Treosulfan, Fludarabine Phosphate, and Total-Body Irradiation in Treating Patients With Hematological Cancer Who Are Undergoing Umbilical Cord Blood Transplant

Study Overview
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Brief Summary
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This phase II trial studies how well giving treosulfan together with fludarabine phosphate and total-body irradiation (TBI) works in treating patients with hematological cancer who are undergoing umbilical cord blood transplant (UCBT). Giving chemotherapy, such as treosulfan and fludarabine phosphate, and TBI before a donor UCBT helps stop the growth of cancer cells and helps stop the patient's immune system from rejecting the donor's stem cells. When the stem cells from a related or unrelated donor, that do not exactly match the patient's blood, 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 also make an immune response against the body's normal cells. Giving cyclosporine (CsA) and mycophenolate mofetil (MMF) after the transplant may stop this from happening.

Detailed Description
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PRIMARY OBJECTIVES: I. Graft failure/rejection and secondary graft failure. II. Day -200 non-relapse mortality. SECONDARY OBJECTIVES: I. Platelet engraftment by six months. II. Grade II-IV and III-IV acute graft-versus-host disease (GVHD) at day 100 and one year. III. Chronic GVHD. IV. Clinically significant infections. V. Overall survival. VI. Relapse or disease progression. VII. Immune reconstitution (Fred Hutchinson Cancer Research Center [FHCRC] only). VIII. Emergence of a dominant unit (FHCRC only). OUTLINE: Patients are assigned to 1 of 2 arms. ARM I (low risk for graft failure): Patients receive a conditioning regimen comprising fludarabine phosphate intravenously (IV) over 1 hour once daily (QD) on days -6 to -2 and treosulfan IV over 120 minutes on days - 6 to -4. Patients undergo TBI on day -1. Patients then undergo donor UCBT on day 0. Patients receive GVHD prophylaxis comprising cyclosporine IV over 1 hour or orally (PO) 2-3 times daily on days -3 to 100, followed by a taper in the absence of GVHD. Patients also receive mycophenolate mofetil IV 3 times daily on days 0 to 40, followed by a taper in the absence of GVHD. ARM II (high risk for graft failure): Patients receive a conditioning regimen, TBI, donor UCBT, GVHD prophylaxis, and mycophenolate mofetil as in Arm I. After completion of the study treatment, patients are followed up at 6 months and 1 and 2 years.

Official Title
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Transplantation of Umbilical Cord Blood in Patients With Hematological Malignancies Using a Treosulfan Based Preparative Regimen

Conditions
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Acute Biphenotypic Leukemia, Acute Lymphoblastic Leukemia in Remission, Acute Myeloid Leukemia in Remission, Blasts Under 5 Percent of Bone Marrow Nucleated Cells, Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Myelodysplastic Syndrome (MDS)

