Combinatorial Therapy to Induce an HIV Remission

• ClinicalTrials.gov Identifier: NCT04357821
• Recruitment Status: Active, not recruiting
• First Posted: April 22, 2020
• Last Update Posted: March 23, 2022
• Sponsor: University of California, San Francisco
• Collaborators: amfAR, The Foundation for AIDS Research; International AIDS Vaccine Initiative; Ichor Medical Systems; National Institute of Allergy and Infectious Diseases (NIAID); Rockefeller University; Mologen AG; GeoVax, Inc.
• Information provided by (Responsible Party): Steven Deeks, University of California, San Francisco

Tracking Information

• First Submitted Date: April 18, 2020
• First Posted Date: April 22, 2020
• Last Update Posted Date: March 23, 2022
• Actual Study Start Date: August 1, 2020
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 21, 2020)

• Proportion of participants who experience a new grade 3 or greater adverse event [ Time Frame: Week 0 through 86 ]
• Proportion of participants achieving post-treatment control. [ Time Frame: Week 34 through 86 ]
  This will be defined as:

  1. Participants who fail to show any consistent rebound above 400 copies RNA/mL between Week 12 of the ATI (when bNAb levels wane) and Week 36 of the ATI
  2. Participants who exhibit a rebound and eventually achieve 24 weeks of virus control will be considered as having achieved post-treatment control

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 22, 2020)

• Occurrence of any unsolicited adverse events for 28 days after administration of each study agent [ Time Frame: Week 0 through 62 ]
• Occurrence of any serious adverse events, medically attended adverse event, and potentially immune-mediated medical condition from the time of administration of the first study injection through 12 months after administration of the final study injection [ Time Frame: Week 0 through 86 ]
• Occurrence of two consecutive measurements HIV RNA >200 copies/mL using conventional assays [ Time Frame: Week 34 to 86 ]
• Resumptions of antiretroviral therapy after treatment interruption and the events that trigger them [ Time Frame: Week 34 to 86 ]
• Frequency of confirmed declines (two consecutive measurements) in CD4+ T cell counts (> 50%) [ Time Frame: Week 34 to 86 ]
• Frequency of confirmed declines (two consecutive measurements) to below 350 cells/mm3 [ Time Frame: Week 34 to 86 ]
• Proportion experiencing any clinically defined episode of acute retroviral syndrome [ Time Frame: Week 34 to 86 ]
• Magnitude of T cell responses [ Time Frame: Week 14 ]
• Breadth of T cell responses [ Time Frame: Week 14 ]
  The proportion of participants with at least one additional epitope response at week 14 (2 weeks after last vaccination) compared to their baseline response

Original Secondary Outcome Measures (submitted: April 21, 2020)

• Occurrence of any unsolicited AEs for 28 days after administration of each study agent [ Time Frame: Week 0 through 62 ]
• Occurrence of any SAE, MAAE, and PIMMC from the time of administration of the first study injection through 12 months after administration of the final study injection [ Time Frame: Week 0 through 86 ]
• Occurrence of two consecutive measurements HIV RNA >200 copies/mL using conventional assays [ Time Frame: Week 34 to 86 ]
• Resumptions of ART after ATI and the events that trigger them [ Time Frame: Week 34 to 86 ]
• Frequency of confirmed declines (two consecutive measurements) in CD4+ T cell counts (> 50%) [ Time Frame: Week 34 to 86 ]
• Frequency of confirmed declines (two consecutive measurements) to below 350 cells/mm3 [ Time Frame: Week 34 to 86 ]
• Proportion experiencing any clinically defined episode of acute retroviral syndrome [ Time Frame: Week 34 to 86 ]
• Magnitude of T cell responses [ Time Frame: Week 14 ]
• Breadth of T cell responses [ Time Frame: Week 14 ]
  The proportion of participants with at least one additional epitope response at week 14 (2 weeks after last vaccination) compared to their baseline response

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Combinatorial Therapy to Induce an HIV Remission
• Official Title: Combinatorial Therapy With a Therapeutic Conserved Element DNA Vaccine, MVA Vaccine Boost, TLR9 Agonist and Broadly Neutralizing Antibodies: a Proof-of-concept Study Aimed at Inducing an HIV Remission
• Brief Summary: Combination approaches will almost certainly be required to generate durable control of HIV in the absence of antiretroviral therapy (a "remission"). In this study, 20 individuals will receive a combination regimen administered during ART and then undergo an analytic treatment interruption (ATI).

