Human Immunodeficiency Virus (HIV)
Conditions
Keywords
Romidepsin, 3BNC117, Broadly neutralizing antibody
Brief summary
The aim of this protocol is to evaluate the effects of romidepsin plus 3BNC117 or romidepsin alone on delaying or preventing viral rebound in ART-treated HIV-1-infected individuals during an analytical interruption of ART.
Detailed description
This is a randomized interventional phase 2a trial of 3BNC117 and romidepsin in human immunodeficiency (HIV-1) infected patients on ART, conducted as a multi-center study at the Department of Infectious Diseases, Aarhus University Hospital, Denmark, the Rockefeller University Hospital, USA, and the University Hospital of Cologne, Germany. Participants will be randomized 1:1 in a non-blinded fashion to receive one of two regimens: A) Two treatment cycles each consisting of one 3BNC117 infusion (30mg/kg) + three romidepsin infusions (5mg/m2); or B) Two treatment cycles each consisting of three romidepsin infusions (5mg/m2). ART will be discontinued 16 weeks after the start of the second treatment cycle (analytical treatment interruption, ATI) and subjects will be monitored weekly for safety and viral rebound. The targeted enrollment is 30 subjects (15 per arm). Leukapheresis will be performed before and after the two treatment cycles to guarantee sufficient material to investigate changes in the reservoir after the interventions. The following criteria will require resumption of ART: * CD4+ T cell-count \<350 cells/mm³ (confirmed by repeat measurement) * 2 consecutive plasma HIV-1 RNA measurements ≥ 200 copies/mL or above their setpoint viremia (if documented) * Subject request * Continued ART interruption will, in the opinion of the investigator or study advisers, pose an unacceptable risk to the subject. If HIV-1 RNA remains undetectable at week 36, subjects will be offered to continue off ART with close monitoring, in conjunction with the subject's primary medical provider, as long as HIV-1 viral rebound does not occur. ART resumption will follow same criteria as detailed above. All subjects will be followed for a total of 48 weeks from enrollment.
Interventions
DRUG3BNC117
Intravenous Infusion of 3BNC117
DRUGRomidepsin
Intravenous Infusion of Romidepsin
Sponsors
University Hospital of Cologne
Aarhus University Hospital
Rockefeller University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Adults age 18-65 years with documented HIV-1 infection * CD4+ T-cell count \>500 cells/mm3 at screening * On ART for a minimum of 24 months and HIV-1 RNA plasma level of \< 50 copies/ml by standard assays for at least 18 months (a single viral load measurement \> 50 but \< 500 copies/ml during this time period is allowable). * Individuals on protease inhibitor or NNRTI-based regimens, or regimens containing cobicistat must be willing to switch to an integrase-inhibitor-based regimen (raltegravir or dolutegravir) prior to enrollment.
Exclusion criteria
* Use of systemic corticosteroids, immunosuppressive anti-cancer, or other medications considered significant by the investigators within the last 6 months * Pregnancy as determined by a positive urine or serum beta-hCG. * Participant unwilling to use two reliable contraception methods (i.e. condom with spermicide, diaphragm with spermicide, progestin-only containing intrauterine device (IUD) (eg, Mirena, Implanon, Nuva Ring), non-estrogen containing formulations of hormonal birth control drugs with condom) for the study duration. * Currently breast-feeding. * History of resistance to 2 or more classes of antiretroviral medications * Any medical, psychiatric, social, or occupational condition that, as judged by the investigators, would interfere with the evaluation of study objectives (such as severe alcohol or drug abuse, dementia). * Acute or chronic hepatitis B or C infection as indicated by the presence of Hepatitis B surface antigen (HBsAg) or hepatitis C virus RNA (HCV-RNA) in blood. * A history of AIDS-defining illness within 3 years prior to enrollment. * History of B-cell lymphoma, including CNS lymphoma * CD4 nadir \< 200 cells/mm3 * History of significant coronary artery disease, myocardial infarction, percutaneous coronary intervention with placement of cardiac stents, or family history of sudden death at age \< 50 years. * ECG at screening that shows QTc \>450 msec when calculated using the Fridericia formula from either lead V3 or V4, pathological Q-waves (Q-wave \> 40 msec or depth \> 0.4-0.5 mV), evidence of a ventricular pre-excitation syndromes, complete or incomplete LBBB or RBBB, second or third degree heart block, QRS duration \> 120 msec, or bradycardia defined by sinus rate \< 50 bps * Use of QT-prolonging medication, renal or hepatic disease, structural heart disease or left ventricular dysfunction * Any symptomatic or asymptomatic arrhythmia excluding sinus arrhythmia and bradycardia ≥ 50 bps. * Laboratory abnormalities in the parameters listed below: 1. Absolute