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Treo/Flu/TBI With Donor Stem Cell Transplant for Patients With Myelodysplastic Syndrome or Acute Myeloid Leukemia

Primary Purpose

Acute Myeloid Leukemia in Remission, Chronic Myelomonocytic Leukemia, Minimal Residual Disease

Status
Unknown status
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Allogeneic Bone Marrow Transplantation
Fludarabine Phosphate
Peripheral Blood Stem Cell Transplantation
Total-Body Irradiation
Treosulfan
Laboratory Biomarker Analysis
Sponsored by
Fred Hutchinson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia in Remission

Eligibility Criteria

undefined - 70 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • MDS, myelodysplastic syndrome/myeloproliferative neoplasia overlap disorders (including chronic myelomonocytic leukemia [CMML], and MDS/myeloproliferative neoplasm [MPN] unclassifiable syndromes)
  • AML, other than acute promyelocytic leukemia (APL), in first or second remission or with minimal residual disease
  • With Karnofsky index or Lansky Play-Performance scale > 70% on pre-transplant evaluation
  • Able to give informed consent (if > 18 years), or with a legal guardian capable of giving informed consent (if < 18 years)
  • Patients with previous autologous or allogeneic HCT are allowed to enroll
  • DONOR: Human leukocyte antigen (HLA)-identical related donors or
  • DONOR: Unrelated donors matched for HLA-A, B, C, DRB1, and DQB1 as defined by high resolution deoxyribonucleic acid (DNA) typing; mismatch for one HLA allele is allowed
  • DONOR: Donors able to undergo peripheral blood stem cell collection or bone marrow harvest
  • DONOR: Donors in good general health, with a Karnofsky or Lansky play performance score > 90%
  • DONOR: Donors able to give informed consent (if > 18 years), or with a legal guardian capable of giving informed consent (if < 18 years)

Exclusion Criteria:

  • Receiving umbilical cord blood
  • With impaired cardiac function as evidenced by ejection fraction < 35% (or, if unable to obtain ejection fraction, shortening fraction of < 26%) or cardiac insufficiency requiring treatment or symptomatic coronary artery disease; patients with a shortening fraction < 26% may be enrolled if approved by a cardiologist
  • With impaired pulmonary function as evidenced by partial pressure of oxygen (pO2) < 70 mm Hg and carbon monoxide diffusing capability test (DLCO) < 70% of predicted or pO2 < 80 mm Hg and DLCO < 60% of predicted; (or, for pediatric patients unable to perform pulmonary function tests, then oxygen (O2) saturation < 92% on room air), or receiving supplementary continuous oxygen
  • With impaired renal function as evidenced by creatinine-clearance < 50% for age, weight, height or serum creatinine > 2 x upper limit of normal or dialysis-dependent
  • With hepatic dysfunction as evidenced by total bilirubin > 2.0 x upper limit of normal or evidence of synthetic dysfunction or severe cirrhosis
  • With hepatic dysfunction as evidenced by aspartate aminotransferase (AST) > 2.0 x upper limit of normal or evidence of synthetic dysfunction or severe cirrhosis
  • With active infectious disease requiring deferral of conditioning, as recommended by an infectious disease specialist
  • With human immunodeficiency virus (HIV)-positivity or active infectious hepatitis
  • With central nervous system (CNS) leukemic involvement not clearing with intrathecal chemotherapy, cranial irradiation or both prior to initiating conditioning (day -6)
  • Patients with active non-hematological malignancies (except non-melanoma skin cancers) or those with non-hematological malignancies who have been rendered with no evidence of disease, but have a greater than 20% chance of having disease recurrence within 5 years; this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy
  • With life expectancy severely limited by diseases other than malignancy
  • Women who are pregnant or lactating
  • With known hypersensitivity to treosulfan or fludarabine (fludarabine phosphate)
  • Receiving another experimental drug within 4 weeks before initiation of conditioning (day -6)
  • Unable to give informed consent (if > 18 years) or with a legal guardian (if < 18 years) unable to give informed consent
  • DONOR: Individuals deemed unable to undergo marrow harvesting or PBSC mobilization and leukapheresis
  • DONOR: Individuals who are HIV-positive
  • DONOR: Individuals with active infectious hepatitis
  • DONOR: Females with a positive pregnancy test
  • DONOR: Persons unable to give informed consent (if > 18 years) or with a legal guardian (if < 18 years) unable to give informed consent

Sites / Locations

  • Fred Hutch/University of Washington Cancer Consortium

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Arm A

Arm B

Arm Description

Arm A: Treosulfan, Fludarabine Phosphate Treosulfan intravenously (IV) over 2 hours on days -6 to -4 and fludarabine phosphate IV over 30 minutes on days -6 to -2.