Detailed Description

The investigators will perform a single arm study of twenty individuals with HIV infection on effective ART. All participants will receive a combination regimen administered during ART and then undergo an analytic treatment interruption. Our strategy has five stages

1. IL-12 adjuvanted p24CE DNA prime (p24CE/IL-12) at Weeks 0 and 4
2. IL-12 adjuvanted DNA boost (p24CE plus p55gag) at Week 12
3. MVA/HIV62B (MVA62B) boost at Week 20
4. single dose of two bNAbs (VRC07-523LS and 10-1074, which target CD4 binding site and V3 loop, respectively) at week 24 with a TLR9 agonist (lefitolimod) administered weekly between Weeks 24 and 33 (10 doses)
5. ATI with single dose of VRC07 and 10-1074 at Week 34

Follow-up off ART will occur through at least Week 46 (expected) and on or off ART (depending on outcome) through Week 86.

Should this approach work, viral load would be expected to rebound in all individuals a few weeks after the bNAb levels decrease to sub-therapeutic levels. This acute rebound would be followed by a new lower viral load set-point and perhaps a long-term remission.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: HIV/AIDS

Intervention

Drug: Combination Intervention

1. IL-12 adjuvanted p24CE DNA prime (p24CE/IL-12) at Weeks 0 and 4
2. IL-12 adjuvanted DNA boost (p24CE plus p55gag) at Week 12
3. MVA/HIV62B (MVA62B) boost at Week 20
4. single dose of two bNAbs (VRC07-523LS and 10-1074, which target CD4 binding site and V3 loop, respectively) at week 24 with a TLR9 agonist (lefitolimod) administered weekly between Weeks 24 and 33 (10 doses)
5. ATI with single dose of VRC07 and 10-1074 at Week 34

Study Arms

Experimental: Combination intervention arm

All volunteers will receive the combination intervention outlined above.

Intervention: Drug: Combination Intervention

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 21, 2022): 11
• Original Estimated Enrollment (submitted: April 21, 2020): 20
• Estimated Study Completion Date: December 2024
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria

1. Willing and able to provide written informed consent.
2. Age ≤67 years at the time of enrollment for those who started treatment during early infection and <65 years for those who started treatment during chronic infection.
3. Documented HIV-1 infection.
4. On continuous antiretroviral therapy for at least 12 months without any interruptions of greater than 14 consecutive days within the last 1 year, and on a stable regimen that does not include an non-nucleoside reverse transcriptase inhibitor (NNRTI) for at least 4 weeks, without plans to modify ART during the study period.
5. Screening plasma HIV RNA levels below the level of quantification on all available determinations in past 24 months.
6. Screening CD4+ T-cell count ≥ 500 cells/mm3.

Key Exclusion Criteria

1. Subjects receiving a non-nucleoside reverse transcriptase inhibitor
2. Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study
3. High-level resistance to both 10-1074 and VRC-07 as defined using the PhenoSense Neutralizing Antibody Assay (Monogram Biosciences).
4. Any history of an HIV-associated malignancy, including Kaposi's sarcoma and any type of lymphoma, or virus-associated cancers.
5. Active or recent non-HIV-associated malignancy requiring systemic chemotherapy or surgery in the preceding 36 months or for whom such therapies are expected in the subsequent 12 months.
6. CD4+ T cell nadir <350 cells/mm3 during the chronic phase of infection (beginning 6 months following the estimated infection date and confirmed on repeat testing).
7. Active hepatitis B (HBV) infection defined as positive HBV surface antigen test.

9. Active hepatitis C (HCV) infection. 10. Presence of significant abnormalities on electrocardiogram. 11. History of potential immune-mediated medical conditions. Individuals with isolated Raynaud's phenomenon or localized disease requiring topical therapy alone will not be excluded.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 67 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04357821
• Other Study ID Numbers: 18-26957
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Steven Deeks, University of California, San Francisco
• Original Responsible Party: Same as current
• Current Study Sponsor: University of California, San Francisco
• Original Study Sponsor: Same as current

Collaborators

• amfAR, The Foundation for AIDS Research
• International AIDS Vaccine Initiative
• Ichor Medical Systems
• National Institute of Allergy and Infectious Diseases (NIAID)
• Rockefeller University
• Mologen AG
• GeoVax, Inc.

• Investigators: Not Provided
• PRS Account: University of California, San Francisco
• Verification Date: March 2022