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Autologous Transplant in HIV Patients (BMT CTN 0803)

This study has been completed.
Sponsor:
Collaborators:
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:
NCT01141712
First received: June 9, 2010
Last updated: February 7, 2017
Last verified: October 2016
  Purpose
This study is a Phase II, multicenter trial assessing overall survival after autologous hematopoietic stem cell transplantation using a BEAM transplant regimen (carmustine, etoposide, cytarabine, melphalan) in lymphoma patients with HIV.

Condition Intervention Phase
Lymphoma HIV Procedure: Autologous transplant Drug: BCNU Drug: Etoposide Drug: Cytarabine Drug: Melphalan Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: High Dose Chemotherapy With Autologous Stem Cell Rescue for Aggressive B Cell Lymphoma and Hodgkin Lymphoma in HIV-infected Patients (BMT CTN #0803)

Resource links provided by NLM:


Further study details as provided by Medical College of Wisconsin:

Primary Outcome Measures:
  • Overall Survival (OS) [ Time Frame: Year 1 and 2 ]
    Assess the OS after autologous hematopoietic stem cell transplantation (HCT) for chemotherapy-sensitive aggressive B cell lymphoma or Hodgkin's lymphoma in patients with HIV using BEAM for pre-transplant conditioning. The primary analysis will consist of estimating the 1 year OS probability from the time of transplantation based on the Kaplan-Meier product limit estimator. The 1 year and 2 year OS and confidence interval will be calculated.


Secondary Outcome Measures:
  • Relapse/Progression [ Time Frame: Year 2 ]
    Relapse is defined as the appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, even if other lesions are decreasing in size. Progression is defined as a lymph node with a diameter of the short axis of less than 1.0 cm must increase by >= 50% and to a size of 1.5 x 1.5 cm or more than 1.5 cm in the long axis.

  • Progression-Free Survival (PFS) [ Time Frame: Year 2 ]
    The time to this event is the time from enrollment until death, relapse/progression, receipt of anti-lymphoma therapy, or last follow up, whichever comes first. Progression-free survival (PFS) will be estimated using the Kaplan Meier product limit estimator. The PFS probability and confidence interval will be calculated at two years post-transplant.

  • Complete Remission (CR) and/or Partial Response (PR) [ Time Frame: Day 100 ]
    The frequencies and proportions of patients who have a CR or PR. CR is defined as the disappearance of all evidence of disease, and PR is defined as the regression of measurable disease and no new sites.

  • Time to Progression After CR [ Time Frame: Year 2 ]
    This will be assessed in patients with CR. Patients are considered failure for this end point if they relapse after complete remission. Surviving patients with no history of relapse/progression are censored at time of last follow-up.

  • Lymphoma Disease-free Survival [ Time Frame: Year 2 ]
    This will be assessed in patients with CR. Patients are considered failure for this end point if they die or if they relapse after complete remission. Patients with no history of relapse or death after complete remission are censored at time of last follow up.

  • Cumulative Incidence of Neutrophil Recovery [ Time Frame: Day 28 ]
    Neutrophil recovery is defined as two consecutive days of absolute neutrophil count (ANC) > 500 neutrophils/μL following the expected nadir.

  • Cumulative Incidence of Platelet Recovery [ Time Frame: Day 100 ]
    Platelet recovery is defined as a platelet count greater than 20,000/μL for the first of two consecutive labs with no platelet transfusions 7 days prior.

  • Hematologic Function [ Time Frame: Days 100 and 365 ]
    Hematologic function will be defined as ANC > 1500 neutrophils/μL, Hemoglobin> 10g/dL without transfusion support, and platelets > 100,000/μL

  • Number of Participants Experiencing Toxicity [ Time Frame: Year 2 ]
    Toxicities will be defined by using the version 3.0 NCI Common Terminology Criteria for Adverse Events (CTCAE) criteria. Only grade 3 and higher toxicities will be collected.

  • Number of Participants Experiencing Infections [ Time Frame: Year 1 ]
    Microbiologically documented infections will be reported by site of disease, date of onset, severity, and resolution, if any.

  • Treatment-Related Mortality (TRM) [ Time Frame: Day 100 ]
    TRM is defined as death occurring in a patient from causes other than relapse or progression. A cumulative incidence curve will be computed along with a 95% confidence interval at 100 days post-transplant.

  • Immunologic Reconstitution [ Time Frame: Year 1 ]
    Immunologic Reconstitution will be assessed by quantitative immunoglobulin measurement (IgM, IgG and IgA)

  • HIV Single-Copy Polymerase Chain Reaction (PCR) [ Time Frame: Baseline, Days 100, 180, 365, and 730 ]
    HIV RNA assay will be performed at the specified time points and summarize the assessments of the viral copy number using descriptive statistics.

  • Microbial Translocation Markers [ Time Frame: Day 30 and 100 ]
    Level of microbial translocation markers will be determined by nonparametric Mann-Whitney tests comparing the distribution of prior microbial translocation markers between patients.