Arm B: Treosulfan, Fludarabine Phosphate, TBI Treosulfan and fludarabine phosphate as in Arm A and undergo low -dose total-body irradiation (TBI) on day 0

Outcomes

Primary Outcome Measures

Number of Participants That Did Not Progress Within 6 Months
Progression is defined as relapse

Secondary Outcome Measures

Number of Participants With Acute GVHD, Graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
Incidence of Chronic GVHD Graded by the NCI CTCAE Version 4.0
Incidence of Relapse/Progression
NRM
Overall Survival (OS)
Change in Gene Expression Profiles
Differences between arms in the changes in gene expression will be compared. 80% power to detect mean differences of approximately 1.4 standard deviation units, at the 2-sided 0.05 level of significance (with Bonferroni correction for 50 genes).
Relapse Risk as Measured by Degree of Change in Gene Expression Profiles
Among genes identified whose expression is modified by conditioning, degree of change in expression will be evaluated to determine if it is correlated with relapse risk and offers improved prediction of relapse risk over that obtained with standard clinical parameters (cytogenetics, blast count, International Prognostic Scoring System score, minimal residual disease. To account for censoring and the competing risk of non-relapse mortality (NRM), the analysis will be a time-to-event analysis of relapse using Cox regression, with change in expression as a continuous covariate (on a log scale). 8

Full Information

First Posted
July 1, 2013
Last Updated
May 13, 2021
Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT01894477
Brief Title
Treo/Flu/TBI With Donor Stem Cell Transplant for Patients With Myelodysplastic Syndrome or Acute Myeloid Leukemia
Official Title
A Randomized Phase II Study of Treosulfan, Fludarabine and Low-Dose TBI as Conditioning for Allogeneic Hematopoietic Cell Transplantation in Patients With Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML)
Study Type
Interventional

