HIV Infection, Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma, Plasmablastic Lymphoma, Recurrent Adult Hodgkin Lymphoma, Recurrent Adult Non-Hodgkin Lymphoma, Recurrent Burkitt Lymphoma, Recurrent Follicular Lymphoma, Stage III Follicular Lymphoma, Stage III Mantle Cell Lymphoma, Stage IV Follicular Lymphoma, Stage IV Mantle Cell Lymphoma
Conditions
Brief summary
This phase I/II trial studies the side effects and best dose of gene therapy in treating patients with human immunodeficiency virus (HIV)-related lymphoma that did not respond to therapy or came back after an original response receiving stem cell transplant. In gene therapy, small stretches of deoxyribonucleic acid (DNA) called "anti-HIV genes" are introduced into the stem cells in the laboratory to make the gene therapy product used in this study. The type of anti-HIV genes and therapy in this study may make the patient's immune cells more resistant to HIV-1 and prevent new immune cells from getting infected with HIV-1.
Detailed description
PRIMARY OBJECTIVE: I. Safety, defined as timely engraftment (the collective establishment of a persistent absolute neutrophil count of at least 500 cells/mm\^3 and platelet count of 20,000 cells/mm\^3 without transfusion for 3 consecutive measurements of laboratory values obtained on different days) by one month post-transplant, in the absence of any grade 3 and 4 non-hematopoietic organ toxicity that can be attributed (possibly, probably, or definitely) to lentiviral transduced stem cell transplant, excluding alopecia, or any clonal expansion and excluding expected toxicities that are associated with the pre-transplant conditioning regimen. SECONDARY OBJECTIVES: I. To determine efficacy of the candidate product, defined as establishment of \> 5% mononuclear blood cells expressing anti-HIV genes in the peripheral blood at 3 months post-transplant. II. To determine the presence, quantity, and duration of gene modified HIV-1 resistant peripheral blood cells and gut mucosal immune cells. III. To study the integration sites of vector sequences in circulating cells. IV. To study progression-free survival. V. To study overall survival. VI. To study complete response rate and duration. VII. To study partial response rate and duration. VIII. To study time to neutrophil engraftment (first measurement of 3 consecutive laboratory values on different days) of absolute neutrophil count \[ANC\] \>= 500 cells/mm\^3). IX. To study time to platelet engraftment (first measurement of 3 consecutive measurements laboratory values obtained on different days) of platelets \>= 20,000 cells/mm\^3 without platelet transfusions 7 days prior). X. To study hematologic function at day 100 (ANC \> 1500, hemoglobin \[Hb\] \> 10 g/dl without transfusion and platelets \> 100,000) XI. To study CD4 recovery at the conclusion of the trial. XII. To study safety in terms of toxicities, infections, transfusions, and infusion-related reactions. XIII. To study HIV-1 viral load over time. XIV. To study persistence of vector-transduced cells over time. EXPLORATORY OBJECTIVE: I. To evaluate the presence and the magnitude of expansion of HIV-1 resistant immune cells in the peripheral blood and gut mucosa of transplanted participants, subsequent to withholding anti-retroviral therapy (ART). OUTLINE: This is a dose-escalation study of lentivirus vector CCR5 shRNA/TRIM5alpha/TAR decoy-transduced autologous CD34-positive hematopoietic progenitor cells. Patients receive BEAM or BEAM-R regimen administered as standard of care comprising carmustine on day -6, cytarabine twice daily (BID) on days -5 to -2, etoposide BID on days -5 to -2, and melphalan on day -1. Patients with B-cell lymphoma also receive rituximab on day -6 before chemotherapy and on days 21 and 28 post-transplant as standard of care. Patients undergo intravenous (IV) infusion of lentivirus vector CCR5 shRNA/TRIM5alpha/TAR decoy-transduced autologous CD34-positive hematopoietic progenitor cells over 1 hour. After completion of study treatment, patients are followed up at days 7, 14, 21, 28, 42, 60, 90, 120, 180, 240, 300, 360, 420, 480, 520, 600, 660, and 720, and then yearly for at least 15 years.
