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HIV Antigen-specific T-cells Targeting Conserved Epitopes (HST-NEETs) BMTCTN1903 (BMTCTN1903)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04975698
Recruitment Status : Recruiting
First Posted : July 23, 2021
Last Update Posted : April 12, 2022
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
National Marrow Donor Program
Children's National Research Institute
Information provided by (Responsible Party):
Catherine Bollard, National Heart, Lung, and Blood Institute (NHLBI)

Brief Summary:
This is a Phase II multi-center trial single arm trial of autologous transplantation (ASCT) followed by administration of HST-NEETs for treatment of HIV associated lymphoma

Condition or disease Intervention/treatment Phase
HIV Associated Lymphoma Biological: HST-NEETs Biological: Bone Marrow Transplant Phase 2

Detailed Description:
Eligible participants will have 100-120 mL of peripheral blood collected and shipped to Children's National Hospital at ambient temperature. The peripheral blood will be used to manufacture the HST-NEET product. The autologous peripheral blood stem cell graft suitable for rescue following conditioning will be obtained either before or after the collection of blood to generate HST-NEETs. Pre-transplant conditioning will consist of BEAM; BCNU 300 mg/m^2 on Day -6, Etoposide 100 mg/m^2 BID and Ara-C 100 mg/m2 BID on Days -5, -4, -3 and -2 and Melphalan 140 mg/m2 on Day -1. ASCT on Day 0. If the mobilized graft contains greater than 5.0 x 106 CD34+ cells per kg, any additional cells should be cryopreserved as a "back-up" graft in the event of graft failure related to the HST-NEETs. Participants will receive one dose (2 x 107 cells/m^2 ) of HST-NEETs between Days +3 to +7 based on the clinical condition of the participant. If this window is missed, the HST-NEETs may be administered up to Day +30 post-ASCT. Participants will be followed for at least one year after ASCT.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Administration of HIV-specific T Cells to HIV+ Patients Receiving High Dose Chemotherapy Followed by Autologous Stem Cell Rescue - Auto -RESIST. BMTCTN1903
Actual Study Start Date : October 25, 2021
Estimated Primary Completion Date : June 2025
Estimated Study Completion Date : June 2026

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS Lymphoma

Arm Intervention/treatment
HST-NEETs
HIV+ Participants that were treated with autologous hematopoietic stem cell transplant.
Biological: HST-NEETs
HST-NEETs are manufactured from an autologous peripheral blood collection and will be administered as a single intravenous (IV) infusion of 2x10^7/m^2 cells between 3 Days and 7 Days post-ASCT.

Biological: Bone Marrow Transplant
Day 0 is the day of bone marrow transplantation.




Primary Outcome Measures :
  1. To determine 1.) the proportion of participants who can be treated with (HST-NEETs) within 1 week of ASCT in a cooperative multi-institutional setting and 2.) the efficacy of HSTNEETs in reducing the HIV intact proviral [ Time Frame: 6 Months ]
    Feasibility is defined as a participant receiving HST-NEETs within 1 week post-ASCT; Efficacy will be measured by the reduction in intact proviral reservoir.


Secondary Outcome Measures :
  1. Progression-free survival [ Time Frame: 6 Months and 1 Year ]
    Participants are considered a failure for this endpoint if they die or if they relapse/progress or receive anti-lymphoma therapy, other than post-transplant consolidative localized radiation (maximum 3 sites) to sites of prior bulk disease pre-transplant (greater than 3cm)

  2. The incidence and severity of acute infusion related toxicities [ Time Frame: 1 Year ]
    Acute infusion related toxicities are defined as toxicities related to the infusion of HST-NEETs that occur within 24 hours of the infusion.

