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Allogeneic Bone Marrow Transplantation Using Less Intensive Therapy

Primary Purpose

Kidney Cancer, Leukemia, Lymphoma

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
anti-thymocyte globulin
cyclophosphamide
cyclosporine
fludarabine
mycophenolate mofetil
stem cell transplantation
total body irradiation
filgrastim
Sponsored by
Masonic Cancer Center, University of Minnesota
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Kidney Cancer focused on measuring leukemia, lymphoma, myeloma

Eligibility Criteria

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

Inclusion Criteria: Standard patients will be enrolled into Arms 1-6. High risk patients (transplant with aplasia) will be considered separately in Arm 7. Age and Graft criteria (all patients) Patient's < or = 75 years old with a 5/6 or 6/6 related donor match are eligible. Patient's < or = 75 years who have a 7-8/8 HLA-A,B,C,DRB1 allele matched unrelated volunteer marrow and/or peripheral blood stem cell (PBSC) donor match are eligible. Disease Criteria (standard risk patients) Acute myelogenous leukemia Acute lymphocytic leukemia Chronic myelogenous leukemia all types except blast crisis (note treated blast crisis in chronic phase is eligible). Non-Hodgkins lymphoma (NHL), Hodgkins, chronic lymphocytic leukemia, multiple myeloma demonstrating chemosensitive disease Acquired bone marrow failure syndromes Myelodysplastic syndrome of all subtypes including refractory anemia (RA) or all IPSS categories if severe pancytopenia, transfusion requirements not responsive to therapy, or high risk cytogenetics. Blasts must be less than 5%. If >5% requires therapy (induction or Hypomethylating agents) pre-transplant to decrease disease burden. Renal cell cancer, Chronic myeloproliferative disorder, i.e. myelofibrosis Disease Criteria (High risk patients on Arm 7) Patients with refractory leukemia or MDS may be taken to transplant in aplasia after induction or re-induction chemotherapy or radiolabeled antibody. These high risk patients will be analyzed separately in Arm 7. Adequate organ function and performance status (all patients) Exclusion Criteria: Pregnancy or breast feeding Evidence of HIV infection or known HIV positive serology Active serious infection Congenital bone marrow failure syndrome Previous irradiation that precludes the safe administration of an additional dose of 200 cGy of total body irradiation (TBI) Chronic myelogenous leukemia (CML) in refractory blast crisis Intermediate or high grade NHL, mantle cell NHL, and Hodgkins disease that is progressive on salvage therapy. Stable disease is acceptable to move forward provided it is non-bulky. Multiple Myeloma progressive on salvage chemotherapy. DONOR ELIGIBILITY Related will undergo apheresis - if donor is unable to undergo apheresis, a bone marrow harvest is acceptable; unrelated volunteer donors must be able to undergo bone marrow harvest or apheresis. All donors must be able to give informed consent. Donors weighing less than 40 kg (children) will need evaluation by a pediatrician for suitability of the apheresis procedure. Informed consent must be obtained from parent or guardian as applicable for minors.

Sites / Locations

  • Masonic Cancer Center, University of Minnesota

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

High Risk Patients

Standard Risk Patients

Arm Description

Nonmyeloablative conditioning using fludarabine, cyclophosphamide and low dose Total Body Irradiation with or without anti-thymocyte globulin followed by allogeneic hematopoietic stem cell transplantation, immunosuppressive cyclosporine and mycophenolate mofetil and post-transplant use of bone marrow-stimulating filgrastim.

Nonmyeloablative conditioning using fludarabine, cyclophosphamide and low dose Total Body Irradiation with or without anti-thymocyte globulin followed by allogeneic hematopoietic stem cell transplantation, immunosuppressive cyclosporine and mycophenolate mofetil and post-transplant use of bone marrow-stimulating filgrastim.

Outcomes

Primary Outcome Measures

Neutrophil and Donor Cell Engraftment
Successful sustained engraftment is defined as primary neutrophil engraftment by day 42 and e90% donor cells at day 100, with or without DLI. Engraftment based on absolute neutrophil count of donor origin > 0.5 x 10e9 /L for 3 days by day 42

Secondary Outcome Measures

Serious Adverse Events
Safety by development of severe adverse events within 100 days of transplant
Transplant Related Mortality
> 30% transplant related mortality at 100 days (non-relapse).
Overall Survival
Acute Graft-Versus-Host Disease
Grade III-IV graft versus host disease

Full Information

First Posted
March 15, 2006
Last Updated
April 29, 2020
Sponsor
Masonic Cancer Center, University of Minnesota
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1. Study Identification

