Allogeneic Transplant in HIV Patients (BMT CTN 0903)

This study is currently recruiting participants.
Verified April 2013 by Medical College of Wisconsin
Sponsor:
Collaborators:
Blood and Marrow Transplant Clinical Trials Network
Information provided by (Responsible Party):
Medical College of Wisconsin
ClinicalTrials.gov Identifier:
NCT01410344
First received: August 3, 2011
Last updated: April 2, 2013
Last verified: April 2013

August 3, 2011
April 2, 2013
September 2011
November 2013   (final data collection date for primary outcome measure)
Non-Relapse Mortality [ Time Frame: 100 days ] [ Designated as safety issue: Yes ]
The events for non-relapse mortality are death due to any cause other than relapse of the underlying malignancy
Same as current
Complete list of historical versions of study NCT01410344 on ClinicalTrials.gov Archive Site
  • Disease Status Following Transplant [ Time Frame: 100 days ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    Overall survival is defined as time from transplant to death or last follow-up.
  • Acute Graft-versus-Host Disease (GVHD) [ Time Frame: 100 Days ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    HIV-1 RNA in plasma will be measured by standard real-time 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 ] [ Designated as safety issue: Yes ]
    Hematologic function will be defined by 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.
  • Disease Status Following Transplant [ Time Frame: 100 days ] [ Designated as safety issue: Yes ]
    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: Day 30, day 100 and day 180 ] [ Designated as safety issue: Yes ]
    Blood samples will be evaluated for T cell and myeloid chimerism on Days 30, 100 and 180 post-transplant.
  • Incidence of Infections [ Time Frame: Date of transplant through one year post-transplant ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    Overall survival is defined as time from transplant to death or last follow-up.
  • Acute Graft-versus-Host Disease (GVHD) [ Time Frame: 100 Days ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 Months, and 12 Months ] [ Designated as safety issue: Yes ]
    This will be measured in all patients at 8 weeks, 6 months and 12 months. 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, 13 Months, and 24 Months ] [ Designated as safety issue: Yes ]
    HIV-1 RNA in plasma will be measured by standard real-time 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.
Not Provided
Not Provided
 
Allogeneic Transplant in HIV Patients (BMT CTN 0903)
Allogeneic Hematopoietic Cell Transplant for Hematological Cancers and Myelodysplastic Syndromes in HIV-Infected Individuals

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.

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 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.

Interventional
Phase 2
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Leukemia
  • Lymphoma
  • HIV
  • Drug: Fludarabine and Busulfan (Flu/Bu)

    RIC Regimen: 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)

    The sequence of fludarabine and busulfan administration in RIC regimens will be done according to institutional standards. Intraveneous busulfan may be administered in divided doses or once daily. Oral busulfan must be administered in divided doses. Busulfan dose adjustments for obesity are listed in Section 2.5.2.4 of the protocol. Fludarabine dose adjustments for renal impairment are listed in Section 2.5.2.3.

    See Section 2.5.4 and Table 2.6.1.4 of the protocol for critical information about antiretroviral management in the setting of a busulfan-containing reduced intensity conditioning regimen when the antiretroviral regimen includes ritonavir.

  • Drug: Fludarabine and Melphalan (Flu/Mel)

    RIC Regimen: 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)

    The sequence of fludarabine and melphalan administration in RIC regimens will be done according to institutional standards as long as the prescribed doses are the same as the regimen above. Dividing the dose of melphalan over two days is permitted. Fludarabine dose adjustments for renal impairment are listed in Section 2.5.2.3 of the protocol.

  • Drug: Busulfan and Fludarabine (Bu/Flu)

    MAC Regimen: 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)

    The sequence of busulfan and fludarabine administration in MAC regimens will be done according to institutional standards. Busulfan may be administered intravenously in divided doses or once daily. Appropriate busulfan dosing adjustments per institutional standard should be made when levels are available to achieve the target Css. Busulfan dose adjustments for obesity are listed in Section 2.5.2.4 of the protocol. Fludarabine dose adjustments for renal impairment are listed in Section 2.5.2.3 of the protocol.

  • Drug: Cyclophosphamide and Total Body Irradiation (Cy/TBI)

    MAC Regimen: 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)

    The sequence of cyclophosphamide, TBI and TBI administration practices in MAC regimens will be done accordingly to institutional standards. Cyclophosphamide dose adjustments for obesity are listed in Section 2.5.2.4 of the protocol. See Appendix F of the protocol for detailed information on pharmacokinetic interactions. MESNA will be given to reduce the risk of cyclophosphamide-associated hemorrhagic cystitis. MESNA will be dosed based on cyclophosphamide dose and may be administered per institutional guidelines.

