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Clinical Trials

MainTitle

Allogeneic Transplant in HIV Patients (BMT CTN 0903)

This study is ongoing, but not recruiting participants.
Sponsor
Medical College of Wisconsin

Collaborator
National Heart, Lung, and Blood Institute (NHLBI)
National Cancer Institute (NCI)
Blood and Marrow Transplant Clinical Trials Network
National Marrow Donor Program

Information provided by (Responsible Party)
Medical College of Wisconsin
ClinicalTrials.gov Identifier
NCT01410344

First received: August 3, 2011
Last updated: August 29, 2017
Last Verified: August 2017
History of Changes
Purpose

Purpose

The rationale for this trial is to demonstrate the feasibility and safety of allogeneic HCT for patients with chemotherapy-sensitive hematological malignancies and coincident HIV-infection. In particular, the trial will focus on the 100-day non-relapse mortality as an indicator of the safety of transplant in this patient population. Correlative assays will focus upon the incidence of infectious complications in this patient population, the evolution of HIV infection and immunological reconstitution. Where feasible (and when this can be accomplished without compromise of either the donor quality or the timeliness of transplantation), an attempt will be made to identify donors who are homozygotes for the delta32 mutation for CCR5.

Condition Intervention Phase
Leukemia
Lymphoma
HIV

Drug : Fludarabine and Busulfan
Drug : Fludarabine and Melphalan
Drug : Busulfan and Fludarabine
Drug : Cyclophosphamide and Total Body Irradiation
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Allogeneic Hematopoietic Cell Transplant for Hematological Cancers and Myelodysplastic Syndromes in HIV-Infected Individuals (BMT CTN #0903)

Further study details as provided by Medical College of Wisconsin:

Primary Outcome Measures

  • Non-Relapse Mortality [ Time Frame: 100 days ]
    The events for non-relapse mortality are death due to any cause other than relapse of the underlying malignancy
Secondary Outcome Measures:
  • Disease Status Following Transplant [ Time Frame: 100 days ]
    Patients will be assessed for disease status at Day 100 post-HCT: complete remission, partial remission (HL, NHL), stable disease (HL, NHL), relapse.
  • Chimerism [ Time Frame: 4 weeks, 100 days and 6 months ]
    Blood samples will be evaluated for T cell and myeloid chimerism at 4 weeks, 100 days and 6 months post-transplant.
  • Incidence of Infections [ Time Frame: Date of transplant through one year post-transplant ]
    Microbiologically documented infections will be reported by site of disease, date of onset, severity, and resolution, if any.
  • Six Month Overall Survival [ Time Frame: Six months post transplant ]
    Overall survival is defined as time from transplant to death or last follow-up.
  • Acute Graft-versus-Host Disease (GVHD) [ Time Frame: 100 Days ]
    Acute GVHD will be graded according to the BMT CTN Manual of Procedures. The time to onset of acute grades II-IV GVHD and grades III-IV GVHD will be recorded, as well as the maximum grade achieved.
  • Chronic Graft-versus-Host Disease (GVHD) [ Time Frame: 100 days, 6 months, 2 years ]
    Chronic GVHD will be scored according to the BMT CTN Manual of Procedures. The time to onset of limited and extensive chronic GVHD will be recorded.
  • Immunologic Reconstitution [ Time Frame: 8 Weeks; 6, 12 and 24 Months ]
    This will be measured in all patients at 8 weeks, 6 months, 12 months and 24 months post-transplant. Tests to be performed on peripheral blood at those time points include CD2, CD3, CD4, CD8, CD19, CD3+/CD25+, CD45 RA/RO, CD56+/CD3-, and quantitative immunoglobulins (IgM, IgG and IgA).
  • Impact of Therapy on the HIV Reservoir [ Time Frame: Day 100, 6 Months, 12 Months, and 24 Months ]
    HIV-1 RNA in plasma will be measured by standard real-time reverse transcription polymerase chain reaction (RT-PCR) (detection limit 40 copies/ml) and by the investigational single copy assay (SCA, detection limit 0.38 copy/ml). HIV-1 DNA in peripheral blood mononuclear cells (PBMCs) and other cells will be quantified using the same primers and probes used for SCA but without a reverse transcription step. HIV-1 RNA levels will be measured in plasma prior to the initiation of ablative chemotherapy, and at Day +100, 1 and 2 years post-transplant.
  • Hematologic Function [ Time Frame: Day 100, 6 months ]
    Hematologic function will be defined by absolute neutrophil count (ANC) greater than 1500, Hemoglobin greater than 10g/dL without transfusion support, and platelets greater than 100,000 and measured at Day 100 and 6 months. Use of growth factors will be noted.