Interventions
PROCEDUREAutologous Hematopoietic Stem Cell Transplantation
Undergo infusion of lentivirus vector CCR5 shRNA/TRIM5alpha/TAR decoy-transduced autologous CD34-positive hematopoietic progenitor cells
DRUGCarmustine
300 mg/m2 on Day -6, as part of BEAM and R-BEAM regimens.
DRUGCytarabine
100 mg/m2 BID on Days -5 through -2, as part of BEAM and R-BEAM regimens.
DRUGEtoposide
VP-16: 100 mg/m2 BID on Days -5 through -2, as part of BEAM and R-BEAM regimens.
OTHERLaboratory Biomarker Analysis
Correlative studies
BIOLOGICALLentivirus Vector CCR5 shRNA/TRIM5alpha/TAR Decoy-transduced Autologous CD34-positive Hematopoietic Progenitor Cells
Undergo infusion of lentivirus vector CCR5 shRNA/TRIM5alpha/TAR decoy-transduced autologous CD34-positive hematopoietic progenitor cells
DRUGMelphalan
140 mg/m2 on Day -1, as part of BEAM and R-BEAM regimens.
PROCEDUREPeripheral Blood Stem Cell Transplantation
Undergo infusion of lentivirus vector CCR5 shRNA/TRIM5alpha/TAR decoy-transduced autologous CD34-positive hematopoietic progenitor cells
Sponsors
AIDS Malignancy Consortium
National Cancer Institute (NCI)
California Institute for Regenerative Medicine (CIRM)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Inclusion criteria associated with type and status of lymphoma, one of the following must be applicable: * Biopsy-proven intermediate or high-grade non-Hodgkin's lymphoma, meeting one of the following criteria (timeline 8 months prior to enrollment in the screening segment): \- In partial remission, \- Relapsed after initial complete remission, \- Failed induction therapy, but responds to salvage therapy (i.e., chemosensitive disease), \- In complete remission with high-risk features as specified by the International Prognostic Index. * Biopsy-proven advanced stage follicular lymphoma, that have failed at least two lines of therapy multi-agent chemotherapy, but responds to salvage therapy i.e.,chemosensitive disease) (timeline 8 months prior to enrollment in the screening segment). * Biopsy-proven advanced stage Mantle cell lymphoma with Ki-67 \> 10% in first complete remission (timeline 8 months prior to enrollment in the screening segment). * Biopsy-proven Hodgkin's lymphoma, meeting one of the following criteria (timeline 8 months prior to enrollment). \- In first, or greater relapse after initial complete remission, \- In partial remission, \- Failed induction therapy, but responds to salvage therapy (i.e., chemosensitive disease). * Biopsy-proven Burkitt's lymphoma, meeting one of the following criteria (timeline 8 months prior to enrollment): \- In second complete remission after relapse following initial complete remission, \- Failed induction therapy, but responds (very good partial remission, complete remission, or near complete remission) to salvage therapy (i.e., chemosensitive disease). * Biopsy proven plasmablastic lymphomas, or peripheral T cell lymphoma (with the exception of ALK+ type in first or second complete remission) \*NOTE: Patients meeting the following criteria are exempt from the 8-month timeline and do not require additional biopsy: * Patients who have never achieved a complete remission on the last biopsy-proven site of disease and went on to the next therapy then achieved a complete remission. * Patients who relapsed quickly (within 3 months of their last chemotherapy) and now have achieved a complete remission with salvage therapy. * Inclusion criteria associated with HIV-1 status * HIV-1 infection, as documented by any federally approved, licensed HIV rapid test performed in conjunction with screening (or ELISA, test kit, and confirmed by Western blot or other approved test). Alternatively, this documentation may include a record demonstrating that another physician has documented the participant's HIV status based on either: 1) approved diagnostic tests, or 2) the referring physician's