  • Ig and Epstein-Barr Virus (EBV) DNA in Blood [ Time Frame: Day 100, 180, and 365 ]
    The presence of clonal Ig DNA in plasma will be assessed, as will EBV copy number in plasma and in peripheral blood


Enrollment: 43
Study Start Date: April 2010
Study Completion Date: June 2016
Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Autologous transplant
Patients will receive BCNU 300 mg/m^2 Day -6, Etoposide 100 mg/m^2 BID Days -5 to -2, Cytarabine 100 mg/m^2 BID Days -5 to -2, and Melphalan 140 mg/m^2 Day -1 followed by autologous HCT.
Procedure: Autologous transplant
Participants will receive the BEAM conditioning regimen followed by autologous HCT.
Drug: BCNU
Participants will receive BCNU 300 mg/m^2 Day -6
Other Name: Carmustine
Drug: Etoposide
Participants will receive Etoposide 100 mg/m^2 BID Days -5 to -2
Other Name: VP-16
Drug: Cytarabine
Participants will receive Cytarabine 100 mg/m^2 BID Days -5 to -2
Other Name: Depocyt
Drug: Melphalan
Participants will receive Melphalan 140 mg/m^2 Day -1
Other Name: Alkeran

Detailed Description:

BACKGROUND:

Non-Hodgkin lymphoma (NHL) is an AIDS-defining diagnosis for patients infected with the Human Immunodeficiency Virus (HIV). While the incidence of NHL has decreased amongst HIV-infected patients since the advent of highly-active anti-retroviral therapy (HAART), lymphoma remains a significant cause of death for this patient population. The prognosis for patients with AIDS-related lymphoma is dramatically different in the era of HAART therapy. In a comparison of treatment outcomes for patients treated before and after the advent of HAART, there is a statistically significant improvement in the overall survival of patients treated with HAART. Unfortunately, despite considerable advances in the treatment of AIDS-related NHL, induction-failure and disease relapse remain key challenges. The prognosis for patients with refractory and relapsed NHL is poor with overall survival rates of less than 20 percent for patients treated with non-transplant salvage therapies. Based upon a randomized trial and numerous phase II trials, high-dose therapy with autologous hematopoietic cell transplantation (HCT) has been established as the standard of care for patients with chemotherapy-sensitive relapsed non-Hodgkin lymphoma.

DESIGN NARRATIVE:

All patients must have chemosensitive disease as demonstrated by response to induction or salvage chemotherapy. Patients must also have less than or equal to 10percent bone marrow involvement after their most recent salvage therapy. Patients cannot have had prior autologous or allogeneic HCT. Patients must initiate conditioning therapy within 3 months of mobilization or bone marrow harvest.

Mobilization therapy may be employed per institutional guidelines. Patients must have an adequate autograft to be eligible for the protocol. Patients may not have HIV refractory to pharmacologic therapy. Patients must not have opportunistic infection that is not responding to therapy. Patients will receive Carmustine (BCNU) 300 mg/m^2 Day -6, Etoposide 100 mg/m^2 twice a day (BID) on Days -5 to -2, Cytarabine 100 mg/m2 BID on Days -5 to -2, and Melphalan 140 mg/m2 Day -1 followed by autologous HCT.

Patients will be followed for 2 years post-transplant. Survival data, time to progression data, progression-free survival data, time to progression after Complete Remission (CR) data, lymphoma disease-free survival data, time to hematopoietic recovery data, hematologic function data, toxicity data, incidence of infections, treatment-related mortality data, immunologic reconstitution data, data assessing the impact of therapy on the HIV reservoir and microbial gut translocation will be recorded and reported periodically to the BMT CTN Data and Coordinating Center (DCC).

