Safety and Immunotherapeutic Activity of an Anti-PD-1 Antibody (Cemiplimab) in Participants With HIV-1 on Suppressive cART

Study Overview
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Brief Summary
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The purpose of this study was to evaluate the safety and immunotherapeutic activity of an anti-PD-1 antibody (cemiplimab) in participants with HIV-1 on suppressive combination antiretroviral therapy (cART).

Detailed Description
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This study evaluated the safety and immunotherapeutic activity of an anti-PD-1 antibody (cemiplimab) in participants with HIV-1 on combination antiretroviral therapy (cART) who have plasma less than the quantification limit of an FDA-approved assay and CD4+ T cell counts ≥350/mm^3. Participants were planned to be enrolled into three sequential dose-rising cohorts. Participants in each cohort received infusions of either cemiplimab or placebo, with planned administration at study entry (Day 0) and Week 6, for a total of two infusions. All participants continued their non-study provided ART regimen. Enrollment in the second and third cohorts would only open after all participants in the previous cohort had reached week 12 and an evaluation of safety outcomes established that it is safe to dose escalate. Participants had screening and pre-entry visits and attended study visits on Day 0 and Weeks 1, 2, 4, 6, 7, 8, 10, 12, 16, 20, 24, 28, 36, and 48. Participants were followed for 48 weeks. Due to observed adverse events which were deemed possibly related to study treatment in two of four treated participants, the study was terminated and did not enroll further participants. The two participants who had adverse events did not receive the second infusion. The treated participants were followed for the planned 48 weeks, while the placebo participant was not followed after a final study visit at week 7.

Official Title
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Safety and Immunotherapeutic Activity of an Anti-PD-1 Antibody (Cemiplimab) in Participants With HIV-1 on Suppressive cART: A Phase I/II, Double-blind, Placebo-controlled, Ascending Multiple Dose Study