2. Study Status

Record Verification Date
May 2021
Overall Recruitment Status
Unknown status
Study Start Date
November 2013 (undefined)
Primary Completion Date
January 9, 2017 (Actual)
Study Completion Date
June 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This randomized phase II trial studies how well treosulfan and fludarabine phosphate, with or without total body irradiation before donor stem cell transplant works in treating patients with myelodysplastic syndrome or acute myeloid leukemia. Giving chemotherapy, such as treosulfan and fludarabine phosphate, and total-body irradiation before a donor 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. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus before and mycophenolate mofetil after the transplant may stop this from happening.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the better of two treosulfan-based conditioning regimens in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), by comparing 6-month progression-free survival. SECONDARY OBJECTIVES: I. Determine the effects of two conditioning regimens on changes in gene expression profiles, and evaluate the association of gene expression profiles and disease relapse. II. Determine the incidence of progression-free survival at 1 year and 2 years after hematopoietic cell transplantation (HCT). III. Evaluate overall survival (OS) at 6 months, at 1 year and at 2 years after HCT. IV. Determine the incidence of grades II-IV acute graft-versus-host disease (GVHD). V. Determine the incidence of chronic GVHD. VI. Determine donor chimerism around days +28 and +84. CONDITIONING REGIMEN: Arm A: Patients receive treosulfan intravenously (IV) over 2 hours on days -6 to -4 and fludarabine phosphate IV over 30 minutes on days -6 to -2. Arm B: Patients receive treosulfan and fludarabine phosphate as in Arm A and undergo low-dose total-body irradiation (TBI) on day 0. TRANSPLANT: Patients in both arms undergo allogeneic peripheral blood stem cell (PBSC) transplant or bone marrow transplant on day 0. GVHD PROPHYLAXIS: Patients with a related donor receive tacrolimus orally (PO) every 8 or 12 hours on days -3 to 56 with taper to day 180. Beginning 4-6 hours after PBSC infusion, patients also receive mycophenolate mofetil PO every 12 hours to day 28. Patients with an unrelated donor receive tacrolimus PO every 8 or 12 hours on days -3 to 100 with taper to day 180. Beginning 4-6 hours after PBSC infusion, patients also receive mycophenolate mofetil PO every 8 hours to day 40 with taper to day 96. NOTE: Patients with related donors eligible for FHCRC protocol 2545 may receive cyclosporine IV, instead of tacrolimus, beginning on day -3 to day 50 with a taper to day 180. After completion of study treatment, patients are followed up periodically.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia in Remission, Chronic Myelomonocytic Leukemia, Minimal Residual Disease, Myelodysplastic Syndrome, Myelodysplastic/Myeloproliferative Neoplasm, Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
102 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm A
Arm Type
Experimental
Arm Description
Arm A: Treosulfan, Fludarabine Phosphate Treosulfan intravenously (IV) over 2 hours on days -6 to -4 and fludarabine phosphate IV over 30 minutes on days -6 to -2.
Arm Title
Arm B
Arm Type
Experimental
Arm Description
Arm B: Treosulfan, Fludarabine Phosphate, TBI Treosulfan and fludarabine phosphate as in Arm A and undergo low -dose total-body irradiation (TBI) on day 0
Intervention Type
Procedure
Intervention Name(s)
Allogeneic Bone Marrow Transplantation
Other Intervention Name(s)
Allo BMT, Allogeneic BMT
Intervention Description
Undergo allogeneic bone marrow transplant
Intervention Type
Drug
Intervention Name(s)
Fludarabine Phosphate
Other Intervention Name(s)
2-F-ara-AMP, Beneflur, Fludara, SH T 586
Intervention Description
Intravenously administered Fludarabine Phosphate
Intervention Type
Procedure
Intervention Name(s)
Peripheral Blood Stem Cell Transplantation
Other Intervention Name(s)
PBPC transplantation, Peripheral Blood Progenitor Cell Transplantation, Peripheral Stem Cell Support, Peripheral Stem Cell Transplantation
Intervention Description
Undergo allogeneic PBSC transplant
Intervention Type
Radiation
Intervention Name(s)
Total-Body Irradiation
Other Intervention Name(s)
TOTAL BODY IRRADIATION, Whole-Body Irradiation
Intervention Description
Undergo TBI
Intervention Type
Drug
Intervention Name(s)
Treosulfan
Other Intervention Name(s)
1,2,3, 4-Butanetetrol, 1,4-dimethanesulfonate, [R-(R*,S*)]-, Dihydroxybusulfan, Ovastat, Treosulphan, Tresulfon
Intervention Description
Intravenously administered Treosulfan
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative Studies
Primary Outcome Measure Information:
Title
Number of Participants That Did Not Progress Within 6 Months
Description
Progression is defined as relapse
Time Frame
At 6 months post-transplant
Secondary Outcome Measure Information:
Title
Number of Participants With Acute GVHD, Graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
Time Frame
Up to 84 days
Title
Incidence of Chronic GVHD Graded by the NCI CTCAE Version 4.0
Time Frame
Up to 5 year
Title
Incidence of Relapse/Progression
Time Frame
Up to 5 year
Title
NRM
Time Frame
Up to 5 years
Title
Overall Survival (OS)
Time Frame
Up to 2 year
Title
Change in Gene Expression Profiles
Description
Differences between arms in the changes in gene expression will be compared. 80% power to detect mean differences of approximately 1.4 standard deviation units, at the 2-sided 0.05 level of significance (with Bonferroni correction for 50 genes).
Time Frame
Baseline and at day 0 within 6 hours of conditioning prior to transplant
Title
Relapse Risk as Measured by Degree of Change in Gene Expression Profiles
Description
Among genes identified whose expression is modified by conditioning, degree of change in expression will be evaluated to determine if it is correlated with relapse risk and offers improved prediction of relapse risk over that obtained with standard clinical parameters (cytogenetics, blast count, International Prognostic Scoring System score, minimal residual disease. To account for censoring and the competing risk of non-relapse mortality (NRM), the analysis will be a time-to-event analysis of relapse using Cox regression, with change in expression as a continuous covariate (on a log scale). 8
Time Frame
Baseline and at day 0 within 6 hours of conditioning prior to transplant