Enrollment: 18
Study Start Date: September 2011
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)

Arms Assigned Interventions
Other: Allogeneic Transplant
One regimen from either reduced-intensity conditioning (RIC) (Fludarabine and Busulfan; or Fludarabine and Melphalan) or myeloablative conditioning (MAC) (Busulfan and Fludarabine; or Cyclophosphamide and Total Body Irradiation) will be administered prior to allogeneic hematopoietic cell transplantation (HCT).
Drug: Fludarabine and Busulfan
    RIC Regimen (Flu/Bu): Fludarabine total dose: 120-180 mg/m^2, Busulfan: ≤ 8 mg/kg PO or 6.4 mg/kg IV). Recommended regimen:
    • Days -6 to -2: Flu (30 mg/m^2/day, total dose of 150 mg/m^2)
    • Days -5 to -4: Busulfan (4mg/kg/day PO or 3.2 mg/kg IV, 130 mg/m^2/day, total dose of 8 mg/kg PO or 6.4 mg/kg IV, or 260 mg/m^2 IV, respectively)
    • Patients with a creatinine clearance of 40-70 ml/min (measured or calculated) should have a 20 percent dose reduction in Fludarabine dosage.
    • Busulfan will be dosed according to the recipient's ideal body weight (IBW), unless the patient weighs more than 125 percent of IBW, in which case the drug will be dosed according to the adjusted IBW.

    Other Name: Fludara and Busulfex
    Drug: Fludarabine and Melphalan
      RIC Regimen (Flu/Mel): Fludarabine total dose: 120-180 mg/m^2, Melphalan total dose: less than or equal to 150 mg/m^2. Recommended regimen:
      • Days -5 to -2: Flu (30mg/m^2/day, total dose of 120 mg/m^2)
      • Day -1: Mel (140mg/m^2)
      • Patients with a creatinine clearance of 40-70 ml/min (measured or calculated) should have a 20 percent dose reduction in Fludarabine dosage.

      Other Name: Fludara and Alkeran
      Drug: Busulfan and Fludarabine
        MAC Regimen (Bu/Flu): Fludarabine total dose: 120-180mg/m^2 Busulfan total dose less than or equal to 16mg/kg PO or 12.8 mg/kg IV. Recommended regimen:
        • Days -5 to -2: Busulfan (4 mg/kg/day PO with Bu Css 900 plus/equal to 100 ng/mL (or per institutional standard), 3.2 mg/kg/day IV or 130 mg/m^2/day IV; total dose of 16 mg/kg, 12.8 mg/kg or 520 mg/m^2, respectively)
        • Days -5 to -2: Flu (30 mg/m^2/day, total dose of 120 mg/m^2)
        • Patients with a creatinine clearance of 40-70 ml/min (measured or calculated) should have a 20 percent dose reduction in Fludarabine dosage.
        • Busulfan will be dosed according to the recipient's ideal body weight (IBW), unless the patient weighs more than 125 percent of IBW, in which case the drug will be dosed according to the adjusted IBW.

        Other Name: Busulfex and Fludara
        Drug: Cyclophosphamide and Total Body Irradiation
          MAC Regimen (Cy/TBI): Cyclophosphamide total dose: 120 mg/kg, Fractionated TBI total dose: 1200-1420 cGy Recommended regimen:
          • Days -7 to -4: TBI (total dose of 1200-1420 cGy)
          • Days -3 to -2: Cy (60 mg/kg/day, total dose of 120 mg/kg)
          • Cyclophosphamide will be dosed according to the recipient's ideal body weight (IBW), unless the patient weighs less than IBW, in which case the drug will be dosed according to the actual body weight.