written record that HIV infection was documented, with supporting information on the participant's relevant medical history and/or current management of HIV infection. * Must be on a multi-drug anti-HIV regimen (excluding zidovudine \[AZT, ZDV, Retrovir®, or agents containing zidovudine (e.g., Combivir® and Trizivir®)\], and efavirenz \[Sustiva®, or agents containing efavirenz (e.g., Atripla®)\]). Participants on zidovudine \[AZT, ZDV, Retrovir®; including Combivir® and Trizivir®\] and efavirenz \[Sustiva®; including Atripla®\] must switch to an alternative regimen without anticipated drug-drug interactions or myelosuppressive properties based on known viral resistance patterns and/or ART history, such as raltegravir and Truvada (emtricitabine and tenofovir) at least two weeks prior to the transplant. o Participant taking ARTs must satisfy one of the following: * Undetectable HIV viral load (\< 50 copies/mL). For patients who have had negative viral loads in the past 6 months and no known HIV viral load \>500 copies/mL within the last 6 months, minor fluctuations of viral load (isolated escalations up to 500 copies/mL) are acceptable. The participant's history of negative viral loads may be documented with recent laboratory results and/or a record from the participant's HIV care provider. * If viral load is detectable at \< 2000 copies/mL a review of previous antiretroviral regimens or previous genotypic or phenotypic testing which indicate the ability to fully suppress virus by addition of sensitive drugs must be performed. This review will be carried out by the protocol ID team or the ID specialist caring for the patient. * If viral load is detectable at ≥ 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 protocol ID team or the ID specialist caring for the patient. General Inclusion Criteria (timeline: within 8 weeks prior to enrollment in the screening segment, unless otherwise specified) * Karnofsky performance status of 70-100%. ECOG performance status \<2 * SGOT and SGPT ≤ 2.5 times upper limit of normal (ULN). Serum bilirubin ≤ 2.5 times ULN except for participants who are on atazanavir or indinavir, or with elevated indirect bilirubin related to bilirubin conjugation issues such as Gilbert's disease, provided that the participant's direct bilirubin is within normal institutional limits. * Participants who are hepatitis C virus antibody positive, or hepatitis B virus surface antigen positive must be free of clinical evidence of cirrhosis as determined by the principal investigator in consultation with the institutional Gastroenterology Service. * Participants with Hepatitis B should be on appropriate anti-viral therapy at the time of the transplant, and their viral load should be negative. * Serum creatinine ≤ 2 times ULN. * Creatinine clearance ≥ 60 mL/min by the modified Cockcroft-Gault Formula. * PT/PTT ≤ 2 times upper limit of normal (ULN), or international normalized ratio (INR)/PTT ≤ 2 times the ULN. * FEV-1 or DLCO (corrected for hemoglobin) ≥ 50% predicted. * LVEF ≥ 50% by 2D ECHO or MUGA scan. * Not pregnant or nursing, with negative serum pregnancy test. Pregnant women are excluded from this study because the conditioning regimen has the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with BEAM, breastfeeding should be discontinued. These potential risks may also apply to other agents used in this study. * Participants should agree to practice effective contraceptive precautions and to use at least one method of contraception for the duration of the study and for 3 months post-transplant. * Age ≥18 years. Because only adult transplant centers are participating as study sites. * Life expectancy of greater than 3 months. * Ability to understand and the willingness to sign a written informed consent document. * Receipt of a stable ART regimen for at least 3 weeks prior to enrollment.
