Long-Acting Cabotegravir Plus VRC-HIVMAB075-00-AB (VRC07-523LS) for Viral Suppression in Adults Living With HIV-1

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety, tolerability, pharmacokinetics, and antiviral activity of long-acting cabotegravir (CAB LA) plus the broadly neutralizing monoclonal antibody,VRC-HIVMAB075-00-AB (VRC07-523LS), in adults living with HIV-1 with suppressed plasma viremia.

Detailed Description
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This study will assess the safety, tolerability, pharmacokinetics, and antiviral activity of long-acting cabotegravir (CAB LA) plus the broadly neutralizing monoclonal antibody, VRC-HIVMAB075-00-AB (VRC07-523LS), in adults living with HIV-1 with suppressed plasma viremia. The study will be conducted in three steps. At Step 1 entry, all participants will discontinue their current antiretroviral therapy (ART) regimen except for nucleoside reverse transcriptase inhibitors (NRTIs), and initiate oral CAB. During Step 1, participants tolerating oral CAB plus their current two NRTIs, and displaying viral suppression (HIV-1 RNA <50 copies/mL), will register to Step 2. At entry into Step 2, eligible participants will stop their oral CAB and NRTIs and will receive a VRC07-523LS infusion plus CAB LA injection. After entry in Step 2, participants will receive CAB LA every 4 weeks through Week R2+44 plus VRC07-523LS every 8 weeks through Week R2+40. At the last visit in Step 2 (Week R2+48), or at premature study treatment discontinuation, all participants who received any CAB LA or VRC07-523LS will enter Step 3 and switch to standard of care (SOC) oral ART for approximately 48 weeks. Participants will attend a number of study visits throughout the study. Study visits may include a physical examination, clinical assessment, pregnancy testing, and blood and urine collection. Participants will remain in the study for up to 101 weeks, including approximately 5 weeks in Step 1, 48 weeks in Step 2, followed by 48 weeks in Step 3.

Official Title
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A Study of Long-Acting Cabotegravir Plus VRC-HIVMAB075-00-AB (VRC07-523LS) to Maintain Viral Suppression in Adults Living With HIV-1

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Oral Cabotegravir (CAB)
* Drug: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
* Drug: Long-Acting Injectable Cabotegravir (CAB LA)
* Biological: VRC07-523LS
* Drug: Standard of Care (SOC) Oral ART


Participation Criteria
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Eligibility Criteria
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Step 1 Inclusion Criteria HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load. NOTE: The term licensed refers to a US Food and Drug Administration (FDA)-approved kit, which is required for all IND studies. World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment. A reactive initial rapid test should be confirmed by either another type of rapid assay or an E/CIA that is based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load. Clinically stable (i.e.,in the opinion of the site investigator, doing well and not sick from treatment) for at least 8 weeks prior to study entry on a three-drug ART regimen that includes a boosted protease inhibitor, a nonnucleoside reverse transcriptase inhibitor (NNRTI), or an integrase inhibitor, plus two NRTIs, with no history of a switch due to virologic failure. NOTE: Previous switches for reasons other than virologic failure prior to screening are allowed. Screening CD4+ T-cell count greater than or equal to 350 cells/mm^3 obtained within 60 days prior to study entry at any US laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent. All available HIV-1 RNA measurements must be less than 50 copies/mL within the 2 years prior to study entry except as allowed by the note below. NOTE: One plasma HIV-1 RNA greater than or equal to 50 copies/mL but less than 200 copies/mL is allowed if followed by a subsequent HIV-1 RNA value below 50 copies/mL. Participants must have at least two documented HIV-1 RNA less than 50 copies/mL within 12 months prior to study entry. NOTE: The HIV-1 RNA level obtained at the screening visit can be used as the second measurement, but must meet the requirements of screening plasma HIV-1 RNA criterion below. Screening plasma HIV-1 RNA less than 50 copies/mL by any FDA-approved