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Reduced Intensity Preparative Regimen Followed by Stem Cell Transplant (FAB)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00579111
Recruitment Status : Terminated (slow accrual)
First Posted : December 21, 2007
Results First Posted : August 9, 2012
Last Update Posted : May 4, 2016
Center for Cell and Gene Therapy, Baylor College of Medicine
The Methodist Hospital System
Information provided by (Responsible Party):
Rammurti Kamble, Baylor College of Medicine

Tracking Information
First Submitted Date  ICMJE December 19, 2007
First Posted Date  ICMJE December 21, 2007
Results First Submitted Date  ICMJE July 3, 2012
Results First Posted Date  ICMJE August 9, 2012
Last Update Posted Date May 4, 2016
Study Start Date  ICMJE June 2007
Actual Primary Completion Date February 2009   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 21, 2012)
Number of Patients With Successful Donor Engraftment [ Time Frame: 100 days ]
Each patient will be classified as a success or failure. A success will be defined as engraftment of at least 35% of cells 100 days after transplant.
Original Primary Outcome Measures  ICMJE
 (submitted: December 20, 2007)
If fewer than or equal to 15/20 exhibit response and more than 11/20 without toxicity.If more than 15/20 exhibit response and fewer than or equal to 11/20 without toxicity. [ Time Frame: 24 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 29, 2016)
Number of Patients With Treatment Related Grade III or IV Non-hematological Toxicity [ Time Frame: 100 days ]
Original Secondary Outcome Measures  ICMJE
 (submitted: December 20, 2007)
If fewer than or equal to 39/50 exhibit response and more than 30/50 without toxicity If more than 39/50 exhibit response and fewer than or equal to 30/50 without toxicity. [ Time Frame: 24 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Reduced Intensity Preparative Regimen Followed by Stem Cell Transplant (FAB)
Official Title  ICMJE Reduced-Intensity Preparative Regiment With Fludarabine, Busulfan, And Alemtuzumab (Campath 1H) Followed By Allogeneic Hematopoietic Stem Cell Transplant For Malignant And Non-Malignant Hematological Diseases
Brief Summary

Blood disorders such as leukemia or lymphoma or hemoglobinopathies can benefit from receiving an allogeneic (meaning that the cells are from a donor) stem cell transplant. Stem cells are created in the bone marrow. They grow into different types of blood cells that the body needs, including red blood cells, white blood cells, and platelets. In a transplant, the body's stem cells would be killed and then replaced by stem cells from the donor. Usually, patients are given very high doses of chemotherapy (drugs which kill cancer cells) prior to receiving a stem cell transplant. However, patients that are older, have received several prior treatments, or have other organ diseases are at a high risk of getting life-threatening treatment-related side effects from high doses of chemotherapy. Over the past several years, some doctors have begun to use lower doses of chemotherapy for preparing patients for a stem cell transplant.

A condition that can occur after a stem cell transplant from a donor is Graft Versus Host Disease (GVHD). It is a rare but serious disorder that can strike persons whose immune system is suppressed and have received either a blood transfusion or a bone marrow transplant. Symptoms may include skin rash, intestinal problems similar to inflammation of the bowel and liver dysfunction.

This research study uses a combination of lower-dose chemotherapy agents that is slightly different from those that have been used before.

The medicines that will be used in this study are Fludarabine, Busulfan, both chemotherapy medicines, and Campath. Campath is a monoclonal antibody (a type of substance produced in the laboratory that binds to cancer cells). It helps the immune system see the cancer cell as something that needs to be destroyed.

This research study will help us learn if using Fludarabine, Busulfan and Campath prior to an allogeneic stem cell transplant can provide treatment for blood disorders while decreasing the incidence of side effects.