Exclusion criteria
Participants who do not fulfill the criteria as listed above, are ineligible. Additionally, the presence of any of the following conditions will exclude a participant from study enrollment (timeline for all the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieve a Timely Engraftment | 1 month post-transplant | Timely engraftment is defined as a persistent an absolute neutrophil count (ANC) of at least 500 cells/mm3 and a platelet count of at least 20,000 cells/mm3 for at least 3 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Study Participants Who Achieve Greater Than 5% Mononuclear Blood Cells Expressing Anti-HIV Genes in Peripheral Blood | 3 months post-transplant | To determine efficacy of the candidate product, defined as establishment of \> 5% mononuclear blood cells expressing anti-HIV genes |
| Proportion of Study Participants With Gene Modified HIV-1 Resistant Peripheral Blood Cells and Gut Mucosal Immune Cells | Up to 24 months post-transplant | To determine the presence, quantity, and duration of gene modified HIV-1 resistant peripheral blood cells and gut mucosal immune cells |
| Quantity of Gene Modified HIV-1 Resistant Peripheral Blood Cells and Gut Mucosal Immune Cells | Up to 24 months post-transplant | Summarized descriptively. Continuous measures will be summarized by mean (standard deviation \[SD\]) and median (range), with log transformation if necessary for skewed measures, as would be typical for cell counts. |
| Integration Sites of Vector Sequences in Circulating Cells | Up to 24 months post-transplant | Single genome sequencing of HIV gp120 and HIV pol will be performed to understand sequence evolution following transplantation and detection of minority resistance variants. |
| Progression-free Survival | Time from start of study treatment to relapse, progression, or death from any cause | Time-to-event data will be presented graphically by Kaplan-Meier plots and summarized by estimated median time to event (if that is estimable from the data) with 95% confidence interval. |
| Overall Survival | Up to 15 years | The length of time from the start of treatment until death |
| Number of Participants With a Complete Response | 24 months | A complete response is the complete disappearance of any disease, as determined by imaging |
| Number of Days From the First Documentation of a Complete Response Until the First Day of Relapse | Time from the first documentation of CR until first date that relapsed or progressive disease is objectively documented, assessed up to 15 years | Complete response is defined as the absence of any disease on imaging or by exam; progressive disease is defined as new lesions or new evidence of disease |
| Partial Response Rate and Duration | Up to 15 years | Will be assessed following the Lugano Classification. In the absence of evident disease progression, response will be assessed formally at 3, 6, 12 and 24 months post transplant per study calendar. |
| Time to Neutrophil Engraftment | Up to 15 years | First measurement of 3 consecutive laboratory values obtained on different days) of ANC \> 500 cells/mm3 . |
| Time to Platelet Engraftment | Up to 15 years | First measurement of 3 consecutive laboratory values obtained on different days) of platelets \> 20,000 cells/mm3 without platelet transfusions 7 days prior |
| Number of Participants With an Absolute Neutrophil Count of at Least 1500 Cells/mm3, Hemoglobin of at Least 10 g/dL, and Platelets Greater Than 100,000. | 100 days | To study hematologic function at Day 100 |
| CD4 Count Recovery | Up to 24 months post-treatment | At six months post-transplant, or later, ART will be voluntarily withheld for a 12 week period only for participants who have a CD4 count of 300 or higher with no detectable viral load. for participants in which the CD4 T-cell count has not risen to ≥ 300 cells/mm3 at the time of the planned ART interruption, ART will continue until the T-cell count has risen to ≥ 300 cells/mm3. |
| Number of Participants With Adverse Events as Assessed by the CTCAE | Up to 15 years | To study safety in terms of the frequency of toxicities, infections, transfusions, and infusion-related reactions |
| HIV-1 Viral Load | At week 4, months 3, 6, 8, 10, 12, 14, 16, 20, and 24 post-transplant. | To study HIV-1 viral load over time |
| Persistence of Vector-transduced Cells Over Time | Up to 15 years | Vector stability analysis will be performed via qPRC sequencing. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORMehrdad Abedi
AIDS Malignancy Consortium
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Anti-HIV Gene Transduced CD34+ Cells) Patients receive BEAM regimen administered as standard of care comprising carmustine on day -6, cytarabine BID on days -5 to -2, etoposide BID on days -5 to -2, and melphalan on day -1. Patients undergo infusion of lentivirus vector CCR5 shRNA/TRIM5alpha/TAR decoy-transduced autologous CD34-positive hematopoietic progenitor cells over 1 hour.
Autologous Hematopoietic Stem Cell Transplantation: Undergo infusion of lentivirus vector CCR5 shRNA/TRIM5alpha/TAR decoy-transduced autologous CD34-positive hematopoietic progenitor cells
Carmustine: 300 mg/m2 on Day -6, as part of BEAM and R-BEAM regimens.
Cytarabine: 100 mg/m2 BID on Days -5 through -2, as part of BEAM and R-BEAM regimens.
Etoposide: VP-16: 100 mg/m2 BID on Days -5 through -2, as part of BEAM and R-BEAM regimens.
Laboratory Biomarker Analysis: Correlative studies
Lentivirus Vector CCR5 shRNA/TRIM5alpha/TAR Decoy-transduced Autologous CD34-positive Hematopoietic Progenitor Cells: Undergo infusion of lentivirus vector CCR5 shRNA/TRIM5alpha/TAR decoy-transduced autologous CD34-positive hematopoietic progenitor cells
Melphalan: 140 mg/m2 on Day -1, as part of BEAM and R-BEAM regimens.