neutrophil count ≤ 1,000 cells/μl 2. Hemoglobin \< 11 gm/dL 3. Platelet count \< 125,000 cells/μl 4. Alanine Aminotransferase (ALT) ≥ 1.25 x ULN 5. Aspartate Aminotransferase (AST) ≥ 1.25 x ULN 6. Total bilirubin \> 1.0 ULN 7. Creatinine \> 1.0 ULN * Any vaccination within 14 days prior to 3BNC117 administration * Receipt of any therapeutic HIV vaccine in the past * Receipt of any monoclonal antibody or HDAC inhibitor of any kind in the past. * Participation in another clinical study of an investigational product currently or within past 12 weeks, or expected participation during this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Days to Viral Rebound During Analytical Treatment Interruption (ATI) | Week 24 to Week 36 | Viral rebound is defined as HIV-1 RNA ≥ 200 copies/mL on 2 consecutive measurements during ATI. If viral rebound occurs, the date of the first measurement of HIV-1 RNA ≥ 200 copies/mL will be defined as date of viral rebound |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of of Adverse Events (AE), Serious Adverse Events (SAE), and Serious Unexpected Serious Adverse Reactions (SUSAR). | 48 weeks | The occurrence of adverse events was assessed during each follow up visit. Adverse events of grades 1 or higher were reported. |
| Change in the Size of the Proviral HIV-1 Reservoir | baseline and week 24 | Determined by total HIV-1 DNA and episomal HIV-1 DNA (2-LTR) in circulating total CD4+ T cells at baseline and prior to the ATI period (week 24). |
| Plasma HIV-1 RNA | 48 weeks | As measured by a routine clinical assay (Cobas Taqman; detection limit 20 copies/mL), a transcription mediated amplification (TMA)-based assay (detection limit 12 copies/ml) and/or a single copy assay (detection limit 1-2 copies/mL) |
Other
| Measure | Time frame | Description |
|---|---|---|
| HIV-1 Transcriptional Activity as Determined by Unspliced HIV-1 RNA (CA usHIV-1 RNA) in Circulating Total CD4+ T Cells. | baseline and week 24 | The median fold-change in cell-associated unspliced HIV-1 RNA concentrations after romidepsin administration across all infusions |
Countries
Denmark, Germany, United States
Participant flow
Recruitment details
48 participants signed informed consent. 22 met eligibility criteria and were randomized to study groups A or B in a 1:1 ratio. 2 participants withdrew consent prior to receiving the investigational products. 20 were available for analyses.
Pre-assignment details
Participants were screened after signing informed consent and underwent a baseline leukapheresis procedure.
Participants by arm
| Arm | Count |
|---|---|
| Group A Two treatment cycles each consisting of 3BNC117 infusions (30mg/kg) + three romidepsin infusions (5mg/m2). 3BNC117 will be administered on Days 0 and 56. Romidepsin will be administered on days 2, 9, 16, 58, 65, and 72 .
3BNC117: Intravenous Infusion of 3BNC117
Romidepsin: Intravenous Infusion of Romidepsin | 11 |
| Group B Two treatment cycles each consisting of three romidepsin infusions (5mg/m2). Romidepsin will be administered on days 0, 7, 14, 56, 63, and 70 .
Romidepsin: Intravenous Infusion of Romidepsin | 9 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Group A | Group B | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 9 Participants | 20 Participants |
| Age, Continuous | 40 years | 51 years | 44 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 9 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 6 Participants | 14 Participants |
| Region of Enrollment Denmark | 3 participants | 2 participants | 5 participants |
| Region of Enrollment Germany | 5 participants | 4 participants | 9 participants |
| Region of Enrollment United States | 3 participants | 3 participants | 6 participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 9 Participants | 8 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 9 |
| other Total, other adverse events | 11 / 11 | 9 / 9 |
| serious Total, serious adverse events | 0 / 11 | 0 / 9 |
Outcome results
Primary
Days to Viral Rebound During Analytical Treatment Interruption (ATI)
Viral rebound is defined as HIV-1 RNA ≥ 200 copies/mL on 2 consecutive measurements during ATI. If viral rebound occurs, the date of the first measurement of HIV-1 RNA ≥ 200 copies/mL will be defined as date of viral rebound
Time frame: Week 24 to Week 36
Population: Of the 11 participants randomized to Group A, 1 chose not to interrupt ART. Of the 9 participants randomized to Group B, 1 stopped ART earlier than planned in the protocol and 1 chose not to interrupt ART.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A | Days to Viral Rebound During Analytical Treatment Interruption (ATI) | 18 days |
| Group B | Days to Viral Rebound During Analytical Treatment Interruption (ATI) | 28 days |
Secondary
Change in the Size of the Proviral HIV-1 Reservoir
Determined by total HIV-1 DNA and episomal HIV-1 DNA (2-LTR) in circulating total CD4+ T cells at baseline and prior to the ATI period (week 24).