  • Drug: Fludarabine

    MAC Regimen (conditioning agent dose adjustments for renal impairment):

    Patients with a creatinine clearance of 40-70 ml/min (measured or calculated) should have a 20 percent dose reduction.

  • Drug: Busulfan, Fludarabine, Cyclophosphamide

    MAC Regimen (conditioning agent dose adjustments for obesity):

    1. 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 (AIBW; see the protocol for formulas).
    2. Fludarabine will not be dose adjusted for obesity.
    3. 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.
Allogeneic Transplant
In general reduced-intensity conditioning (RIC) is reserved for patients with co-morbidities or older patients in whom regimen-related mortality weighs against myeloablative conditioning (MAC). However, the selection of a RIC or MAC regimen in any particular patient is left to the discretion of investigators at the participating center in accordance with institutional standards.
Interventions:
  • Drug: Fludarabine and Busulfan (Flu/Bu)
  • Drug: Fludarabine and Melphalan (Flu/Mel)
  • Drug: Busulfan and Fludarabine (Bu/Flu)
  • Drug: Cyclophosphamide and Total Body Irradiation (Cy/TBI)
  • Drug: Fludarabine
  • Drug: Busulfan, Fludarabine, Cyclophosphamide
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
15
November 2015
November 2013   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • 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 greater than or equal to 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.
  • Patients must be willing to comply with effective Antiretroviral Therapy.
  • Patients must be greater than or equal to 15 years of age.
  • Hematological malignancy associated with a poor prognosis with medical therapy alone. Diagnoses to be included: a)Patients with the diagnosis of Acute Myeloid or Lymphocytic Leukemia (AML or ALL) in first or second complete remission; b)Patients with advanced myelodysplastic syndromes (MDS), including those with International Prognostic Scoring System (IPSS) Int-2 and high-risk disease with less than 10 percent 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; c)Hodgkin Lymphoma beyond first remission achieving at least a partial response to most recent therapy with no evidence of progression prior to transplant; d)Non-Hodgkin Lymphoma beyond first remission achieving at least a partial response to most recent therapy with no evidence of progression prior to transplant.
  • Donor/recipient HLA matching: a) 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; b) 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).
  • Patients with adequate organ function as measured by: a)Cardiac -Left ventricular ejection fraction at rest greater than or equal to 40 percent demonstrated by 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; bi)Hepatic - Total Bilirubin less than 2.0 mg/dL (except for isolated hyperbilirubinemia attributed to Gilbert syndrome or antiretroviral therapy as specified in the protocol Appendix E) and ALT and AST less than 5x the upper limit of normal; bii)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) greater than 40 mL/min; d)Pulmonary: DLCO, FEV1, FVC greater than or equal to 45 percent of predicted (corrected for hemoglobin).
  • Signed Informed Consent

Exclusion Criteria:

  • Karnofsky/Lansky performance score less than 70 percent.
  • Active CNS malignancy; however, patients with a history of positive CSF cytology that has become negative with intrathecal chemotherapy are eligible.
  • Uncontrolled bacterial, viral or fungal infection (currently taking medication and with progression or no clinical improvement).
  • Active CMV retinitis or other CMV-related organ dysfunction.
  • AIDS related syndromes or symptoms that pose a perceived excessive risk for transplantation-related morbidity as determined by the principal investigator.
  • Untreatable HIV infection due to multidrug antiretroviral resistance. Patients with a detectable viral load greater than 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. This Review Committee will make the final determination as to whether HIV viremia could potentially be suppressed with alternate antiretroviral therapy.
  • Pregnant (positive β-HCG) or breastfeeding.
  • Fertile men or women unwilling to use contraceptive techniques from the time of initiation of mobilization until six-months post-transplant.
  • Prior allogeneic HCT.
  • Patients with psychosocial conditions that would prevent study compliance and follow-up, as determined by the principal investigator.
  • T-cell depletion (including ATG or alemtuzumab) is not allowed.
  • Use of cord blood as the source of hematopoietic cells is not allowed.
Both
15 Years and older
No
Contact: Mary Horowitz, MD, MS marymh@mcw.edu
Contact: Sandi Sykes ssykes@emmes.com
United States
 
NCT01410344
710, U01HL069294, BMT CTN 0903
Yes
Medical College of Wisconsin
Medical College of Wisconsin
  • National Heart, Lung, and Blood Institute (NHLBI)
  • National Cancer Institute (NCI)
  • Blood and Marrow Transplant Clinical Trials Network
Study Chair: Joseph Alvarnas, MD City of Hope National Medical Center
Study Chair: Richard Ambinder, MD Johns Hopkins Medical Institutions
Medical College of Wisconsin
April 2013

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