Peripheral Blood Stem Cell Transplantation: Undergo infusion of lentivirus vector CCR5 shRNA/TRIM5alpha/TAR decoy-transduced autologous CD34-positive hematopoietic progenitor cells | 11 |
| Total | 11 |
Baseline characteristics
| Characteristic | Treatment (Anti-HIV Gene Transduced CD34+ Cells) |
|---|---|
| Age, Continuous Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:0 Ratio | 61 years STANDARD_DEVIATION 6.4 |
| Age, Continuous Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:1 Ratio | 51 years STANDARD_DEVIATION 4.7 |
| Age, Continuous Treatment (Anti-HIV Gene Transduced CD34+ Cells): 5:1 Ratio | 61 years STANDARD_DEVIATION 9.9 |
| Bone Marrow Biopsy status Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:0 Ratio | 4 Participants |
| Bone Marrow Biopsy status Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:1 Ratio | 4 Participants |
| Bone Marrow Biopsy status Treatment (Anti-HIV Gene Transduced CD34+ Cells): 5:1 Ratio | 2 Participants |
| Ethnicity (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:0 Ratio Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:0 Ratio Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:0 Ratio Unknown or Not Reported | 0 Participants |
| Ethnicity (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:1 Ratio Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:1 Ratio Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:1 Ratio Unknown or Not Reported | 0 Participants |
| Ethnicity (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 5:1 Ratio Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 5:1 Ratio Not Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 5:1 Ratio Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:0 Ratio American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:0 Ratio Asian | 0 Participants |
| Race (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:0 Ratio Black or African American | 1 Participants |
| Race (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:0 Ratio More than one race | 0 Participants |
| Race (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:0 Ratio Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:0 Ratio Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:0 Ratio White | 3 Participants |
| Race (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:1 Ratio American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:1 Ratio Asian | 0 Participants |
| Race (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:1 Ratio Black or African American | 0 Participants |
| Race (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:1 Ratio More than one race | 0 Participants |
| Race (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:1 Ratio Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:1 Ratio Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:1 Ratio White | 3 Participants |
| Race (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 5:1 Ratio American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 5:1 Ratio Asian | 0 Participants |
| Race (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 5:1 Ratio Black or African American | 0 Participants |
| Race (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 5:1 Ratio More than one race | 0 Participants |
| Race (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 5:1 Ratio Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 5:1 Ratio Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Treatment (Anti-HIV Gene Transduced CD34+ Cells): 5:1 Ratio White | 2 Participants |
| Sex: Female, Male Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:0 Ratio Female | 0 Participants |
| Sex: Female, Male Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:0 Ratio Male | 5 Participants |
| Sex: Female, Male Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:1 Ratio Female | 1 Participants |
| Sex: Female, Male Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:1 Ratio Male | 3 Participants |
| Sex: Female, Male Treatment (Anti-HIV Gene Transduced CD34+ Cells): 5:1 Ratio Female | 0 Participants |
| Sex: Female, Male Treatment (Anti-HIV Gene Transduced CD34+ Cells): 5:1 Ratio Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 5 | 2 / 4 | 1 / 2 |
| other Total, other adverse events | 2 / 5 | 4 / 4 | 0 / 2 |
| serious Total, serious adverse events | 1 / 5 | 1 / 4 | 0 / 2 |
Outcome results
Primary
Percentage of Participants Who Achieve a Timely Engraftment
Timely engraftment is defined as a persistent an absolute neutrophil count (ANC) of at least 500 cells/mm3 and a platelet count of at least 20,000 cells/mm3 for at least 3 days
Time frame: 1 month post-transplant
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:0 Ratio | Percentage of Participants Who Achieve a Timely Engraftment | 60 percentage of participants who achieve a |
| Treatment (Anti-HIV Gene Transduced CD34+ Cells): 1:1 Ratio | Percentage of Participants Who Achieve a Timely Engraftment | 75 percentage of participants who achieve a |
| Treatment (Anti-HIV Gene Transduced CD34+ Cells): 5:1 Ratio | Percentage of Participants Who Achieve a Timely Engraftment | 100 percentage of participants who achieve a |
Secondary
CD4 Count Recovery
At six months post-transplant, or later, ART will be voluntarily withheld for a 12 week period only for participants who have a CD4 count of 300 or higher with no detectable viral load. for participants in which the CD4 T-cell count has not risen to ≥ 300 cells/mm3 at the time of the planned ART interruption, ART will continue until the T-cell count has risen to ≥ 300 cells/mm3.
