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Allogeneic HCT Using Nonmyeloablative Host Conditioning With TLI & ATG vs SOC in AML

Primary Purpose

Leukemia, Myeloid, Leukemia, Acute Myeloid Leukemia (AML)

Status
Terminated
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Allogeneic HSCT
Anti-thymocyte globulin (ATG)
Cyclosporine (CSP)
Mycophenolate mofetil (MMF)
Total lymphoid irradiation (TLI)
Methylprednisolone sodium succinate
Best standard care
Sponsored by
Stanford University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Leukemia, Myeloid

Eligibility Criteria

50 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

INCLUSION CRITERIA

  • ≥ 50 years of age and ≤ 75 years of age.
  • De novo acute myelogenous leukemia (AML), based on FAB and WHO criteria.
  • Intermediate or unfavorable cytogenetic abnormalities based on Southwest Oncology Group (SWOG) Cytogenetic Criteria.
  • First morphologic complete remission (CR), or CRp (a complete remission but with low platelets) following 1 or 2 courses of induction therapy, documented no more than 8 weeks prior to the date of enrollment and confirmed at time of enrollment.
  • Karnofsky Performance Score ≥ 60.
  • Suitable for non-myeloablative transplantation or best treatment.
  • Able to understand and willing to sign a written informed consent document.

EXCLUSION CRITERIA

  • AML with favorable cytogenetic features based on SWOG Cytogenetic Criteria
  • AML, either treatment-related or MDS-related
  • Active CNS disease as identified by positive CSF cytospin at time of enrollment.
  • Prior or concurrent malignancies except localized non-melanoma skin malignancies or treated cervical carcinoma in situ. (EXCEPTION: Cancer treated with curative intent > 5 years previously is allowed. EXCEPTION: Low grade lymphoma is allowed as long as active treatment is not required for control of disease)
  • Planned for allogeneic transplant using a full-dose conditioning
  • Life expectancy < 1 year due to diseases other than malignancy
  • Pregnant or breastfeeding.
  • HIV-seropositive.
  • Uncontrolled infection (presumed or documented) with progression after appropriate therapy for greater than one month.
  • Symptomatic coronary artery disease or uncontrolled congestive heart failure. Left ventricular ejection fraction (LVEF) is not required to be measured, however if measured, exclusion if ejection fraction is < 30%.
  • Requiring supplementary continuous oxygen. Diffusing capacity of the lungs for carbon monoxide (DLCO) is not required to be measured, however if it is measured, exclusion if DLCO < 35%.
  • Fulminant liver failure
  • Cirrhosis with evidence of portal hypertension or bridging fibrosis
  • Alcoholic hepatitis
  • Esophageal varices
  • A history of bleeding esophageal varices
  • Hepatic encephalopathy
  • Uncorrectable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time
  • Ascites related to portal hypertension
  • Chronic viral hepatitis with total serum bilirubin > 3 mg/dL
  • Symptomatic biliary disease

Sites / Locations

  • Kaiser Permanente Northern California
  • Cedars-Sinai Medical Center
  • Univeristy of California Davis Medical Center
  • Stanford University School of Medicine
  • West Virginia University Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Allo-HSCT + TLI + ATG

Best Standard Care

Arm Description

Participants achieving complete remission after consolidation therapy & who have 5 of 6 HLA-match sibling donor to provide PBSC harvest for transplant. Pre-transplant subjects receive: Total lymphoid radiation (TLI) Days -11 to -7, and Days -4 to -1 (2 fractions on day -1) Anti-thymocyte globulin (ATG) Days -11 to -7 Methylprednisolone Days -11 to -7 Cyclosporine (CSP) Days -4 to +2 5+ of 6 HLA-matched CD34+ cells on Day 0 Mycophenolate mofetil (MMF), Day 0 to Day +28

Regular medical care for participants who achieve complete remission after standard consolidation therapy, but do not have a 5 of 6 HLA-match sibling donor. Treatment may consist of: Additional consolidation chemotherapy (3-4 cycles of cytarabine +/- an anthracycline agent, or other consolidation) Autologous transplantation Non-Myeloablative unrelated-donor transplant, +/- TLI and ATG conditioning Umbilical cord blood transplantation Haploidentical transplantation

Outcomes

Primary Outcome Measures

Overall Survival (OS)
Overall survival defined as the time interval between the date of attaining a first complete remission (CR) and the date of death from any cause. The outcome is reported as the number of participants alive (without dispersion).

