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

NCT ID: NCT00796068

Last Updated: 2023-02-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 130 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-02-24
• Study Completion Date: 2021-12-14

Brief Summary

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

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.

Conditions

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)

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm I (low risk for graft failure)

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.

Group Type: EXPERIMENTAL

Cyclosporine

Intervention Type: DRUG

Given IV or PO

Fludarabine Phosphate

Intervention Type: DRUG

Given IV

Laboratory Biomarker Analysis

Intervention Type: OTHER

Correlative studies

Mycophenolate Mofetil

Intervention Type: DRUG

Given IV

Total-Body Irradiation

Intervention Type: RADIATION

TBI administered day -1: 200 cGy (or escalated to 300 cGy, 400 cGy, or 450 cGy per protocol statistical section)

Treosulfan

Intervention Type: DRUG

Given IV

Umbilical Cord Blood Transplantation

Intervention Type: PROCEDURE

Undergo single or double unit UCBT

Arm II (high risk for graft failure)

Patients receive a conditioning regimen, TBI, donor UCBT, GVHD prophylaxis, and mycophenolate mofetil as in Arm I.

Group Type: EXPERIMENTAL

Cyclosporine

Intervention Type: DRUG

Given IV or PO

Fludarabine Phosphate

Intervention Type: DRUG

Given IV

Laboratory Biomarker Analysis

Intervention Type: OTHER

Correlative studies

Mycophenolate Mofetil

Intervention Type: DRUG

Given IV

Total-Body Irradiation

Intervention Type: RADIATION

TBI administered day -1: 200 cGy (or escalated to 300 cGy, 400 cGy, or 450 cGy per protocol statistical section)

Treosulfan

Intervention Type: DRUG

Given IV

Umbilical Cord Blood Transplantation

Intervention Type: PROCEDURE

Undergo single or double unit UCBT

Interventions

Cyclosporine

Given IV or PO

Intervention Type: DRUG

Fludarabine Phosphate

Given IV

Intervention Type: DRUG

Laboratory Biomarker Analysis

Correlative studies

Intervention Type: OTHER

Mycophenolate Mofetil

Given IV

Intervention Type: DRUG

Total-Body Irradiation

TBI administered day -1: 200 cGy (or escalated to 300 cGy, 400 cGy, or 450 cGy per protocol statistical section)

Intervention Type: RADIATION

Treosulfan

Given IV

Intervention Type: DRUG

Umbilical Cord Blood Transplantation

Undergo single or double unit UCBT

Intervention Type: PROCEDURE

Other Intervention Names

27-400; Ciclosporin; CsA; Cyclosporin; Cyclosporin A; Gengraf; Neoral; OL 27-400; Sandimmun; Sandimmune; SangCya; 2-F-ara-AMP; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; Beneflur; Fludara; SH T 586; Cellcept; MMF; Total Body Irradiation; Whole-Body Irradiation; 1,2,3, 4-Butanetetrol, 1,4-dimethanesulfonate, [R-(R*,S*)]-; Dihydroxybusulfan; Ovastat; Treosulphan; Tresulfon; Cord Blood Transplantation; UCB transplantation

Eligibility Criteria

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

• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Fred Hutchinson Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Filippo Milano

Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Filippo Milano

Role: PRINCIPAL_INVESTIGATOR

Fred Hutch/University of Washington Cancer Consortium

Locations

University of Colorado Hospital

Aurora, Colorado, United States

Oregon Health and Science University

Portland, Oregon, United States

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, United States

Countries

United States

References

Milano F, Gutman JA, Deeg HJ, Nemecek ER, Baumgart J, Thur L, Dahlberg A, Salit RB, Summers C, Appelbaum FR, Delaney C. Treosulfan-based conditioning is feasible and effective for cord blood recipients: a phase 2 multicenter study. Blood Adv. 2020 Jul 28;4(14):3302-3310. doi: 10.1182/bloodadvances.2020002222.

Reference Type: DERIVED

PMID: 32706891 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

NCI-2010-00299

Identifier Type: REGISTRY

Identifier Source: secondary_id

2275

Identifier Type: -

Identifier Source: secondary_id

2275.00

Identifier Type: OTHER

Identifier Source: secondary_id

RG2808000

Identifier Type: OTHER

Identifier Source: secondary_id

2275.00

Identifier Type: -

Identifier Source: org_study_id