Unique Protocol Identification Number
NCT00303719
Brief Title
Allogeneic Bone Marrow Transplantation Using Less Intensive Therapy
Official Title
Allogeneic Bone Marrow Transplantation Using Less Intensive Therapy
Study Type
Interventional

2. Study Status

Record Verification Date
April 2020
Overall Recruitment Status
Terminated
Why Stopped
IRB Study Closure
Study Start Date
March 26, 2002 (Actual)
Primary Completion Date
May 8, 2019 (Actual)
Study Completion Date
May 8, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Masonic Cancer Center, University of Minnesota

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
RATIONALE: A peripheral stem cell transplant may be able to replace blood-forming cells that were destroyed by chemotherapy and radiation therapy, or that have become cancer. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclophosphamide and fludarabine together with total-body irradiation followed by cyclosporine and mycophenolate mofetil before the transplant may stop this from happening. PURPOSE: This clinical trial is studying how well giving combination chemotherapy together with radiation therapy followed by cyclosporine and mycophenolate mofetil works in treating patients who are undergoing a donor stem cell transplant for hematologic cancer, metastatic breast cancer, or kidney cancer.
Detailed Description
OBJECTIVES: Determine if a nonmyeloablative regimen comprising cyclophosphamide, fludarabine, and radiotherapy followed by cyclosporine and mycophenolate mofetil provides a prompt and durable donor engraftment in patients with hematologic malignancies or kidney cancer who are undergoing allogeneic stem cell transplantation. Determine the safety of this nonmyeloablative transplantation regimen in these patients. Determine the risk of graft-versus-host-disease in patients treated with this regimen. Determine the antineoplastic potency of nonmyeloablative stem cell transplantation in patients treated with this regimen. Determine the effect of lower doses of daily fludarabine on treatment-related mortality (TRM) OUTLINE: Patients are stratified according to risk (standard vs high). Preparative regimen*: Patients receive cyclophosphamide intravenously (IV) over 2 hours on day -6 and fludarabine IV over 1 hour on days -6 to -2. Patients undergo total body irradiation on day -1. Some patients also receive anti-thymocyte globulin (ATG)** IV every 12 hours on days -6 to -4. Patients who receive ATG* include the following: Related donor recipients who have not received combination chemotherapy within the past 6 months Unrelated donor recipients who have not received combination chemotherapy within the past 3 months Unrelated donor recipients who have received only 1 induction course for the treatment of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), or blastic phase chronic myelogenous leukemia (CML) NOTE: **Patients who underwent prior autologous stem cell transplantation in the past year do not receive ATG. Allogeneic peripheral blood stem cell transplantation (PBSCT): Patients undergo allogeneic PBSCT on day 0. Graft-versus-host-disease prophylaxis: Patients receive cyclosporine IV over 2 hours beginning on day -3 and continuing until at least day 100. Patients also receive mycophenolate mofetil IV or orally twice daily on days -3 to 30. Donor lymphocyte infusion (DLI): Patients without active GVHD but deteriorating donor chimerism may receive DLI IV over 2 hours. After completion of study treatment, patients are followed periodically for 2 years. PROJECTED ACCRUAL: A total of 300 patients will be accrued for this study.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Kidney Cancer, Leukemia, Lymphoma, Multiple Myeloma, Plasma Cell Neoplasm, Myelodysplastic Syndromes
Keywords
leukemia, lymphoma, myeloma