assay with minimum limit of detection of 50 copies/mL or lower obtained within 60 days prior to study entry by any US laboratory that has a CLIA certification or its equivalent. The following laboratory values obtained within 60 days prior to entry at any US laboratory that has a CLIA certification or its equivalent. Absolute neutrophil count (ANC) greater than or equal to 750/mm^3 Hemoglobin greater than or equal to 11.0 g/dL for men or greater than or equal to 10.0 g/dL for women Platelet count greater than or equal to 100,000/mm^3 Calculated creatinine clearance (Cockcroft-Gault formula) greater than or equal to 50 mL/min Aspartate aminotransferase (AST) (SGOT) less than or equal to 2.0 x ULN Alanine aminotransferase (ALT) (SGPT) less than or equal to 2.0 x ULN For females of reproductive potential, negative serum or urine pregnancy test within 48 hours prior to entry by any clinic or laboratory that has a CLIA certification or its equivalent, or is using a point of care (POC)/CLIA-waived test. NOTE A: Reproductive potential is defined as girls who have reached menarche and women who have had menses within the prior 12 months, and have not undergone surgical sterilization. If no menses for a year or longer, the follicle-stimulating hormone (FSH) should be less than or equal to 40 IU/mL to be considered of reproductive potential. If an FSH is not available, and they have not had menses in 24 or more consecutive months, they would be considered not to be of reproductive potential. Women who have undergone surgical sterilization (e.g., hysterectomy, bilateral oophorectomy, tubal micro-inserts, tubal ligation or salpingectomy) are considered not to be of reproductive potential. NOTE B: Participant-reported history of hysterectomy and bilateral oophorectomy, tubal ligation, bilateral salpingectomy, tubal micro-inserts, and menopause is acceptable documentation. Female participants of reproductive potential, who are participating in sexual activity that could lead to pregnancy, must agree to use an effective form of contraception from 30 days prior to the first dose of study medication, while receiving the study drugs, and for 30 days after stopping oral medications, or the duration specified in the product label if receiving ARV drugs not supplied by the study, or for approximately 48 weeks after last dose of CAB LA or VRC07-523LS. Acceptable methods of contraception include: Contraceptive subdermal implant Intrauterine device or intrauterine system Combined estrogen and progestogen oral contraceptive Injectable progestogen Contraceptive vaginal ring Percutaneous contraceptive patches Women who are not of reproductive potential are eligible to start study treatment drugs without requiring the use of contraceptives. Refer to above criterion for definition of female who is not of reproductive potential. NOTE: All participants in the study should be counseled on safer sexual practices including the use and benefit/risk of effective barrier methods (e.g., male condom) and on the risk of HIV transmission to a partner without HIV. Men and women aged greater than or equal to 18 years. Ability and willingness of participant to provide written informed consent. Negative HBsAg results obtained within 60 days prior to study entry. Negative hepatitis C virus (HCV) antibody result obtained within 60 days prior to study entry or, if the HCV antibody result is positive, a negative HCV RNA result obtained within 60 days prior to study entry. Susceptibility to VRC07-523LS based on IC50 of less than or equal to 0.25 µg/mL and a Maximum Percent Inhibition greater than 98% using the Monogram PhenoSense Assay on sample obtained at the screening visit. NOTE: Participants who were in screening as of March 16, 2020 and had their samples drawn for PhenoSense susceptibility testing to VRC07-523LS or completed on or before this date do not need to repeat this testing as part of the re-screening when the study re-opens, provided that there is no documented detectable HIV viral load since the original screen. Adequate venous access in at least one arm. Willingness to continue current two NRTIs and expects to have continued access to NRTIs in Step 1. NOTE: NRTIs will not be provided by the study. Participants without continued access to NRTIs will be provided reimbursement for these drugs by the study. Willingness to not actively engage in the conception process for the duration of the study. Step 1 Exclusion Criteria Any previous receipt of humanized or human monoclonal antibody (licensed or investigational). Weight greater than 115 kg or less than 53 kg. AIDS-defining illness within 60 days prior to study entry. History of a severe allergic reaction with generalized urticarial, angioedema, or anaphylaxis within 2 years prior to study entry. Currently breastfeeding or pregnant. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements. Acute or serious illness that, in the opinion of the site investigator, requires systemic treatment, quarantine, and/or hospitalization within 30 days prior to entry. Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 60 days prior to study entry. NOTE: Participants receiving stable physiologic doses of glucocorticoids, defined as the equivalent of prednisone less than or equal to 10 mg/day, will not be excluded. Stable physiologic glucocorticoid doses should not be discontinued for the duration of the study. In addition, participants receiving inhaled or topical corticosteroids will not be excluded. Treatment for hepatitis C within 24 weeks prior to study entry. Vaccinations within 7 days prior to study entry. NOTE: Participants are encouraged to get routine vaccinations, such as seasonal influenza vaccine outside this window. If vaccination occurs within 7 days prior to study entry, the entry visit should be postponed for at least 7 days after the vaccination. Initiation of ART during acute HIV-1 infection (as determined by the site investigator by history and/or available medical records). Personal or known family history of prolonged QT syndrome or, in the opinion of the site investigator, a clinically significant finding on the screening electrocardiogram (ECG) based on an assessment of the screening ECG by that site investigator. Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). Moderate or severe hepatic impairment (Class B or C) as determined by Child-Pugh classification. History of seizures or treatment for seizures within the past 2 years prior to study entry. NOTE: For candidates with a remote (greater than 2 year) history of seizure, consult the A5357 Clinical Management Committee [CMC] for eligibility determination. Current acute illness that in the opinion of the investigator will prevent the participant from complying with study visits. Step 2 Inclusion Criteria HIV-1 RNA less than 50 copies/mL at week 4 (Step 1), or HIV-1 RNA of 50-199 copies/mL at week 4 followed by HIV-1 RNA less than 50 copies/mL at week 5 (Step 1). Females of reproductive potential must have a negative serum or urine pregnancy test obtained within 48 hours prior to Step 2 registration. NOTE: Refer to the criteria above for definition of reproductive potential and acceptable documentation. Confirmation that female participant agrees to continue to use an effective form of contraception (see criterion above) while on study, and for approximately 48 weeks after last dose of CAB LA or VRC07-523LS. Confirmation of willingness to not actively engage in the conception process for the duration of the study. Step 2 Exclusion Criteria Discontinuation or temporary hold of oral CAB for greater than 7 consecutive days for any reason during Step 1. Discontinuation or temporary hold of NRTIs for greater than 7 consecutive days for any reason during Step 1. Grade 3 or 4 adverse event thought to be related to oral CAB during Step 1 according to the site investigator. Vaccination (e.g., influenza) within 7 days prior to the Step 2 registration. Currently breastfeeding or pregnant. Any greater than or equal to Grade 2 ALT (greater than 2.5 times ULN) that developed during Step 1. Current implants and/or direct silicone injections on or around the subcutaneous area where the study product will be administered. An overlying tattoo (that is located on or around the skin area where the study product will be administered) that, per the site investigator's best clinical judgement, would impede clinical care or management in any way. Step 3 Inclusion Criterion Received any CAB LA or VRC07-523LS during Step 2. NOTE: Participants who prematurely discontinue study treatment for any reason in Step 2 remain eligible for Step 3. Step 3 Exclusion Criterion There are no exclusion criteria to Step 3.