          Other Name: Cytoxan® and radiation

          Detailed Description:

          The study is designed to evaluate the feasibility and safety of reduced-intensity and fully-ablative allogeneic hematopoietic cell transplantation (HCT) for patients with hematological malignancies or myelodysplastic syndromes (MDS) who have HIV infection. The goal of the study is to assess the 100 day Non-relapse Mortality as well as immunological reconstitution in this patient population. Where feasible, an attempt will be made to identify human leukocyte antigen (HLA)-compatible hematopoietic stem cell donors who are homozygotes for the delta32 mutation of the chemokine receptor 5 (CCR5delta32). Patients will undergo a treatment plan review prior to registration on the trial. All patients will undergo allogeneic HCT from a matched sibling or unrelated donor.

          Eligibility

          Eligibility

          Ages Eligible for Study: 15 Years and older  
          Sexes Eligible for Study: All  
          Accepts Healthy Volunteers: No  

          Criteria

          Inclusion Criteria:

            1. HIV-1 infection, as documented by a rapid HIV test or any FDA-Approved HIV-1 Enzyme or Chemiluminescence Immunoassay (E/CIA) test kit and confirmed by Western Blot at any time prior to study entry. HIV antigen, plasma HIV-1 RNA, or a secondary antibody test by a method other than rapid HIV and E/CIA is acceptable as an alternative test. Alternatively, if a rapid HIV test or any FDA-Approved HIV-1 Enzyme or Chemiluminescence Immunoassay (E/CIA) test is not available, two HIV-1 RNA values ≥ 2000 copies/mL at least 24 hours apart performed by any laboratory that has CLIA certification, or its equivalent, may be used to document infection.
            2. Patients must be willing to comply with effective Antiretroviral Therapy.
            3. Patients must be ≥ 15 years of age.
            4. Hematological malignancy associated with a poor prognosis with medical therapy alone. Diagnoses to be included:
                1. Patients with the diagnosis of Acute Myeloid or Lymphocytic Leukemia (AML or ALL) in first or second complete remission.
                2. Patients with advanced myelodysplastic syndromes (MDS), including those with International Prognostic Scoring System (IPSS) Int-2 and high-risk disease with less than 10% marrow blasts and no circulating myeloblasts after most recent therapy. Patients with acute leukemia that develops from a pre-existing MDS must meet the inclusion criteria for patients with AML detailed above.
                3. Hodgkin Lymphoma beyond first remission achieving at least a partial response to most recent therapy with no evidence of progression prior to transplant.
                4. Non-Hodgkin Lymphoma beyond first remission achieving at least a partial response to most recent therapy with no evidence of progression prior to transplant.
              1. Donor/Recipient HLA Matching:
                  1. Related donor: must be an 8/8 match at HLA-A, -B, -C, (serologic typing or higher resolution) and -DRB1 (at high resolution using DNA based typing). A 7/8 related donor match is permitted only if an 8/8 unrelated donor cannot be identified.
                  2. Unrelated donor: must be a 7/8 or 8/8 match at HLA-A, -B, -C, and -DRB1 (at high resolution using DNA based typing).
                1. Patients with adequate organ function as measured by:
                    1. Cardiac: Left ventricular ejection fraction at rest ≥ 40% demonstrated by Multi Gated Acquisition Scan (MUGA) or echocardiogram. Patients with known heart disease must have a functional status no worse than American Heart Association Class I defined as patients with cardiac disease but without resulting limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.
                    2. Hepatic:

                    i. Total Bilirubin < 2.0 mg/dL (except for isolated hyperbilirubinemia attributed to Gilbert syndrome or antiretroviral therapy as specified in Appendix E) and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 5x the upper limit of normal.

                  ii. Concomitant Hepatitis: Patients with chronic hepatitis B or C may be enrolled on the trial providing the above bilirubin and transaminase criteria are met. In addition, there must be no clinical or pathologic evidence of irreversible chronic liver disease, and there must be no active viral replication as evidenced by an undetectable hepatitis viral load by a PCR-based assay.

                c) Renal: Creatinine clearance (calculated creatinine clearance is permitted) > 40 mL/min.

              d) Pulmonary: Diffusing capacity of the lung for carbon monoxide (DLCO), forced expiratory volume in one second (FEV1), or forced vital capacity (FVC) ≥ 45% of predicted (corrected for hemoglobin).
          1. Signed Informed Consent