Secondary Outcome Measures

Disease-free Survival (DFS)
Disease-free survival is defined as the time interval between the date of attaining a first complete remission (CR) and the date of relapse. Disease free survival (DFS) will compared to conventional therapy vs Non-myeloablative Host Conditioning (NMA HCT). The outcome is reported as the number of participants which never experienced disease relapse (without dispersion).
Non-relapse Mortality
Non-relapse mortality is defined as death that occurs after therapy, from any cause except a cause associated with relapse. This will be reported as the number of participants experiencing non-relapse mortality (a number without dispersion).
Relapse Rate
Relapse will be determined as ≥ 5% blast cells in the bone marrow, not secondary to regeneration after myelosuppressive therapy; OR emergence of extramedullary leukemia; OR the re-emergence of blasts in the peripheral blood. The outcome will be reported as the number and percentage of participants that meet these criteria (a number without dispersion).
Transplant-related Mortality
Transplant-related mortality will be assessed as any death occurring within 6 months post-transplant, from any cause except relapse. It will be measured at 100 day and 6 months after transplant. The outcome is expressed as at the number of participants experiencing transplant-related mortality (a number without dispersion).
Complete Donor Hematopoietic Cell Chimerism
Complete donor hematopoietic cell chimerism was evaluated in transplant recipients. Complete donor chimerism will be assessed as the presence of > 95% donor T-cells (CD3+) in the blood. The outcome is reported as the percentage of participants that achieve complete donor chimerism, a number without dispersion.
Early Graft Loss
Early graft loss means a failure to achieve donor T-cell chimerism of > 5% at any time after transplant. The outcome is reported as the percentage of participants that experience early graft loss, a number without dispersion.
Patients Completing the Intended Therapy in Both Arms
The assessment for completion of the intended therapy (in both arms) will be reported as the percentage of participants, a number without dispersion

Full Information

First Posted
December 4, 2007
Last Updated
September 11, 2019
Sponsor
Stanford University
Collaborators
Genzyme, a Sanofi Company
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1. Study Identification

Unique Protocol Identification Number
NCT00568633
Brief Title
Allogeneic HCT Using Nonmyeloablative Host Conditioning With TLI & ATG vs SOC in AML
Official Title
A California Cooperative Clinical Study Comparing Allogeneic Hematopoietic Cell Transplantation Using Nonmyeloablative Host Conditioning With Total Lymphoid Irradiation and Anti-thymocyte Globulin Versus Best Standard of Care in Acute Myeloid Leukemia (AML) in First Complete Remission
Study Type
Interventional

2. Study Status

Record Verification Date
August 2019
Overall Recruitment Status
Terminated
Why Stopped
Poor accrual
Study Start Date
August 2007 (Actual)
Primary Completion Date
December 31, 2015 (Actual)
Study Completion Date
December 31, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Stanford University
Collaborators
Genzyme, a Sanofi Company