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CAB LA + VRC07-523LS<br>Step 1: CAB administered orally as one 30 mg tablet once daily, plus two NRTIs, for 5 weeks. Step 2: CAB LA loading dose (600 mg) administered as one IM injection at Step 2 entry study visit, and maintenance dose (400 mg), starting at 4 weeks after CAB LA loading dose, and then every 4 weeks through Week R2+44. VRC07-523LS (40 mg/kg) administered as an IV infusion starting at Step 2 entry and then every 8 weeks through Week R2+40. Step 3: SOC oral ART regimen for approximately 48 weeks. | Drug: Oral Cabotegravir (CAB)<br>* 30 mg tablets administered orally<br>Drug: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)<br>* NRTIs will not be provided by the study. Participants will obtain NRTIs outside of the study through routine care.<br>Drug: Long-Acting Injectable Cabotegravir (CAB LA)<br>* 600 mg loading dose followed by 400 mg maintenance doses administered by intramuscular (IM) injection<br>Biological: VRC07-523LS<br>* 40 mg/kg administered as an intravenous (IV) infusion<br>* Other names: VRC-HIVMAB075-00-AB;Drug: Standard of Care (SOC) Oral ART<br>* SOC ART will not be provided by the study. Participants will obtain SOC ART outside of the study through routine care.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of either 1) the occurrence of a Grade 3 or higher adverse event (AE); or 2) premature study treatment discontinuation due to an AE (regardless of grade) | Both of which are possibly, probably, or definitely related (as judged by the core team) to the CAB LA plus VRC07-523LS combination. | Measured through Week R3+48 of Step 3 | 
| Number of participants who experience virologic failure | Defined as confirmed HIV-1 RNA greater than or equal to 200 copies/mL | Measured through Week R2+44 of Step 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough levels of the concentration of VRC07-523LS | Based on PK sampling | Measured through Week R2+48 of Step 2 | 
| Trough levels of the concentration of CAB LA | Based on PK sampling | Measured through Week R2+48 of Step 2 | 
| Frequency of viral resistance of breakthrough isolates | Based on laboratory evaluations | Measured through Week R2+44 of Step 2 | 
| Number of participants who experience virologic failure | Defined as confirmed HIV-1 RNA greater than or equal to 200 copies/mL | Measured through Week R2+24 of Step 2 | 
| Frequency of either 1) virologic failure (confirmed HIV-1 RNA greater than or equal to 200 copies/mL); or 2) premature discontinuation of the CAB LA plus VRC07-523LS combination | Based on laboratory evaluations | Measured through Week R2+44 of Step 2 | 
| Number of participants with confirmed HIV-1 RNA greater than or equal to 50 copies/mL | Based on laboratory evaluations | Measured through Week R2+44 of Step 2 | 
| Number of participants with confirmed HIV-1 RNA greater than or equal to 50 copies/mL | Based on laboratory evaluations | Measured through Week R2+24 of Step 2 | 
| Number of participants with either 1) confirmed HIV-1 RNA greater than or equal to 50 copies/mL; or 2) premature discontinuation of the CAB LA plus VRC07-523LS combination | Based on laboratory evaluations | Measured through Week R2+44 of Step 2 | 
| Number of participants who experience virologic failure | Defined by the U.S. Food and Drug Administration (FDA) snapshot algorithm | Measured through Week R2+44 of Step 2 | 
| Frequency of anti-idiotype antibodies against VRC07-523LS in samples collected from representative time points throughout the study | Based on laboratory evaluations | Measured through Week R2+48 of Step 2 | 
| Frequency of either 1) the occurrence of a Grade 3 or higher AE; or 2) premature oral CAB discontinuation due to an AE (regardless of grade) | Both of which are possibly, probably, or definitely related (as judged by the core team) to oral CAB. | Measured through Week 5 of Step 1 | 
| Number of participants who prematurely discontinue oral CAB or the CAB LA plus VRC07-523LS combination | Based on self report | Measured through Week R2+44 of Step 2 | 
| Frequency of the occurrence of a Grade 3 or higher AE that is possibly, probably, or definitely related (as judged by the core team) to oral CAB or the CAB LA plus VRC07-523LS combination | Frequency of the occurrence of a Grade 3 or higher AE that is possibly, probably, or definitely related (as judged by the core team) to oral CAB or the CAB LA plus VRC07-523LS combination | Measured through Week R3+48 of Step 3 |