          Exclusion Criteria:
            1. Karnofsky/Lansky performance score < 70%.
            2. Active central nervous system (CNS) malignancy; however, patients with a history of positive Cerebrospinal fluid (CSF) cytology that has become negative with intrathecal chemotherapy are eligible.
            3. Uncontrolled bacterial, viral or fungal infection (currently taking medication and with progression or no clinical improvement).
            4. Active Cytomegalovirus (CMV) retinitis or other CMV-related organ dysfunction.
            5. AIDS related syndromes or symptoms that pose a perceived excessive risk for transplantation-related morbidity as determined by the principal investigator.
            6. Untreatable HIV infection due to multidrug antiretroviral resistance. Patients with a detectable viral load > 750 copies/ml should be evaluated with an HIV drug resistance test (HIV-1 genotype). The results should be included as part of the Antiretroviral Review (described in Appendix D). This Review Committee will make the final determination as to whether HIV viremia could potentially be suppressed with alternate antiretroviral therapy. .
            7. Pregnant (positive β-HCG) or breastfeeding.
            8. Fertile men or women unwilling to use contraceptive techniques from the time of initiation of mobilization until six-months post-transplant.
            9. Prior allogeneic HCT.
            10. Patients with psychosocial conditions that would prevent study compliance and follow-up, as determined by the principal investigator.
            11. T-cell depletion (including ATG or alemtuzumab) is not allowed.
            12. Use of cord blood as the source of hematopoietic cells is not allowed.

          contacts and locations

          Contacts and Locations

          Choosing to participate in a study is an important personal decision.Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.For general information, see Learn About Clinical Studies.

          Please refer to this study by its ClinicalTrials.gov identifier: NCT01410344

          Locations

          United States, Arizona
          Mayo Clinic - Phoenix
          Phoenix, Arizona, United States, 85054
          United States, California
          City of Hope National Medical Center
          Duarte, California, United States, 91010
          University of CA, SF
          San Francisco, California, United States, 94143-0324
          United States, Florida
          H. Lee Moffitt Cancer Center
          Tampa, Florida, United States, 33624
          United States, Georgia
          Blood & Marrow Transplant Program at Northside Hospital
          Atlanta, Georgia, United States, 30342
          United States, Maryland
          Johns Hopkins
          Baltimore, Maryland, United States, 21231
          United States, Minnesota
          Mayo Clinic - Rochester
          Rochester, Minnesota, United States, 55905
          United States, Pennsylvania
          University of Pennsylvania Cancer Center
          Philadelphia, Pennsylvania, United States, 19104
          United States, Texas
          University of Texas/MD Anderson CRC
          Houston, Texas, United States, 77030
          Texas Transplant Institute
          San Antonio, Texas, United States, 78229
          United States, Wisconsin
          Medical College of Wisconsin
          Milwaukee, Wisconsin, United States, 53211

          Sponsors and Collaborators

          Medical College of Wisconsin
          National Heart, Lung, and Blood Institute (NHLBI)
          National Cancer Institute (NCI)
          Blood and Marrow Transplant Clinical Trials Network
          National Marrow Donor Program

          Investigators

          Study Director: Mary Horowitz, MD Center for International Blood and Marrow Transplant Research
          More Information

          More Information

          Additional Information:

          Blood and Marrow Transplant Clinical Trials Network

          Additional Information:

          National Marrow Donor Program

          Responsible Party: Medical College of Wisconsin  
          ClinicalTrials.gov Identifier: NCT01410344   History of Changes  
          Other Study ID Numbers: BMTCTN0903  
            U01HL069294  
            BMT CTN 0903  
            5U24CA076518  
          Study First Received: August 3, 2011  
          Last Updated: August 29, 2017  

          Keywords provided by Medical College of Wisconsin:

          HIV
          ALL
          AML
          MDS
          Non-Hodgkin Lymphoma

          Additional relevant MeSH terms:
          Cyclophosphamide
          Fludarabine phosphate
          Melphalan
          Busulfan
          Fludarabine
          Vidarabine

          ClinicalTrials.gov processed this data on October 23, 2017
          This information is provided by ClinicalTrials.gov.