Intervention / Treatment
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* Drug: Cyclosporine
* Drug: Fludarabine Phosphate
* Other: Laboratory Biomarker Analysis
* Drug: Mycophenolate Mofetil
* Radiation: Total-Body Irradiation
* Drug: Treosulfan
* Procedure: Umbilical Cord Blood Transplantation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Acute myeloid leukemia/acute lymphoblastic leukemia, including biphenotypic acute leukemia or mixed-lineage leukemia: Must have < 5% morphologic marrow blasts in an evaluable marrow sample (> 25% of normal cellularity for age collected less than one month prior to start of conditioning; patients in which adequate marrow/biopsy specimens cannot be obtained to determine remission status by morphologic assessment, but have fulfilled criteria of remission by flow cytometry, recovery of peripheral blood counts with no circulating blasts, and/or normal cytogenetics (if applicable) may still be eligible; reasonable attempts must be made to obtain an adequate specimen for morphologic assessment, including possible repeat procedures; these patients must be discussed with the principal investigator prior to enrollment; patients persistently aplastic for greater than one month since completing last chemotherapy are also eligible with principal investigator (PI) approval Myelodysplastic syndrome (MDS): Any 2001 World Health Organization (WHO) classification subtype; refractory anemia with excess blasts (RAEB)-2 patients may proceed directly to transplant, but may also be considered for induction chemotherapy before transplant; patients with >= 20% morphologic marrow blasts require induction therapy to reduce morphologic marrow blasts below 5% before transplant Chronic myelogenous leukemia: All types, except refractory blast crisis; chronic phase patients must have failed or been intolerant to Gleevec or other tyrosine kinase inhibitors Patients =< 50 must have performance status score: Karnofsky (for adults) >= 70 or Eastern Cooperative Oncology Group (ECOG) 0-1; Lansky (for children) score >= 50 Patients > 50 must have Karnofsky performance score >= 70 or ECOG 0-1 and comorbidity index < 5 Adequate cardiac function defined as absence of decompensated congestive heart failure or uncontrolled arrhythmia AND left ventricular ejection fraction >= 35% OR fractional shortening > 22% Adequate pulmonary function defined as absence of oxygen (O2) requirements and one of the following: Diffusion lung capacity for carbon monoxide (DLCO) corrected >= 70% mm Hg DLCO corrected between 60% - 69% mm Hg and partial pressure of oxygen (pO2) >= 70 mm Hg DLCO corrected between 50% - 59% mm Hg and pO2 >= 80 mm Hg Pediatric patients unable to perform pulmonary function tests must have O2 saturation > 92% on room air; may not be on supplemental oxygen Adequate hepatic function; patients with clinical or laboratory evidence of liver disease will be evaluated for the cause of liver disease, its clinical severity in terms of liver function, histology, and the degree of portal hypertension; patients with fulminant liver failure, cirrhosis with evidence of portal hypertension or bridging fibrosis, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, or correctable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL, and symptomatic biliary disease will be excluded Adequate renal function defined as creatinine =< 2.0 mg/dl (adults) or estimated creatinine clearance > 40 ml/min (pediatrics); all adults with a creatinine > 1.2 or a history of renal dysfunction must have estimated creatinine clearance > 40 ml/min If recent mold infection, e.g., Aspergillus, must be cleared by infectious disease to proceed Prior hematopoietic cell transplant: must be >= 3 months after previous transplant DONOR: Human leukocyte antigen (HLA) matching: Minimum requirement: The cord blood (CB) graft(s) must be matched at a minimum at 4/6 HLA-A, B, DRB1 loci with the recipient; therefore 0-2 mismatches at the A or B or DRB1 loci based on intermediate resolution A, B antigen and DRB1 allele typing for determination of HLA-match is allowed HLA-matching determined by high resolution typing is allowed per institutional guidelines as long as the minimum criteria (above) are met DONOR: Selection of two CB units is mandatory when a single cord blood unit does not meet the following criteria in the table below Match grade 6/6 Single unit allowed for total nucleated cell (TNC) dose >= 2.5 x 10^7/kg 5/6, 4/6 Single unit allowed for TNC dose >= 4.0 (+/- 0.5) x 10^7/kg If two CB units are used, the total cell dose of the combined units must be at least 3.0 x 10^7 TNC per kilogram recipient weight based on pre-cryopreservation numbers, with each CB unit containing a MINIMUM of 1.5 x 10^7 TNC/kg DONOR: The minimum recommended CD34/kg cell dose should be 2 x 10^5 CD34/kg, total dose from a single or combined double DONOR: The unmanipulated CB unit(s) will be Food and Drug Administration (FDA) licensed or will be obtained under a separate investigational new drug (IND), such as the National Marrow Donor Program (NMDP) Protocol 10-CBA conducted under BB IND-7555 or another IND sponsored by (1) a participating institution or (2) an investigator at FHCRC or one of the participating institutions DONOR (FHCRC only): Up to 5% of the unmanipulated cord blood product (s), when ready for infusion, may be withheld for research purposes as long as thresholds for infused TNC dose are met; these products will be used to conduct studies involving the kinetics of engraftment and immunobiology of double cord transplantation Exclusion Criteria: Pregnancy or breastfeeding Evidence of human immunodeficiency virus (HIV) infection or known HIV positive serology Uncontrolled viral or bacterial infection at the time of study enrollment Active or recent (prior 6 month) invasive fungal infection without infectious diseases (ID) consult and approval Central nervous system (CNS) leukemic involvement not clearing with intrathecal chemotherapy and/or cranial radiation prior to initiation of conditioning (day -6) DONOR: Any cord blood units with < 1.5 x 10^7 total nucleated cells per kilogram recipient weight DONOR: Any cord blood units that have not passed donor screening for infectious disease markers as recommended by NMDP will not be used unless a waiver is signed by the clinical attending allowing use of CB unit. Cord blood units are presumed to be cytomegalovirus (CMV) negative regardless of serologic testing due to passive transmission of maternal CMV antibodies

