Busulfan, Fludarabine Phosphate, and Anti-Thymocyte Globulin Followed By Donor Stem Cell Transplant and Azacitidine in Treating Patients With High-Risk Myelodysplastic Syndrome and Older Patients With Acute Myeloid Leukemia

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Brief Title

Busulfan, Fludarabine Phosphate, and Anti-Thymocyte Globulin Followed By Donor Stem Cell Transplant and Azacitidine in Treating Patients With High-Risk Myelodysplastic Syndrome and Older Patients With Acute Myeloid Leukemia

Official Title

Phase II Study of the Addition of Azacitidine (NSC#102816) to Reduced-Intensity Conditioning Allogeneic Transplantation for Myelodysplasia (MDS) and Older Patients With AML

Brief Summary

      This phase II clinical trial is studying how well giving busulfan, fludarabine phosphate, and
      anti-thymocyte globulin followed by donor stem cell transplant and azacitidine works in
      treating patients with high-risk myelodysplastic syndrome and older patients with acute
      myeloid leukemia. Giving low doses of chemotherapy, such as busulfan and fludarabine
      phosphate, before a donor stem cell transplant helps stop the growth of cancer cells. It also
      stops 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-vs-tumor effect). Sometimes the transplanted cells from a donor can also make an
      immune response against the body's normal cells. Giving anti-thymocyte globulin before
      transplant and giving azacitidine, tacrolimus, and methotrexate after the transplant may stop
      this from happening.
    

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine if this treatment can improve 2-year progression-free survival (PFS) in
      patients with high risk myelodysplastic syndrome (MDS) and in patients with acute myeloid
      leukemia (AML) >= 60 yrs age

      SECONDARY OBJECTIVES:

      I. To determine the safety and feasibility of using post-transplantation azacitidine.

      II. To determine the ability to use pharmacokinetic-directed busulfan to achieve area under
      the curve (AUC) within 20% of target AUC in > 80% of patients.

      III. To determine the rate of grade II-IV and III-IV acute graft-vs-host disease (GVHD).

      IV. To determine the incidence of extensive chronic GVHD. V. To determine treatment-related
      mortality at 100 days and at 1 year. VI. To determine 5-year overall survival.

      OUTLINE:

      REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate intravenously (IV)
      over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and
      anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor [MSD]) or
      -6 to -4 (matched unrelated donor [MUD]).

      TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0
      or on days 0-1.

      GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus orally (PO) or IV on days -2
      to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6
      (MSD), and 11 (MUD).

      CONSOLIDATION: Beginning on day 42, patients receive azacitidine subcutaneously (SC) or IV on
      days 1-5.

      Treatment repeats every 4 weeks for 6 courses. Blood and bone marrow samples may be collected
      periodically for correlative and pharmacokinetic studies.

      After completion of study treatment, patients are followed up every 6 months for 5 years.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Progression-free Survival

Secondary Outcome

 Overall Survival (OS)

Condition

Acute Myeloid Leukemia

Intervention

Allogeneic Hematopoietic Stem Cell Transplantation

Study Arms / Comparison Groups

 Treatment (chemotherapy and transplant)
Description:  REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor [MSD]) or -6 to -4 (matched unrelated donor [MUD]).
TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0 or on days 0-1.
GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus PO or IV on days -2 to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6 (MSD), and 11 (MUD).
CONSOLIDATION: Beginning on day 42, patients receive azacitidine SC or IV on days 1.

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

Procedure

Estimated Enrollment

68

Start Date

July 15, 2010


Primary Completion Date

November 15, 2015

Eligibility Criteria

        Inclusion Criteria:

          -  Meets one of the following sets of criteria:

               -  Myelodysplastic syndromes (MDS):

                    -  Disease with high-risk features (found either at diagnosis or before
                       initiation of cytotoxic therapy), defined as one of the following:

                         -  International prognostic scoring system (IPSS) risk >= intermediate-2

                         -  Refractory anemia with excess blasts by French-American-British (FAB)
                            classification

                         -  High-risk cytogenetics (either complex or -7)

                    -  Less than 10% bone marrow blasts as determined by bone marrow biopsy within
                       the past 4 weeks (reduction in marrow blast percentage may be achieved with
                       chemotherapy or other therapy)

                    -  Less than 75 years old

               -  Acute myeloid leukemia (AML):

                    -  No FAB M3

                    -  No acute leukemia following blast transformation of prior chronic
                       myelogenous leukemia or other myeloproliferative disease

                    -  Patients with preceding MDS or treatment-related AML are eligible

                    -  Prior central nervous system (CNS) involvement is allowed provided the
                       disease is in remission at transplantation

                    -  Morphologic complete remission (leukemia-free state) is defined as meeting
                       all of the following criteria:

                         -  Bone marrow blasts < 5% (as determined by bone marrow within the past 4
                            weeks), but without requirement for normal peripheral blood counts

                         -  No extramedullary leukemia

                         -  No blasts in peripheral blood

                    -  Achieved complete remission (CR) after no more than 2 courses of induction
                       chemotherapy

                         -  Patients treated with azacitidine or decitabine who achieve a
                            leukemia-free state are eligible (may have required up to 4 courses of
                            therapy to reach this status)

                    -  Age 60 to 74 years

          -  Donors must meet the following criteria:

               -  One of the following:

                    -  HLA-identical sibling (6/6) by serologic typing for class (A, B) and
                       low-resolution molecular typing for class II (DRB1)

                    -  Matched unrelated donor (8/8) by high-resolution molecular typing at HLA-A,
                       -B, -C, and DRB1

               -  No syngeneic donors

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2

          -  Calculated creatinine clearance ≥ 40 mL/min

          -  Bilirubin < 2 mg/dL OR bilirubin 2-3 mg/dL provided direct bilirubin is normal

          -  Aspartate aminotransferase (AST) < 3 times upper limit of normal

          -  Diffusing capacity of the lung for carbon monoxide (DLCO) > 40% with no symptomatic
             pulmonary disease

          -  Left ventricle ejection fraction (LVEF) >= 30% by echocardiogram (ECHO) or multigated
             acquisition (MUGA)

          -  Not pregnant or nursing

          -  Negative pregnancy test

          -  Fertile patients must use effective contraception

          -  No uncontrolled diabetes mellitus or active serious infections

          -  No known hypersensitivity to E. coli-derived products, azacitidine, or mannitol

          -  No human immunodeficiency virus (HIV) infection or active hepatitis B or C

          -  Prior azacitidine or decitabine allowed

               -  No patients who progressed from MDS to AML during treatment with azacitidine or
                  decitabine

          -  At least 4 weeks since prior deoxyribonucleic acid (DNA)-hypomethylating chemotherapy,
             radiotherapy, and/or surgery

          -  No more than 2 courses of consolidation therapy before transplantation (for patients
             with AML)

               -  Any consolidation regimen that does not require transplantation can be used

               -  No more than 6 months from documentation of morphologic CR to transplantation
      

Gender

All

Ages

18 Years - 74 Years

Accepts Healthy Volunteers

No

Contacts

Ravi Vij, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01168219

Organization ID

NCI-2011-02053

Secondary IDs

NCI-2011-02053

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Ravi Vij, Principal Investigator, Alliance for Clinical Trials in Oncology


Verification Date

June 2020