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
High Risk Patients
Arm Type
Experimental
Arm Description
Nonmyeloablative conditioning using fludarabine, cyclophosphamide and low dose Total Body Irradiation with or without anti-thymocyte globulin followed by allogeneic hematopoietic stem cell transplantation, immunosuppressive cyclosporine and mycophenolate mofetil and post-transplant use of bone marrow-stimulating filgrastim.
Arm Title
Standard Risk Patients
Arm Type
Experimental
Arm Description
Nonmyeloablative conditioning using fludarabine, cyclophosphamide and low dose Total Body Irradiation with or without anti-thymocyte globulin followed by allogeneic hematopoietic stem cell transplantation, immunosuppressive cyclosporine and mycophenolate mofetil and post-transplant use of bone marrow-stimulating filgrastim.
Intervention Type
Biological
Intervention Name(s)
anti-thymocyte globulin
Other Intervention Name(s)
ATG
Intervention Description
ATG dose is 15 mg/kg intravenous (IV) every 12 hours for 6 doses on days -6, -5, and -4. Those that should/will receive ATG in the preparative regimen: Related donor recipients who have not had exposure to combination chemotherapy in the 6 months preceding transplant should Unrelated donor recipients who have not had exposure to combination chemotherapy in the 3 months preceding transplant will Unrelated donor recipients who have had only a single induction cycle for the treatment of ALL/AML or MDS or CML blast crisis should Recipients with a prior autologous transplant in the year prior to second transplant do not require ATG.
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide
Other Intervention Name(s)
Cytoxan
Intervention Description
Cyclophosphamide will be given in a two hour infusion, total dose 50 mg/kg on day -6.
Intervention Type
Drug
Intervention Name(s)
cyclosporine
Other Intervention Name(s)
CSA
Intervention Description
Patients will receive cyclosporine A (CSA) therapy beginning on day -3 maintaining a level of >200. For adults the initial dose will be 2.5 mg/kg IV over 2 hours every 12 hours. For children < 40 kg the initial dose will be 2.5 mg/kg IV over 2 hours every 8 hours. Patients will receive CSA until day +100.
Intervention Type
Drug
Intervention Name(s)
fludarabine
Other Intervention Name(s)
Fludara
Intervention Description
Fludarabine 30 mg/m^2/day intravenous (IV) on day -6 through day -2., total dose 150 mg/m^2 for 5 days.
Intervention Type
Drug
Intervention Name(s)
mycophenolate mofetil
Other Intervention Name(s)
MMF
Intervention Description
Mycophenolate mofetil (MMF) 1.5 gram twice a day (BID) or if < 50 kg will be given 15 mg/kg orally(po) BID,beginning on day -3, and discontinue at day +30 or 7 days after engraftment (3 consecutive days of absolute neutrophil count (ANC) > 0.5 x 109 /L).
Intervention Type
Procedure
Intervention Name(s)
stem cell transplantation
Other Intervention Name(s)
peripheral blood stem cell transplantation, bone marrow transplant
Intervention Description
On day 0, if related donor, stem cells are infused via central line. If unrelated donor, marrow/PBSC is infused after arrival and processing on day 0.
Intervention Type
Radiation
Intervention Name(s)
total body irradiation
Other Intervention Name(s)
TBI
Intervention Description
The dose of TBI will be 200 cGy given in a single fraction on day -1.
Intervention Type
Drug
Intervention Name(s)
filgrastim
Other Intervention Name(s)
G-CSF
Intervention Description
Patients with white blood cell (WBC) counts < 2500 any time after stem cell infusion will be started on G-CSF support at Day +5 at a dose of 5 mcg/kg intravenously or subcutaneously (IV/SQ) daily rounded to vial size until absolute neutrophil count (ANC) > 2500 for 2 consecutive days.
Primary Outcome Measure Information:
Title
Neutrophil and Donor Cell Engraftment
Description
Successful sustained engraftment is defined as primary neutrophil engraftment by day 42 and e90% donor cells at day 100, with or without DLI. Engraftment based on absolute neutrophil count of donor origin > 0.5 x 10e9 /L for 3 days by day 42
Time Frame
Day 42 and Day 100
Secondary Outcome Measure Information:
Title
Serious Adverse Events
Description
Safety by development of severe adverse events within 100 days of transplant
Time Frame
Day 100
Title
Transplant Related Mortality
Description
> 30% transplant related mortality at 100 days (non-relapse).
Time Frame
Day 100
Title
Overall Survival
Time Frame
1 year
Title
Acute Graft-Versus-Host Disease
Description
Grade III-IV graft versus host disease
Time Frame
Day 100