Detailed Description

Allogeneic stem cell transplantation with high-dose chemotherapy affords a better chance of cure of malignant and non-malignant hematological diseases compared to autologous transplantation, because of the lack of stem cell contamination and the immune mediated graft vs. leukemia effect. Unfortunately, high-dose chemotherapy and allogeneic stem cell transplantation has a substantial treatment related mortality, that is particularly high in older patients (greater than 50 yrs of age), or in those with co-morbidities such as congestive heart disease and pulmonary disease. Patients who have pre-existing infections or who have had multiple relapses with prior chemotherapy are also at high risk. In all these groups, treatment related mortality may exceed 50%, making them ineligible for high-dose chemotherapy and allogeneic stem cell transplantation.

Recently interest has increased in using less toxic chemotherapy protocols that are termed submyeloablative. The intent is to allow partial engraftment of a donor immune and hemopoietic systems with subsequent progressive replacement of the host's own hemopoiesis and immunity. As the donor immune system becomes established, patients may develop full donor chimerism, without passing through the period of prolonged aplasia associated with conventional conditioning regimens, and with less of the associated toxicity. Preliminary results in high-risk patients have shown treatment related mortality (TRM) of 15-20%, versus 50% expected, with an overall survival rate of 70-80% at 1-2 years post transplant.

As might be anticipated, the major problem with sub-ablative conditioning is that the graft failure rate is increased, with published figures of 5-30% versus 1-5% predicted in fully ablated patients. The incorporation of lymphodepleting antibodies in the preliminary conditioning regimen may allow these rejection rates to be diminished. Moreover, a highly efficient lymphodepleting MAb or MAb combination might be successfully substituted in part or in whole for cytotoxic and immunosuppressive drugs, further increasing the safety and efficacy of the subablative approach to stem cell transplantation. Our own data using the crude polyclonal mixture of antibodies in ATG as a component of pre-transplant conditioning revealed an improvement in engraftment during matched unrelated donor transplantation.The lymphodepleting monoclonal antibody Campath IH has many of the properties desired for this application, and we propose to incorporate it in our conditioning regimen. Since CAMPATH1H persists after infusion, we would expect it to have additional anti-GvHD effector function, further reducing treatment related mortality (TRM).

The following preparative regimen will be delivered to all patients:

  1. Busulfan 3.2 mg/kg/day IV daily for 2 days, infused over 3 hours, on Day -5 and Day -4
  2. Fludarabine 30mg/m2/day IV daily for 4 days on Day -5 to D -2
  3. Campath 10 mg/day IV daily for 3 days on days -6 to D-4.

Because CAMPATH-1H infusions will provide a persisting level of antibody over the transplant period, it will contribute to anti-GvHD activity. Additional Graft vs. host disease prophylaxis will consist of FK506 administered from Day-2.