  Eligibility

Ages Eligible for Study:   15 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of persistent or recurrent World Health Organization (WHO) classification diffuse large B-cell lymphoma, composite lymphoma with > 50% diffuse large B-cell lymphoma, mediastinal B-cell lymphoma, immunoblastic, plasmablastic, Burkitt's or Burkitt-like or classical Hodgkin's lymphoma. Patients transformed from follicular lymphoma are eligible for the study, pending fulfillment of other criteria.
  • 15 years old or older
  • Three or fewer prior regimens of chemotherapy over the entire course of their disease treatment (including one induction chemotherapy and no more than 2 salvage chemotherapies). Monoclonal antibody therapy and involved field radiation therapy will not be counted as prior therapies.
  • All patients must have chemosensitive disease as demonstrated by at least a partial response to induction or salvage therapy.
  • Less than or equal to 10% bone marrow involvement.
  • Patients with adequate organ function as measured by: a)Cardiac: American Heart Association Class I: Patients with cardiac disease but without resulting limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain. Additionally, all patients must have a left ventricular ejection fraction at rest greater than or equal to 40% demonstrated by Multi Gated Acquisition Scan (MUGA) or echocardiogram; b)Hepatic: (i) Bilirubin less than 2.0 mg/dL (except for isolated hyperbilirubinemia attributed to Gilbert syndrome or antiretroviral therapy) and alanine transaminase (ALT) and aspartate transaminase (AST) greater than 3x the upper limit of normal; (ii) Concomitant Hepatitis: Patients with chronic hepatitis B or C may be enrolled on the trial providing the above criteria are met. In addition, no active viral replication - undetectable (viral load less than 500 copies/ml) hepatitis B DNA level by PCR and no clinical or pathologic evidence of irreversible chronic liver disease; c)Renal: Creatinine clearance (calculated creatinine clearance is permitted) greater than 40 mL/min; d)Pulmonary: Carbon Monoxide Diffusing Capacity (DLCO), forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) greater than or equal to 45% of predicted (corrected for hemoglobin).
  • Autologous peripheral stem cell graft with a minimum of greater than or less than 1.5 x 10^6 CD 34+ cells/kg (target greater than or less than 2.0 x 10^6 CD 34+ cells/kg) or if peripheral blood stem cell (PBSC) mobilization fails, cells can be obtained by bone marrow harvest per institutional practices (in cases where bone marrow will be used for transplantation, the required CD34+ dose does not apply and institutional requirements for total nucleated cell dose should apply).
  • Initiate conditioning therapy within 3 months of mobilization or bone marrow harvest.
  • Signed informed consent.
  • Patients on antiretroviral therapies (ARVs) can either have: a) Undetectable HIV viral load (VL less than 50 copies); b) If VL detectable at less than 2000 copies/mL must have review of previous antiretroviral regimens or previous genotypic or phenotypic testing which indicate the ability to fully suppress virus by addition of sensitive drugs. This review will be carried out by the Infectious Disease (ID) specialist caring for the patient; c)If VL detectable at greater than 2000 copies/mL, a current HIV genotype and/or phenotype must be obtained. If a HAART regimen to which the patient's virus is sensitive can be determined based on genotype and previous antiretroviral experience, then the patient will be considered eligible in this regard. This review will be carried out by the ID specialist caring for the patient.

Exclusion Criteria:

  • Karnofsky performance score less than 70%.
  • Uncontrolled bacterial, viral or fungal infection (currently taking medication and with progression or no clinical improvement).
  • Prior malignancy in the 5 years prior to enrollment except resected basal cell carcinoma, treated cervical carcinoma in situ or Kaposi's sarcoma: a)Symptomatic Kaposi's sarcoma currently requiring therapy is excluded (patients receiving topical therapy for minimal disease are not included in this definition); b)Prior treatment with topical agents, local radiation, or up to 6 cycles of cytotoxic chemotherapy at least six months prior is permitted; c) Other cancers treated with curative intent less than 5 years previously will not be allowed unless approved by the Medical Monitor or Protocol Chair; d)Cancer treated with curative intent more than 5 years previously will be allowed.
  • 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 autologous or allogeneic HCT.
  • Patients with evidence of Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) or abnormal cytogenetic analysis indicative of MDS on the pre-transplant bone marrow examination. Pathology report documentation need not be submitted.
  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: NCT01141712

Locations
United States, California
City of Hope National Medical Center
Duarte, California, United States, 91010-3000
University of California San Diego Medical Center
La Jolla, California, United States, 92093
UCLA
Los Angeles, California, United States, 90035
University of CA, SF
San Francisco, California, United States, 94143
United States, Florida
University of Florida College of Medicine
Gainesville, Florida, United States, 32610
H. Lee Moffitt Cancer Center
Tampa, Florida, United States, 33624
United States, Georgia
Emory University
Atlanta, Georgia, United States, 30322
BMT Program at Northside Hospital
Atlanta, Georgia, United States, 30342
United States, Maryland
University of Maryland Medical Systems, Greenebaum Cancer Center
Baltimore, Maryland, United States, 21201
Johns Hopkins Medical Institution
Baltimore, Maryland, United States, 21231
United States, Missouri
Washington University/Barnes Jewish Hospital
St. Louis, Missouri, United States, 63110
United States, New York
Weill Cornell Medical College
New York, New York, United States, 10065
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10174
University of Rochester
Rochester, New York, United States, 14642
United States, Ohio
Ohio State University Medical Center
Columbus, Ohio, United States, 43210
United States, Texas
University of Texas/MD Anderson Cancer Center
Houston, Texas, United States, 77030
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

Additional Information:
Publications:
Responsible Party: Medical College of Wisconsin
ClinicalTrials.gov Identifier: NCT01141712     History of Changes
Other Study ID Numbers: BMTCTN0803
U01HL069294 ( US NIH Grant/Contract Award Number )
U01HL069294-06 ( US NIH Grant/Contract Award Number )
U01CA121947 ( US NIH Grant/Contract Award Number )
Study First Received: June 9, 2010
Results First Received: August 10, 2016
Last Updated: February 7, 2017
Individual Participant Data  
Plan to Share IPD: Yes
Plan Description: Findings will be published in a manuscript

Keywords provided by Medical College of Wisconsin:
HIV
B-cell Lymphoma
Burkitt's Lymphoma
Follicular Lymphoma
Hodgkin's Lymphoma

Additional relevant MeSH terms:
Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Etoposide
Etoposide phosphate
Cytarabine
Melphalan
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists

ClinicalTrials.gov processed this record on June 28, 2017