10. Eligibility

Sex
All
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Standard patients will be enrolled into Arms 1-6. High risk patients (transplant with aplasia) will be considered separately in Arm 7. Age and Graft criteria (all patients) Patient's < or = 75 years old with a 5/6 or 6/6 related donor match are eligible. Patient's < or = 75 years who have a 7-8/8 HLA-A,B,C,DRB1 allele matched unrelated volunteer marrow and/or peripheral blood stem cell (PBSC) donor match are eligible. Disease Criteria (standard risk patients) Acute myelogenous leukemia Acute lymphocytic leukemia Chronic myelogenous leukemia all types except blast crisis (note treated blast crisis in chronic phase is eligible). Non-Hodgkins lymphoma (NHL), Hodgkins, chronic lymphocytic leukemia, multiple myeloma demonstrating chemosensitive disease Acquired bone marrow failure syndromes Myelodysplastic syndrome of all subtypes including refractory anemia (RA) or all IPSS categories if severe pancytopenia, transfusion requirements not responsive to therapy, or high risk cytogenetics. Blasts must be less than 5%. If >5% requires therapy (induction or Hypomethylating agents) pre-transplant to decrease disease burden. Renal cell cancer, Chronic myeloproliferative disorder, i.e. myelofibrosis Disease Criteria (High risk patients on Arm 7) Patients with refractory leukemia or MDS may be taken to transplant in aplasia after induction or re-induction chemotherapy or radiolabeled antibody. These high risk patients will be analyzed separately in Arm 7. Adequate organ function and performance status (all patients) Exclusion Criteria: Pregnancy or breast feeding Evidence of HIV infection or known HIV positive serology Active serious infection Congenital bone marrow failure syndrome Previous irradiation that precludes the safe administration of an additional dose of 200 cGy of total body irradiation (TBI) Chronic myelogenous leukemia (CML) in refractory blast crisis Intermediate or high grade NHL, mantle cell NHL, and Hodgkins disease that is progressive on salvage therapy. Stable disease is acceptable to move forward provided it is non-bulky. Multiple Myeloma progressive on salvage chemotherapy. DONOR ELIGIBILITY Related will undergo apheresis - if donor is unable to undergo apheresis, a bone marrow harvest is acceptable; unrelated volunteer donors must be able to undergo bone marrow harvest or apheresis. All donors must be able to give informed consent. Donors weighing less than 40 kg (children) will need evaluation by a pediatrician for suitability of the apheresis procedure. Informed consent must be obtained from parent or guardian as applicable for minors.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Erica Warlick, MD
Organizational Affiliation
Masonic Cancer Center, University of Minnesota
Official's Role
Principal Investigator
Facility Information:
Facility Name
Masonic Cancer Center, University of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
22408257
Citation
Warlick E, Ahn KW, Pedersen TL, Artz A, de Lima M, Pulsipher M, Akpek G, Aljurf M, Cahn JY, Cairo M, Chen YB, Cooper B, Deol A, Giralt S, Gupta V, Khoury HJ, Kohrt H, Lazarus HM, Lewis I, Olsson R, Pidala J, Savani BN, Seftel M, Socie G, Tallman M, Ustun C, Vij R, Vindelov L, Weisdorf D. Reduced intensity conditioning is superior to nonmyeloablative conditioning for older chronic myelogenous leukemia patients undergoing hematopoietic cell transplant during the tyrosine kinase inhibitor era. Blood. 2012 Apr 26;119(17):4083-90. doi: 10.1182/blood-2012-02-409763. Epub 2012 Mar 9.
Results Reference
background
PubMed Identifier
30077015
Citation
Warlick ED, DeFor TE, Bejanyan N, Holtan S, MacMillan M, Blazar BR, Dusenbery K, Arora M, Bachanova V, Cooley S, Lazaryan A, McGlave P, Miller JS, Rashidi A, Slungaard A, Vercellotti G, Ustun C, Brunsein C, Weisdorf D. Reduced-Intensity Conditioning Followed by Related and Unrelated Allografts for Hematologic Malignancies: Expanded Analysis and Long-Term Follow-Up. Biol Blood Marrow Transplant. 2019 Jan;25(1):56-62. doi: 10.1016/j.bbmt.2018.07.038. Epub 2018 Aug 1.
Results Reference
background
PubMed Identifier
22430088
Citation
Bachanova V, Burke MJ, Yohe S, Cao Q, Sandhu K, Singleton TP, Brunstein CG, Wagner JE, Verneris MR, Weisdorf DJ. Unrelated cord blood transplantation in adult and pediatric acute lymphoblastic leukemia: effect of minimal residual disease on relapse and survival. Biol Blood Marrow Transplant. 2012 Jun;18(6):963-8. doi: 10.1016/j.bbmt.2012.02.012. Epub 2012 Mar 16.
Results Reference
derived
PubMed Identifier
21403127
Citation
Bachanova V, Sandhu K, Yohe S, Cao Q, Burke MJ, Verneris MR, Weisdorf D. Allogeneic hematopoietic stem cell transplantation overcomes the adverse prognostic impact of CD20 expression in acute lymphoblastic leukemia. Blood. 2011 May 12;117(19):5261-3. doi: 10.1182/blood-2011-01-329573. Epub 2011 Mar 14.
Results Reference
derived
PubMed Identifier
19179301
Citation
Bachanova V, Verneris MR, DeFor T, Brunstein CG, Weisdorf DJ. Prolonged survival in adults with acute lymphoblastic leukemia after reduced-intensity conditioning with cord blood or sibling donor transplantation. Blood. 2009 Mar 26;113(13):2902-5. doi: 10.1182/blood-2008-10-184093. Epub 2009 Jan 28.
Results Reference
derived
Links:
URL
https://doi.org/10.1182/blood-2012-02-409763
Description
Related Info
URL
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310652/
Description
Related Info

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Allogeneic Bone Marrow Transplantation Using Less Intensive Therapy

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