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

NCT00796068 | Completed Phase 2 Results FDA Drug

• 4 other identifiers: 2275.00NCI-2010-002992275RG2808000
• Study Type: interventional
• Target: 130
• Locations: 1 country
• Sites: 3

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.

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)

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (9)

• Number of Participants Surviving by 1 Year

  At 1 year

• The Number of Participants Alive at Two-years Follow up.

  Up to 2 years

• Non-relapse Mortality

  Up to 2 years

• Duration (Days) Until Participants Obtained Platelet Engraftment

  At 6 months

• Number of Participants With Acute Graft-versus-host Disease (GVHD) Grade II-IV by Day 100

  Day 100

Study Arms (2)

Arm I (low risk for graft failure)

EXPERIMENTAL

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; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Radiation: Total-Body Irradiation; Drug: Treosulfan; Procedure: Umbilical Cord Blood Transplantation

Arm II (high risk for graft failure)

EXPERIMENTAL

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

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

Interventions

Cyclosporine DRUG

Given IV or PO

Also known as: 27-400, Ciclosporin, CsA, Cyclosporin, Cyclosporin A, Gengraf, Neoral, OL 27-400, Sandimmun, Sandimmune, SangCya

Arm I (low risk for graft failure); Arm II (high risk for graft failure)

Fludarabine Phosphate DRUG

Given IV

Also known as: 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586

Arm I (low risk for graft failure); Arm II (high risk for graft failure)

Laboratory Biomarker Analysis OTHER

Correlative studies

Arm I (low risk for graft failure); Arm II (high risk for graft failure)

Mycophenolate Mofetil DRUG

Given IV

Also known as: Cellcept, MMF

Arm I (low risk for graft failure); Arm II (high risk for graft failure)

Total-Body Irradiation RADIATION

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

Also known as: Total Body Irradiation, Whole-Body Irradiation

Arm I (low risk for graft failure); Arm II (high risk for graft failure)

Treosulfan DRUG

Given IV

Also known as: 1,2,3, 4-Butanetetrol, 1,4-dimethanesulfonate, [R-(R*,S*)]-, Dihydroxybusulfan, Ovastat, Treosulphan, Tresulfon

Arm I (low risk for graft failure); Arm II (high risk for graft failure)

Umbilical Cord Blood Transplantation PROCEDURE

Undergo single or double unit UCBT

Also known as: Cord Blood Transplantation, UCB transplantation

Arm I (low risk for graft failure); Arm II (high risk for graft failure)

Eligibility Criteria

• Age: Up to 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Fred Hutchinson Cancer Center: lead

Study Sites (3)

University of Colorado Hospital

Aurora, Colorado, 80045, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, 98109, United States

Location

Related Publications (1)

• 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.

  PMID: 32706891 DERIVED

MeSH Terms

Conditions

Leukemia, Biphenotypic, Acute; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Myelodysplastic Syndromes

Interventions

Cyclosporine; Cyclosporins; fludarabine phosphate; Mycophenolic Acid; Whole-Body Irradiation; treosulfan; Cord Blood Stem Cell Transplantation

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Myeloid; Myeloproliferative Disorders; Bone Marrow Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids; Radiotherapy; Therapeutics; Investigative Techniques; Stem Cell Transplantation; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Transplantation; Surgical Procedures, Operative

Results Point of Contact

• Title: Dr. Filippo Milano
• Organization: Fred Hutchinson Cancer Center

fmilano@fredhutch.org

206-667-5925

Study Officials

• Filippo Milano

  Fred Hutch/University of Washington Cancer Consortium

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: November 21, 2008
• First Posted: November 24, 2008
• Study Start: February 24, 2009
• Primary Completion: December 14, 2021
• Study Completion: December 14, 2021
• Last Updated: February 17, 2023
• Results First Posted: February 17, 2023

Record last verified: 2023-01

Locations

US (3)