Time frame: baseline and week 24
Population: Participants who completed dosing per protocol and underwent leukapheresis at baseline and following the interventions (week 24).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A | Change in the Size of the Proviral HIV-1 Reservoir | 58 HIV-1 DNA per million CD4+ T cells |
| Group B | Change in the Size of the Proviral HIV-1 Reservoir | 46 HIV-1 DNA per million CD4+ T cells |
Secondary
Number of of Adverse Events (AE), Serious Adverse Events (SAE), and Serious Unexpected Serious Adverse Reactions (SUSAR).
The occurrence of adverse events was assessed during each follow up visit. Adverse events of grades 1 or higher were reported.
Time frame: 48 weeks
Population: All participants who received at least a single dose of the investigational products.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A | Number of of Adverse Events (AE), Serious Adverse Events (SAE), and Serious Unexpected Serious Adverse Reactions (SUSAR). | All Adverse events related to Romidepsin | 112 events |
| Group A | Number of of Adverse Events (AE), Serious Adverse Events (SAE), and Serious Unexpected Serious Adverse Reactions (SUSAR). | All Adverse events related to 3BNC117 | 4 events |
| Group A | Number of of Adverse Events (AE), Serious Adverse Events (SAE), and Serious Unexpected Serious Adverse Reactions (SUSAR). | Grade 2 or higher Adverse Events Related to Romidepsin | 29 events |
| Group A | Number of of Adverse Events (AE), Serious Adverse Events (SAE), and Serious Unexpected Serious Adverse Reactions (SUSAR). | Grade 2 or higher Adverse Events Related to 3BNC117 | 1 events |
| Group B | Number of of Adverse Events (AE), Serious Adverse Events (SAE), and Serious Unexpected Serious Adverse Reactions (SUSAR). | Grade 2 or higher Adverse Events Related to 3BNC117 | 0 events |
| Group B | Number of of Adverse Events (AE), Serious Adverse Events (SAE), and Serious Unexpected Serious Adverse Reactions (SUSAR). | All Adverse events related to Romidepsin | 66 events |
| Group B | Number of of Adverse Events (AE), Serious Adverse Events (SAE), and Serious Unexpected Serious Adverse Reactions (SUSAR). | Grade 2 or higher Adverse Events Related to Romidepsin | 5 events |
| Group B | Number of of Adverse Events (AE), Serious Adverse Events (SAE), and Serious Unexpected Serious Adverse Reactions (SUSAR). | All Adverse events related to 3BNC117 | 0 events |
Secondary
Plasma HIV-1 RNA
As measured by a routine clinical assay (Cobas Taqman; detection limit 20 copies/mL), a transcription mediated amplification (TMA)-based assay (detection limit 12 copies/ml) and/or a single copy assay (detection limit 1-2 copies/mL)
Time frame: 48 weeks
Population: Participants with detectable plasma HIV-1RNA during the treatment cycles measure by commercial assays.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A | Plasma HIV-1 RNA | 4 Participants |
| Group B | Plasma HIV-1 RNA | 4 Participants |
Other Pre-specified
HIV-1 Transcriptional Activity as Determined by Unspliced HIV-1 RNA (CA usHIV-1 RNA) in Circulating Total CD4+ T Cells.
The median fold-change in cell-associated unspliced HIV-1 RNA concentrations after romidepsin administration across all infusions
Time frame: baseline and week 24
Population: Participants who completed dosing according to protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A | HIV-1 Transcriptional Activity as Determined by Unspliced HIV-1 RNA (CA usHIV-1 RNA) in Circulating Total CD4+ T Cells. | 9 CA-us HIV-1 RNA per million CD4 T cells |
| Group B | HIV-1 Transcriptional Activity as Determined by Unspliced HIV-1 RNA (CA usHIV-1 RNA) in Circulating Total CD4+ T Cells. | 11 CA-us HIV-1 RNA per million CD4 T cells |