  3. Impact of therapy on the HIV intact proviral reservoir [ Time Frame: 1 Year ]
    Impact on intact proviral reservoir will be assessed using the IPDA at 4-8 weeks prior to transplant and 12 months following ASCT


Other Outcome Measures:
  1. Time to hematopoietic recovery [ Time Frame: 1 Year ]
    Time to neutrophil recovery will be the first of three consecutive labs of greater than or equal to 500 neutrophils/μL following the expected nadir. Time to platelet engraftment will be the date platelet count is greater than or equal to 20,000/μL for the first of three consecutive labs with no platelet transfusions 7 days prior.

  2. Incidence of infections [ Time Frame: 1 Year ]
    The incidence of viral, fungal and bacterial infections will be tabulated. All Grade 2 and Grade 3 infections will be reported according to the BMT CTN Technical MOP from Day 0 up to 1 year post-transplant. Infections of interest will be captured and described. The incidence rate of infections is defined by the number of infections divided by the total person-time accumulated over the duration of the study.

  3. Non-relapse mortality [ Time Frame: 6 Months 1 Year ]
    Non-Relapse Mortality (NRM) is defined as death occurring in a participant without relapse progression and will be measured at 6 months and at 1 year.

  4. Toxicities [ Time Frame: 1 Year ]
    Toxicities related to the BEAM conditioning regimen and HST-NEETs infusion beyond the 24 hour acute toxicity monitoring period will be defined by using the version 5.0 CTCAE criteria. All grades of toxicity related to HST-NEETs will be collected. Only grade 3 or higher conditioning regimen related toxicities will be collected.

  5. Assessment of plasma DNA in blood (clonal Ig DNA) as a tumor marker [ Time Frame: 100 days, 6 months, 1 year ]
    Blood specimens will be collected prior to the initiation of conditioning, and at Days 100, 6 months and 1 year post-ASCT. The presence of clonal Ig DNA in plasma will be assessed at each of these time points.

  6. Impact of therapy on the HIV intact proviral reservoir [ Time Frame: 100 Days ]
    Impact on intact proviral reservoir assessed using the IPDA Day 100 post-ASCT as compared to baseline at 4-8 weeks prior to transplant.

  7. HIV RNA in plasma [ Time Frame: 100 Days, 6 Months, 1 Year ]
    HIV RNA in plasma will be measured by a sensitive investigational single copy assay (SCA, detection limit 0.38 copy/ml). Blood specimens will be collected, and plasma HIV RNA measured, at study visits corresponding to those associated with IPDA testing: 4-8 weeks prior to transplant, and at Days 100, 6 months and 1 year post-ASCT.

  8. HST-NEETs persistence and expansion in vivo [ Time Frame: 100 Days, 6 Months, and 1 Year ]
    Persistence and expansion of HST-NEETs will be measured by frequency of HIV-1 antigen-specific (gag, pol, nef) CD8+ T-cells by ELIspot at baseline and post-infusion at timepoints at Day 100, 6 months, and 1 year post transplant. Change in T cell responses from baseline to post-infusion, measured by frequency of cells secreting IFN-γ by multimer analysis and/or intracellular cytokine staining and/or ELIspot and/or TCR sequencing will be done depending on PBMC cell numbers available and reagent availability.



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

Eligible participants are HIV positive and plan to be treated by high dose chemotherapy followed by an autologous stem cell transplant (ASCT). Participants are a minimum of 15 years of age with Karnofsky performance status greater than or equal to 70% that have primary refractory or recurrent diffuse large B-cell, immunoblastic, plasmablastic, high grade, Burkitt, primary effusion lymphoma, or classical Hodgkin lymphoma. Participants must have received 2 or 3 prior treatment regimens, including an induction chemotherapy and 1 or 2 salvage regimens. Monoclonal antibody therapy and local radiation will not be counted as prior therapies. Participants must have chemosensitive disease as demonstrated by complete or partial response to induction or most recent salvage chemotherapy. Participants cannot have had prior autologous, allogeneic HCT, or CART-cell therapy. Participants must initiate conditioning therapy within 3 months of stem cell mobilization or bone marrow harvest. Blood cell mobilization or bone marrow harvest will be carried out per institutional guidelines. Participants may not have HIV refractory to pharmacologic therapy. Patients must not have an uncontrolled infection. Participants must not have received previous cellular therapy