Time frame: Up to 24 months post-treatment
Secondary
HIV-1 Viral Load
To study HIV-1 viral load over time
Time frame: At week 4, months 3, 6, 8, 10, 12, 14, 16, 20, and 24 post-transplant.
Secondary
Integration Sites of Vector Sequences in Circulating Cells
Single genome sequencing of HIV gp120 and HIV pol will be performed to understand sequence evolution following transplantation and detection of minority resistance variants.
Time frame: Up to 24 months post-transplant
Secondary
Number of Days From the First Documentation of a Complete Response Until the First Day of Relapse
Complete response is defined as the absence of any disease on imaging or by exam; progressive disease is defined as new lesions or new evidence of disease
Time frame: Time from the first documentation of CR until first date that relapsed or progressive disease is objectively documented, assessed up to 15 years
Secondary
Number of Participants With a Complete Response
A complete response is the complete disappearance of any disease, as determined by imaging
Time frame: 24 months
Secondary
Number of Participants With Adverse Events as Assessed by the CTCAE
To study safety in terms of the frequency of toxicities, infections, transfusions, and infusion-related reactions
Time frame: Up to 15 years
Secondary
Number of Participants With an Absolute Neutrophil Count of at Least 1500 Cells/mm3, Hemoglobin of at Least 10 g/dL, and Platelets Greater Than 100,000.
To study hematologic function at Day 100
Time frame: 100 days
Secondary
Overall Survival
The length of time from the start of treatment until death
Time frame: Up to 15 years
Secondary
Partial Response Rate and Duration
Will be assessed following the Lugano Classification. In the absence of evident disease progression, response will be assessed formally at 3, 6, 12 and 24 months post transplant per study calendar.
Time frame: Up to 15 years
Secondary
Persistence of Vector-transduced Cells Over Time
Vector stability analysis will be performed via qPRC sequencing.
Time frame: Up to 15 years
Secondary
Progression-free Survival
Time-to-event data will be presented graphically by Kaplan-Meier plots and summarized by estimated median time to event (if that is estimable from the data) with 95% confidence interval.
Time frame: Time from start of study treatment to relapse, progression, or death from any cause
Secondary
Proportion of Study Participants Who Achieve Greater Than 5% Mononuclear Blood Cells Expressing Anti-HIV Genes in Peripheral Blood
To determine efficacy of the candidate product, defined as establishment of \> 5% mononuclear blood cells expressing anti-HIV genes
Time frame: 3 months post-transplant
Secondary
Proportion of Study Participants With Gene Modified HIV-1 Resistant Peripheral Blood Cells and Gut Mucosal Immune Cells
To determine the presence, quantity, and duration of gene modified HIV-1 resistant peripheral blood cells and gut mucosal immune cells
Time frame: Up to 24 months post-transplant
Secondary
Quantity of Gene Modified HIV-1 Resistant Peripheral Blood Cells and Gut Mucosal Immune Cells
Summarized descriptively. Continuous measures will be summarized by mean (standard deviation \[SD\]) and median (range), with log transformation if necessary for skewed measures, as would be typical for cell counts.
Time frame: Up to 24 months post-transplant
Secondary
Time to Neutrophil Engraftment
First measurement of 3 consecutive laboratory values obtained on different days) of ANC \> 500 cells/mm3 .
Time frame: Up to 15 years
Secondary
Time to Platelet Engraftment
First measurement of 3 consecutive laboratory values obtained on different days) of platelets \> 20,000 cells/mm3 without platelet transfusions 7 days prior
Time frame: Up to 15 years
Other Pre-specified
Expansion of HIV-1 Resistant Immune Cells
Presence and the magnitude of expansion of HIV-1 resistant immune cells in the peripheral blood and gut mucosa of transplanted participants, subsequent to withholding ART
Time frame: Up to 24 months post-transplant