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Acute myeloid leukemia (AML) is a cancer of the bone marrow that mostly affects older adults. Even with the best chemotherapy, two-year disease-free survival is achieved in a minority of patients. Bone marrow transplantation from a sibling donor may improve cure rates; however, patients over 50 years of age have a high risk of complications and therefore generally are excluded from this treatment option. Recently our group developed a transplantation strategy for older cancer patients that protects against transplant-associated complications, yet does not interfere with the ability of the transplanted donor cells to destroy cancer cells. With this new method, we can now safely evaluate transplantation as a curative therapy for AML patients over the age of 50. We have assembled clinical and scientific researchers throughout the state of California to study and compare bone marrow transplantation using our new approach with the best standard of care chemotherapy in AML patients over the age of 50. The results of this study have the potential to establish a new treatment standard that will improve survival of older AML patients.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia, Myeloid, Leukemia, Acute Myeloid Leukemia (AML)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
Treatment assignment was based on availability of an HLA-matched donor.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
58 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Allo-HSCT + TLI + ATG
Arm Type
Experimental
Arm Description
Participants achieving complete remission after consolidation therapy & who have 5 of 6 HLA-match sibling donor to provide PBSC harvest for transplant. Pre-transplant subjects receive: Total lymphoid radiation (TLI) Days -11 to -7, and Days -4 to -1 (2 fractions on day -1) Anti-thymocyte globulin (ATG) Days -11 to -7 Methylprednisolone Days -11 to -7 Cyclosporine (CSP) Days -4 to +2 5+ of 6 HLA-matched CD34+ cells on Day 0 Mycophenolate mofetil (MMF), Day 0 to Day +28
Arm Title
Best Standard Care
Arm Type
Active Comparator
Arm Description
Regular medical care for participants who achieve complete remission after standard consolidation therapy, but do not have a 5 of 6 HLA-match sibling donor. Treatment may consist of: Additional consolidation chemotherapy (3-4 cycles of cytarabine +/- an anthracycline agent, or other consolidation) Autologous transplantation Non-Myeloablative unrelated-donor transplant, +/- TLI and ATG conditioning Umbilical cord blood transplantation Haploidentical transplantation
Intervention Type
Procedure
Intervention Name(s)
Allogeneic HSCT
Other Intervention Name(s)
Hematopoietic stem cell transplantation (HSCT), Peripheral blood stem cell (PBSC) transplantation
Intervention Description
Allogeneic, 5+ of 6 HLA-matched PBSC transplant from sibling, mobilized to target of 5 x 10e6 CD34+ cells/kg and < 7 x 10e8 CD3+ cells/kg.
Intervention Type
Drug
Intervention Name(s)
Anti-thymocyte globulin (ATG)
Other Intervention Name(s)
Thymoglobulin, Anti-thymocyte globulin (rabbit) (ATG)
Intervention Description
1.5 mg/kg for 5 days by IV
Intervention Type
Drug
Intervention Name(s)
Cyclosporine (CSP)
Other Intervention Name(s)
Ciclosporin, cyclosporin A, cyclosporin
Intervention Description
6.25 mg/kg twice daily oral
Intervention Type
Drug
Intervention Name(s)
Mycophenolate mofetil (MMF)
Other Intervention Name(s)
Cellcept
Intervention Description
15 mg/kg twice daily oral
Intervention Type
Radiation
Intervention Name(s)
Total lymphoid irradiation (TLI)
Intervention Description
80 cGy/fraction radiotherapy in 10 fractions.
Intervention Type
Drug
Intervention Name(s)
Methylprednisolone sodium succinate
Other Intervention Name(s)
Solumedrol, Medrol, Depo-Medrol, P-Care D40, P-Care D80
Intervention Description
1.0 mg/kg for 5 days by IV
Intervention Type
Drug
Intervention Name(s)
Best standard care
Other Intervention Name(s)
Standard of Care (physician discretion), Regular medical care
Intervention Description
Intervention consist of: Consolidation chemotherapy (3-4 cycles of cytarabine +/- an anthracycline agent, or other consolidation) Autologous transplantation Non-Myeloablative unrelated-donor transplant, +/- TLI and ATG conditioning Umbilical cord blood transplantation Haploidentical transplantation
Primary Outcome Measure Information:
Title
Overall Survival (OS)
Description
Overall survival defined as the time interval between the date of attaining a first complete remission (CR) and the date of death from any cause. The outcome is reported as the number of participants alive (without dispersion).
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Disease-free Survival (DFS)
Description
Disease-free survival is defined as the time interval between the date of attaining a first complete remission (CR) and the date of relapse. Disease free survival (DFS) will compared to conventional therapy vs Non-myeloablative Host Conditioning (NMA HCT). The outcome is reported as the number of participants which never experienced disease relapse (without dispersion).
Time Frame
2 years
Title
Non-relapse Mortality
Description