  1. Age 15 years old or older at time of enrollment.
  2. Receiving antiretroviral therapies (ART) with HIV viral load below the limit of detection by standard commercial assay. A single plasma HIV-1 RNA measurement that is ≥ the limit of quantification of the FDA-approved commercial assay but <500 copies is allowed if this is followed by an HIV-1 RNA measurement below the limit of detection.
  3. Diagnosis of refractory or recurrent diffuse large B-cell lymphoma, composite lymphoma with greater than 50% diffuse large B-cell lymphoma, mediastinal B-cell lymphoma, immunoblastic, plasmablastic, Burkitt or high grade B cell lymphoma or classical Hodgkin lymphoma. Participants with aggressive B-cell lymphoma that is transformed from follicular lymphoma are eligible for the study, pending fulfillment of other criteria.
  4. Two or three prior regimens of chemotherapy over the entire course of their disease treatment (induction chemotherapy and salvage chemotherapies). Monoclonal antibody therapy and involved field radiation therapy will not be counted as prior therapies
  5. All participants must have chemosensitive disease as demonstrated by at least a partial response (as defined by the criteria in Chapter 3) to induction or salvage therapy.
  6. Absolute Lymphocyte Count (ALC) greater than or equal to 1000/µL.
  7. Participants with adequate organ function as measured by:

    1. Cardiac: Participants must have a left ventricular ejection fraction at rest greater than or equal to 40% demonstrated by MUGA or echocardiogram.
    2. b) Hepatic: i. Bilirubin less than or equal to 2.0 mg/dL (except for isolated hyperbilirubinemia attributed to Gilbert syndrome or antiretroviral therapy as specified in Appendix D) and ALT and AST less than or equal to 3x the upper limit of normal. ii. Concomitant Hepatitis: Participants with chronic hepatitis B or C may be enrolled on the trial providing the above criteria are met. In addition, they must not have evidence of active viral replication by PCR, and no clinical or pathologic evidence of irreversible chronic liver disease.
    3. Renal: Creatinine clearance (calculated creatinine clearance is permitted based on institutional practice) greater than 40 mL/min.
    4. Pulmonary DLCO (corrected for hemoglobin), FEV1, FVC greater than or equal to 45% of predicted.
  8. Plan to treat participant with high dose chemotherapy and autologous hematopoietic stem cell transplantation (ASCT).
  9. Voluntary written consent or assent obtained prior to enrollment on study with the understanding that consent or assent may be withdrawn by the participant at any time without prejudice to future medical care.

Exclusion Criteria:

  1. Karnofsky performance score less than 70%.
  2. Participant is known to have an HIV subtype other than B.
  3. Participant has documented raltegravir or protease inhibitor resistance.
  4. Myocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia.
  5. Uncontrolled bacterial, viral or fungal infection (currently taking medication and with progression or no clinical improvement).
  6. Participant has active CNS involvement.
  7. Participants with prior malignancies except resected non-melanoma skin cancer or treated cervical carcinoma in situ. Cancer treated with curative intent greater than or equal to 5 years previously will be allowed. Cancer treated with curative intent less than 5 years BMT CLINICAL TRIALS NETWORK HIV T-Cell - Protocol 1903 Version 1.0 Dated February 24, 2021 2-4 Confidential previously may be eligible must be reviewed and approved by the Protocol Officer or Chairs.
  8. Female participants that are pregnant as per institutional definition or breastfeeding.
  9. Fertile men or women unwilling to use contraceptive techniques from the time of initiation of mobilization until six-months post-transplant.
  10. Prior autologous or allogeneic HCT, or prior therapy with chimeric antigen receptor (CAR) T-cells.
  11. Participants with evidence of MDS/AML or abnormal cytogenetic analysis indicative of MDS on the pre-transplant bone marrow examination. Pathology report documentation need not be submitted.
  12. Steroids greater than 0.5 mg/kg/day prednisone equivalents.
  13. Bone marrow involvement by lymphoma at time of workup. Prior history of bone marrow involvement is allowed if cleared prior to ASCT.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04975698