Conditions
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HIV Infections

Intervention / Treatment
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* Biological: Cemiplimab
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infection On ART for at least 24 months Receiving ART with no changes of the components of ART medications within 90 days prior to study entry Changes within drug class, in drug formulation or dose are allowed more than 30 days prior to study entry. CD4+ T cell count ≥350 cells/mm^3 At least two plasma HIV-1 RNA less than the quantification limit of an FDA-approved assay within 18 months A single detectable HIV-1 RNA but less than 1000 copies/mL is allowed if followed by HIV-1 RNA below quantifiable limits. HIV-1 RNA level less than the quantification limit of an FDA-approved assay within 90 days prior to study entry The following laboratory values within 90 days prior to entry: Absolute neutrophil count (ANC) ≥1500 cells/mm^3 Hemoglobin ≥14.0 g/dL for men and ≥12.0 g/dL for women Platelet count ≥150,000/mm^3 Creatinine clearance ≥60 mL/min Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal limits Normal thyroid, adrenal and diabetes testing Negative tuberculosis (TB) test result, OR documentation of completed TB prophylaxis treatment HCV antibody negative result or, if HCV antibody positive, undetectable HCV RNA result Negative HBsAg result Ability and willingness to provide informed consent. Ability and willingness to continue non-study-provided cART throughout the study. Female participants must have a negative pregnancy test. Agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization, egg donation) during the study. When participating in sexual activity that could lead to pregnancy, agree to use at least two reliable forms of contraception simultaneously during the study through week 48. Participants who are not of reproductive potential (women who have been post-menopausal for at least 24 consecutive months or have undergone hysterectomy and/or bilateral oophorectomy or salpingectomy or men who have documented azoospermia or undergone vasectomy) are eligible without requiring the use of contraceptives. Weight ≥50 kg (110 pounds) Exclusion Criteria: History of malignancy within the last 5 years. Prior non-melanoma skin cancer (e.g., basal cell carcinoma or squamous cell skin cancer) is not exclusionary with documentation of complete resection at least 3 months prior to enrollment. HIV-related opportunistic infections within the last 5 years Chronic obstructive pulmonary disease (COPD). Prior radiation therapy. Active or previously treated active TB. Active asthma requiring any treatment in the prior 2 years Type I or type II diabetes mellitus. History of or active autoimmune disorders including but not limited to inflammatory bowel diseases, scleroderma, severe psoriasis, myocarditis, uveitis, pneumonitis, systemic lupus erythematosus, rheumatoid arthritis, optic neuritis, myasthenia gravis, adrenal insufficiency, hypothyroidism and/or hyperthyroidism, autoimmune thyroiditis, hypophysitis, or sarcoidosis. Immune deficiency other than that caused by HIV infection. Currently breastfeeding or pregnant. Known allergy/sensitivity or any hypersensitivity to mAb-based biologics, cemiplimab (anti-PD-1) or its formulation. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements. Receipt of investigational drug or use of investigational medical device within 6 months prior to study entry. Use of or intent to use immunomodulators (e.g., interleukins, interferons, cyclosporine, systemic corticosteroids exceeding physiologic doses), HIV vaccine, or systemic cytotoxic chemotherapy within 60 days prior to study entry. NOTE: Participants receiving stable physiologic glucocorticoid doses, defined as prednisone ≤10 mg/day or the equivalent, will not be excluded. Stable physiologic glucocorticoid doses should not be discontinued for the duration of the study. In addition, participants receiving topical corticosteroids will not be excluded. Any vaccination within 30 days HCV treatment within 6 months Prior immunoglobulin (IgG) therapy. Current use or intent to use biotin ≥5 mg/day, including within dietary supplements. History of chronic congestive heart failure or other significant cardiac conditions. Any active, clinically significant medical condition that, in the opinion of the site investigator, would place the participant at increased risk.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 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
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Cemiplimab<br>Participants received 0.3 mg/kg of cemiplimab, administered at Day 0 and Week 6 for a total of two infusions. Participants continued their current non-study provided ART regimen. | Biological: Cemiplimab<br>* Administered as an intravenous (IV) infusion<br>* Other names: REGN2810;|
| Placebo Comparator: Cohort 1: Placebo<br>Participants received placebo, administered at Day 0 and Week 6 for a total of two infusions. Participants continued their current non-study provided ART regimen. | Biological: Placebo<br>* Diluent for REGN2810, administered as an IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Count of Participants With a Grade >=3 Adverse Event (AE) or Grade >=1 Immune-related AE (irAE) Related to Study Treatment | Relationship to study treatment was judged by the Clinical Management Committee (CMC), blinded to treatment arm. Immune-related AEs include, but were not limited to, pneumonitis, colitis, adrenal insufficiency, or hypothyroidism. Adverse events were graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017. Infusion reactions, adrenal insufficiency, and pneumonitis were graded per the National Cancer Institute's (NCI) Common Terminology Criteria for AEs (CTCAE), Version 5.0 guidelines | Study Entry through Week 48 or premature discontinuation | 
| Count of Participants With a Grade >=1 irAE Related to Study Treatment | Relationship to study treatment was judged by the Clinical Management Committee (CMC), blinded to treatment arm. Immune-related AEs include, but were not limited to, pneumonitis, colitis, adrenal insufficiency, or hypothyroidism. Adverse events were graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017. Infusion reactions, adrenal insufficiency, and pneumonitis were graded per the National Cancer Institute's (NCI) Common Terminology Criteria for AEs (CTCAE), Version 5.0 guidelines | Study Entry through Week 48 or premature discontinuation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HIV-1 Gag-specific CD8+ T Cells by Intracellular Staining for CD107a and Interferon Gamma (IFNg) From Baseline to Post-baseline | Change evaluated from baseline (average of pre-entry and entry measures) to post-baseline (average of weeks 2-12 measures). Results for each week are calculated by subtracting the corresponding background control value. If the result was less than zero after background subtraction, the result was set to zero. | Baseline through Week 12 | 
| Change in HIV-1 Gag-specific CD8+ T Cells by Intracellular Staining for IFNg or CD107a Alone From Baseline to Post-baseline | Change evaluated from baseline (average of pre-entry and entry measures) to post-baseline (average of weeks 2-12 measures). Results for each week are calculated by subtracting the corresponding background control value. If the result was less than zero after background subtraction, the result was set to zero. | Baseline through Week 12 | 
| Change in Polyfunctional Response of HIV-1 Gag-specific CD8+ T Cells by Intracellular Staining for IFNg, CD107a, IL-2, and Tumor Necrosis Factor Alpha (TNFa) From Baseline to Post-baseline | Change evaluated from baseline (average of pre-entry and entry measures) to post-baseline (average of weeks 2-12 measures). Polyfunctional response was defined as being positive for two or more cytokines. Results for each week are calculated by subtracting the corresponding background control value. If the result was less than zero after background subtraction, the result was set to zero. | Baseline through Week 12 | 
| Change in HIV-1 Gag-specific CD8+ T Cells by Intracellular Staining for IFNg and CD107a After Each Infusion | Change evaluated from baseline (average of pre-entry and entry measures) to after the first dose (average of Weeks 2-6), and from baseline to after the second dose (average of Weeks 8-12). Results for each week are calculated by subtracting the corresponding background control value. If the result was less than zero after background subtraction, the result was set to zero. | Baseline through Week 12 |