The stem cells will be infused on day 0.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Myelodysplastic and Myeloproliferative Disorders
  • Acute Myelogenous Leukemia
  • Acute Lymphoblastic Leukemia
  • Chronic Myelogenous Leukemia
  • Multiple Myeloma
  • Plasma Cell Dyscrasia
  • Lymphoproliferative Disorders
  • Hematologic Diseases
Intervention  ICMJE
  • Drug: Campath
    10 mg/day IV daily for 3 days on days -6 to D-4. Campath may be omitted from the conditioning regimen for patients with malignant diseases and matched related donor transplants
    Other Name: Alemtuzumab
  • Drug: Busulfan
    3.2 mg/kg/day IV daily for 2 days, infused over 3 hours, on Day -5 and Day -4
  • Drug: Fludarabine
    30mg/m2/day IV daily for 4 days on Day -5 to D -2
  • Procedure: Hematopoietic stem cell infusion
    Peripheral blood stem cells when possible. Bone marrow cells will be used if peripheral blood cells are insufficient or unavailable.
  • Drug: FK-506
    FK-506 at a dose of 0.03 mg/kd/day will be administered via continuous infusion over 24 hours from 4pm on Day -2 until engraftment or when the patient is able to take PO, then 0.03 mg/kg PO every 12 hours.
    Other Name: Tacrolimus
Study Arms  ICMJE
  • Experimental: HLA-identical sibling transplant
    Recipients of HLA identical sibling stem cell transplants
    • Drug: Campath
    • Drug: Busulfan
    • Drug: Fludarabine
    • Procedure: Hematopoietic stem cell infusion
    • Drug: FK-506
  • Experimental: Unrelated Matched or Single Antigen Mismatched transplant
    Recipients of unrelated matched or single antigen mismatched donor stem cell transplant or single antigen mismatched family donor stem cell transplants
    • Drug: Campath
    • Drug: Busulfan
    • Drug: Fludarabine
    • Procedure: Hematopoietic stem cell infusion
    • Drug: FK-506
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: June 21, 2012)
Original Estimated Enrollment  ICMJE
 (submitted: December 20, 2007)
Actual Study Completion Date  ICMJE October 2010
Actual Primary Completion Date February 2009   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Diagnosis of myelodysplastic and myeloproliferative disorders, acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, multiple myeloma, plasma cell dyscrasia, lymphoproliferative disorders (non-Hodgkin lymphoma, hairy cell leukemia, chronic lymphocytic leukemia, and Hodgkin's disease) and non malignant hematologic diseases considered treatable with an allogeneic transplant including but not limited to bone marrow failure syndrome, hemoglobinopathy and severe immunodeficiency states.
  2. Performance status 0-2 on Zubrod scale
  3. Ejection fraction > 30%
  4. AST/ALT and bilirubin not > 4 times normal
  5. FEV1 greater than 1.0 and diffusion capacity > 40%
  6. Age birth to 70 years of age
  7. Conditions that increase treatment related mortality (need more than one to be eligible):

    • Age > 35 years
    • EF of less than 45%
    • DLCO less than 50% or FEV1 50-75% of predicted value
    • Diabetes mellitus
    • Renal insufficiency, defined by increase in serum creatinine level of 1.5 times ULN or decrease in GFR by 25%
    • Prior recent history of systemic fungal infection
    • 3rd or greater remission of AML or ALL
    • More than 1 year of diagnosis (CML or myeloma patients only)
    • Multiple types of treatment regimens (equal to or more than 3)
    • Prior autologous or allogeneic stem cell transplantation
    • Significant Grade III or IV neurologic or hepatic toxicity as defined by NCI CTC toxicity from previous treatment
    • No matched sibling donor
  8. Available healthy donor without any contraindications for donation

    • 5/6 or 6/6 related
    • 5/6 or 6/6 unrelated (molecular typing for DRB1)
  9. Patient and/or responsible person able to understand and sign consent
  10. For women of childbearing potential, negative pregnancy test

Exclusion Criteria:

  1. Pregnant and lactating women or women unwilling to use contraception.
  2. HIV positive patient.
  3. Uncontrolled intercurrent infection.
  4. Refractory AML or ALL.
  5. Untreated blast crisis for CML.
  6. Uncontrolled high-grade lymphoproliferative disease/lymphoma.
  7. Unstable angina and uncompensated congestive heart failure (Zubrod of 3 or greater).
  8. Severe chronic pulmonary disease requiring oxygen (Zubrod of 3 or greater).
  9. Hemodialysis dependent.
  10. Active Hepatitis or cirrhosis with total bilirubin, SGOT, and SGPT greater than 3 x normal.
  11. Serum creatinine >2x ULN.
  12. Unstable cerebral vascular disease and recent hemorrhagic stroke (less than 6 months).
  13. Active CNS disease from hematological disorder.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 70 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT00579111
Other Study ID Numbers  ICMJE 19386
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Rammurti Kamble, Baylor College of Medicine
Study Sponsor  ICMJE Baylor College of Medicine
Collaborators  ICMJE
  • Center for Cell and Gene Therapy, Baylor College of Medicine
  • The Methodist Hospital System
Investigators  ICMJE
Principal Investigator: Rammurti T Kamble, MD Baylor College of Medicine
PRS Account Baylor College of Medicine
Verification Date March 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP