms
Neoplasms by Histologic Type
Precancerous Conditions
Cyclophosphamide
Cyclosporine
Cyclosporins
Fludarabine
Fludarabine phosphate
Lenograstim
Mycophenolate mofetil
Mycophenolic Acid
Adjuvants, Immunologic
Alkylating Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Dermatologic Agents
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents

ClinicalTrials.gov processed this record on October 30, 2014