10. Eligibility

Sex
All
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: MDS, myelodysplastic syndrome/myeloproliferative neoplasia overlap disorders (including chronic myelomonocytic leukemia [CMML], and MDS/myeloproliferative neoplasm [MPN] unclassifiable syndromes) AML, other than acute promyelocytic leukemia (APL), in first or second remission or with minimal residual disease With Karnofsky index or Lansky Play-Performance scale > 70% on pre-transplant evaluation Able to give informed consent (if > 18 years), or with a legal guardian capable of giving informed consent (if < 18 years) Patients with previous autologous or allogeneic HCT are allowed to enroll DONOR: Human leukocyte antigen (HLA)-identical related donors or DONOR: Unrelated donors matched for HLA-A, B, C, DRB1, and DQB1 as defined by high resolution deoxyribonucleic acid (DNA) typing; mismatch for one HLA allele is allowed DONOR: Donors able to undergo peripheral blood stem cell collection or bone marrow harvest DONOR: Donors in good general health, with a Karnofsky or Lansky play performance score > 90% DONOR: Donors able to give informed consent (if > 18 years), or with a legal guardian capable of giving informed consent (if < 18 years) Exclusion Criteria: Receiving umbilical cord blood With impaired cardiac function as evidenced by ejection fraction < 35% (or, if unable to obtain ejection fraction, shortening fraction of < 26%) or cardiac insufficiency requiring treatment or symptomatic coronary artery disease; patients with a shortening fraction < 26% may be enrolled if approved by a cardiologist With impaired pulmonary function as evidenced by partial pressure of oxygen (pO2) < 70 mm Hg and carbon monoxide diffusing capability test (DLCO) < 70% of predicted or pO2 < 80 mm Hg and DLCO < 60% of predicted; (or, for pediatric patients unable to perform pulmonary function tests, then oxygen (O2) saturation < 92% on room air), or receiving supplementary continuous oxygen With impaired renal function as evidenced by creatinine-clearance < 50% for age, weight, height or serum creatinine > 2 x upper limit of normal or dialysis-dependent With hepatic dysfunction as evidenced by total bilirubin > 2.0 x upper limit of normal or evidence of synthetic dysfunction or severe cirrhosis With hepatic dysfunction as evidenced by aspartate aminotransferase (AST) > 2.0 x upper limit of normal or evidence of synthetic dysfunction or severe cirrhosis With active infectious disease requiring deferral of conditioning, as recommended by an infectious disease specialist With human immunodeficiency virus (HIV)-positivity or active infectious hepatitis With central nervous system (CNS) leukemic involvement not clearing with intrathecal chemotherapy, cranial irradiation or both prior to initiating conditioning (day -6) Patients with active non-hematological malignancies (except non-melanoma skin cancers) or those with non-hematological malignancies who have been rendered with no evidence of disease, but have a greater than 20% chance of having disease recurrence within 5 years; this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy With life expectancy severely limited by diseases other than malignancy Women who are pregnant or lactating With known hypersensitivity to treosulfan or fludarabine (fludarabine phosphate) Receiving another experimental drug within 4 weeks before initiation of conditioning (day -6) Unable to give informed consent (if > 18 years) or with a legal guardian (if < 18 years) unable to give informed consent DONOR: Individuals deemed unable to undergo marrow harvesting or PBSC mobilization and leukapheresis DONOR: Individuals who are HIV-positive DONOR: Individuals with active infectious hepatitis DONOR: Females with a positive pregnancy test DONOR: Persons unable to give informed consent (if > 18 years) or with a legal guardian (if < 18 years) unable to give informed consent
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
H. Joachim Deeg
Organizational Affiliation
Fred Hutch/University of Washington Cancer Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fred Hutch/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Treo/Flu/TBI With Donor Stem Cell Transplant for Patients With Myelodysplastic Syndrome or Acute Myeloid Leukemia

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