Non-relapse mortality is defined as death that occurs after therapy, from any cause except a cause associated with relapse. This will be reported as the number of participants experiencing non-relapse mortality (a number without dispersion).
Time Frame
2 years
Title
Relapse Rate
Description
Relapse will be determined as ≥ 5% blast cells in the bone marrow, not secondary to regeneration after myelosuppressive therapy; OR emergence of extramedullary leukemia; OR the re-emergence of blasts in the peripheral blood. The outcome will be reported as the number and percentage of participants that meet these criteria (a number without dispersion).
Time Frame
2 years
Title
Transplant-related Mortality
Description
Transplant-related mortality will be assessed as any death occurring within 6 months post-transplant, from any cause except relapse. It will be measured at 100 day and 6 months after transplant. The outcome is expressed as at the number of participants experiencing transplant-related mortality (a number without dispersion).
Time Frame
100 days and 6 months
Title
Complete Donor Hematopoietic Cell Chimerism
Description
Complete donor hematopoietic cell chimerism was evaluated in transplant recipients. Complete donor chimerism will be assessed as the presence of > 95% donor T-cells (CD3+) in the blood. The outcome is reported as the percentage of participants that achieve complete donor chimerism, a number without dispersion.
Time Frame
2 years
Title
Early Graft Loss
Description
Early graft loss means a failure to achieve donor T-cell chimerism of > 5% at any time after transplant. The outcome is reported as the percentage of participants that experience early graft loss, a number without dispersion.
Time Frame
2 years
Title
Patients Completing the Intended Therapy in Both Arms
Description
The assessment for completion of the intended therapy (in both arms) will be reported as the percentage of participants, a number without dispersion
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
50 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
INCLUSION CRITERIA ≥ 50 years of age and ≤ 75 years of age. De novo acute myelogenous leukemia (AML), based on FAB and WHO criteria. Intermediate or unfavorable cytogenetic abnormalities based on Southwest Oncology Group (SWOG) Cytogenetic Criteria. First morphologic complete remission (CR), or CRp (a complete remission but with low platelets) following 1 or 2 courses of induction therapy, documented no more than 8 weeks prior to the date of enrollment and confirmed at time of enrollment. Karnofsky Performance Score ≥ 60. Suitable for non-myeloablative transplantation or best treatment. Able to understand and willing to sign a written informed consent document. EXCLUSION CRITERIA AML with favorable cytogenetic features based on SWOG Cytogenetic Criteria AML, either treatment-related or MDS-related Active CNS disease as identified by positive CSF cytospin at time of enrollment. Prior or concurrent malignancies except localized non-melanoma skin malignancies or treated cervical carcinoma in situ. (EXCEPTION: Cancer treated with curative intent > 5 years previously is allowed. EXCEPTION: Low grade lymphoma is allowed as long as active treatment is not required for control of disease) Planned for allogeneic transplant using a full-dose conditioning Life expectancy < 1 year due to diseases other than malignancy Pregnant or breastfeeding. HIV-seropositive. Uncontrolled infection (presumed or documented) with progression after appropriate therapy for greater than one month. Symptomatic coronary artery disease or uncontrolled congestive heart failure. Left ventricular ejection fraction (LVEF) is not required to be measured, however if measured, exclusion if ejection fraction is < 30%. Requiring supplementary continuous oxygen. Diffusing capacity of the lungs for carbon monoxide (DLCO) is not required to be measured, however if it is measured, exclusion if DLCO < 35%. Fulminant liver failure Cirrhosis with evidence of portal hypertension or bridging fibrosis Alcoholic hepatitis Esophageal varices A history of bleeding esophageal varices Hepatic encephalopathy Uncorrectable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time Ascites related to portal hypertension Chronic viral hepatitis with total serum bilirubin > 3 mg/dL Symptomatic biliary disease
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Robert Lowsky
Organizational Affiliation
Stanford University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Kaiser Permanente Northern California
City
Hayward
State/Province
California
ZIP/Postal Code
94545
Country
United States
Facility Name
Cedars-Sinai Medical Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90048
Country
United States
Facility Name
Univeristy of California Davis Medical Center
City
Sacramento
State/Province
California
ZIP/Postal Code
95817
Country
United States
Facility Name
Stanford University School of Medicine
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
West Virginia University Hospital
City
Morgantown
State/Province
West Virginia
ZIP/Postal Code
26506
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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Allogeneic HCT Using Nonmyeloablative Host Conditioning With TLI & ATG vs SOC in AML

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