Ages Eligible for Study
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Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (low risk for graft failure)<br>Patients receive a conditioning regimen comprising fludarabine phosphate IV over 1 hour QD on days -6 to -2 and treosulfan IV over 120 minutes on days - 6 to -4. Patients undergo TBI on day -1. Patients then undergo donor UCBT on day 0. Patients receive GVHD prophylaxis comprising cyclosporine IV over 1 hour or PO 2-3 times daily on days -3 to 100, followed by a taper in the absence of GVHD. Patients also receive mycophenolate mofetil IV 3 times daily on days 0 to 40, followed by a taper in the absence of GVHD. | Drug: Cyclosporine<br>* Given IV or PO<br>* Other names: SangCya;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Mycophenolate Mofetil<br>* Given IV<br>* Other names: MMF;Radiation: Total-Body Irradiation<br>* TBI administered day -1: 200 cGy (or escalated to 300 cGy, 400 cGy, or 450 cGy per protocol statistical section)<br>* Other names: Whole-Body Irradiation;Drug: Treosulfan<br>* Given IV<br>* Other names: Tresulfon;Procedure: Umbilical Cord Blood Transplantation<br>* Undergo single or double unit UCBT<br>* Other names: UCB transplantation;|
| Experimental: Arm II (high risk for graft failure)<br>Patients receive a conditioning regimen, TBI, donor UCBT, GVHD prophylaxis, and mycophenolate mofetil as in Arm I. | Drug: Cyclosporine<br>* Given IV or PO<br>* Other names: SangCya;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Mycophenolate Mofetil<br>* Given IV<br>* Other names: MMF;Radiation: Total-Body Irradiation<br>* TBI administered day -1: 200 cGy (or escalated to 300 cGy, 400 cGy, or 450 cGy per protocol statistical section)<br>* Other names: Whole-Body Irradiation;Drug: Treosulfan<br>* Given IV<br>* Other names: Tresulfon;Procedure: Umbilical Cord Blood Transplantation<br>* Undergo single or double unit UCBT<br>* Other names: UCB transplantation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Graft Failure/Rejection | Patients will be considered primary graft failure provided they meet any criteria listed below, in the absence of documented disease persistence/recurrence or active bone marrow infection (ex. Cytomegalovirus (CMV)): i. Absence of 3 consecutive days with neutrophils >500/u1 combined with host CD3+ peripheral blood chimerism ≥50% at day 42 ii. Absence of 3 consecutive days with neutrophils >500/u1 under any circumstances at day 55 iii. Death after day 28 with neutrophil count <100/u1 without any evidence of engraftment (< 5% donor CD3+) iv. Primary autologous count recovery with < 5% donor CD3+ peripheral blood chimerism at count recovery and without relapse | Up to 100 days | 
| Number of Participants With Secondary Graft Failure | Secondary graft failure is defined as decline of neutrophil count to <500/ul with loss of donor chimerism after day 55 | Up to 2 years | 
| Number of Patients With Non-relapse Mortality (NRM) | Defined as death from any cause without sign of disease progression or relapse. Loss to follow up are censored, whereas disease relapse or progression are considered competing risks. | At day -200 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Surviving by 1 Year | Overall survival was measured from the first day of CBT infusion until death from any cause. | At 1 year | 
| The Number of Participants Alive at Two-years Follow up. | Overall survival of participants after two-years of follow up. | Up to 2 years | 
| Non-relapse Mortality | Death of any cause other than relapse or disease progression was considered. | Up to 2 years | 
| Duration (Days) Until Participants Obtained Platelet Engraftment | Summarized using a range and median of measure in days until participants reached platelet engraftment. Platelet engraftment was defined as the first of 7 consecutive days when the platelet count exceeded 20 x 109/L (untransfused). | At 6 months | 
| Number of Participants With Acute Graft-versus-host Disease (GVHD) Grade II-IV by Day 100 | Grade I GVHD is characterized as mild disease, grade II GVHD as moderate, grade III as severe, and grade IV life-threatening. Diagnosing and grading acute GVHD is based on clinical findings (the organ stage, response to treatment and whether GVHD was a major cause of death) and frequently varies between transplant centers and independent reviewers. | Day 100 | 
| Incidence of Acute or Chronic Graft-versus-host Disease (GVHD) | Overall GVHD is determined based on the organ stage, response to treatment and whether GVHD was a major cause of death. Chronic GVHD will be defined according to the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease. Described as mild, moderate, or severe as graded according to the attached Organ Scoring Sheet. Symptoms consistent with both chronic and acute GVHD occurring after day 100 will be considered overlap chronic GVHD syndrome. | At 1 year | 
| Incidence of Relapse or Disease Progression | Cumulative incidence estimates using non-relapse mortality as competitive event. | Up to 2 years | 
| Number of Participants Surviving up to 2 Years Without Disease Progression | Progression-free survival is the time interval from start of treatment to documented evidence of disease progression. Disease progression was defined by European LeukemiaNet 2017 criteria and International Working Group (IWG) within 3 years of transplant. | Up to 2 years | 
| Incidence of Clinically Significant Infections | Collected and graded according to the modified National Cancer Institute Common Toxicity Criteria. | At 6 months |