Contacts
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Contact: Christine Borchert 301-251-1161 ext 12789 bmtctn1903@emmes.com
Contact: Nicole Ritzau nritzau@emmes.com

Locations
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United States, California
City of Hope National Medical Center Recruiting
Duarte, California, United States, 91010
Contact: Joseph Alvanas, MD       jalvarnas@coh.org   
United States, District of Columbia
Georgetown Not yet recruiting
Washington, District of Columbia, United States, 20057
Contact: Kieron Dunleavy       Kieron.M.Dunleavy@medstar.net   
United States, Florida
H. Lee Moffitt Cancer Center Not yet recruiting
Tampa, Florida, United States, 33612
Contact: Alex Lazaryan       alexander.lazaryan@moffitt.org   
United States, Georgia
Northside Recruiting
Atlanta, Georgia, United States, 30342
Contact: Jasper Barnes    404-851-6908    jasper.barnes@northside.edu   
United States, Illinois
University of Illinois Not yet recruiting
Chicago, Illinois, United States, 60612
Contact: Paul Rubinstein         
Contact       paulgr@uic.edu   
United States, Maryland
Johns Hopkins University Not yet recruiting
Baltimore, Maryland, United States, 21231
Contact: Rich Ambinder       rambind1@jhmi.edu   
United States, New York
Icahn School of Medicine at Mount Sinai Recruiting
New York, New York, United States, 10029
Contact: Uroosa Ibrahim       Uroosa.Ibrahim@mssm.edu   
Cornell Not yet recruiting
New York, New York, United States, 10065
Contact: Constance Moussouris       com3001@med.cornell.edu   
Memorial Sloan Kettering (MSKCC) Recruiting
New York, New York, United States, 10065
Contact: Parastoo Dahi       dahip@mskcc.org   
United States, Pennsylvania
University of Pennsylvania Not yet recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Harjeet Sembhi       Harjeet.Sembhi@pennmedicine.upenn.edu   
United States, Texas
Baylor College of Medicine Recruiting
Houston, Texas, United States, 77030
Contact: Deborah Dowlin    832-824-4306    Deborah.dowlin@bcm.edu   
MD Anderson Not yet recruiting
Houston, Texas, United States, 77030
Contact: Uday Popat       upopat@mdanderson.org   
Sponsors and Collaborators
Catherine Bollard
National Heart, Lung, and Blood Institute (NHLBI)
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
National Marrow Donor Program
Children's National Research Institute
Investigators
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Study Chair: Steve Devine, MD, MS National Marrow Donor Program
  Study Documents (Full-Text)

Documents provided by Catherine Bollard, National Heart, Lung, and Blood Institute (NHLBI):
Additional Information:
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Responsible Party: Catherine Bollard, Primary Investigator, National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier: NCT04975698    
Other Study ID Numbers: BMTCTN1903
2U10HL069294-11 ( U.S. NIH Grant/Contract )
First Posted: July 23, 2021    Key Record Dates
Last Update Posted: April 12, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Results will be published in a manuscript and supporting information submitted to NIH BioLINCC (including data dictionaries, case report forms, data submission documentation, documentation for outcomes dataset, etc where indicated).
Supporting Materials: Study Protocol
Time Frame: Within 6 months of official study closure at participating sites
Access Criteria: Available to public
URL: https://biolincc.nhlbi.nih.gov/home/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lymphoma, AIDS-Related
Lymphoma, B-Cell
Lymphoma, Non-Hodgkin
Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases