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

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Brief Title

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

Official Title

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 Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Number of Patients With Successful Donor Engraftment

Secondary Outcome

 Number of Patients With Treatment Related Grade III or IV Non-hematological Toxicity

Condition

Myelodysplastic and Myeloproliferative Disorders

Intervention

Campath

Study Arms / Comparison Groups

 HLA-identical sibling transplant
Description:  Recipients of HLA identical sibling stem cell transplants

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

4

Start Date

June 2007

Completion Date

October 2010

Primary Completion Date

February 2009

Eligibility Criteria

        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.
      

Gender

All

Ages

N/A - 70 Years

Accepts Healthy Volunteers

No

Contacts

Rammurti T Kamble, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00579111

Organization ID

19386

Secondary IDs

FAB

Responsible Party

Principal Investigator

Study Sponsor

Baylor College of Medicine

Collaborators

 Center for Cell and Gene Therapy, Baylor College of Medicine

Study Sponsor

Rammurti T Kamble, MD, Principal Investigator, Baylor College of Medicine


Verification Date

March 2016