Safety and Immune Response of BMS-936559 in HIV-Infected People Taking Combination Antiretroviral Therapy

NCT02028403 | Completed Phase 1 DMC

• 2 other identifiers: A532611921
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 5

Brief Summary

People infected with HIV may have low levels of the virus in their body, even if they are taking HIV medications. This study will evaluate the safety, pharmacokinetics (PK) (which is how the body interacts with drugs), and immune response to BMS-936559, a drug that will be administered by an intravenous (IV) infusion, in HIV-infected people receiving combination antiretroviral therapy (cART) who have viral load levels below the limit of detection.

Conditions

HIV Infections

Outcome Measures

Primary Outcomes (4)

• Occurrence of a Grade 3 or greater adverse event (AE), including sign/symptom, lab toxicity, or clinical event that is definitely, probably, or possibly related to study treatment

  As judged by the core team, blinded to treatment arm; any time from study treatment administration until 28 days after the administration.

  Measured through Day 28

• Occurrence of a Grade 1 or > AE of all incident adrenal insufficiency or adrenal crisis (confirmed), myocarditis, pneumonitis, uveitis, immune-mediated hyperthyroidism or hypothyroidism, that is definitely, probably, or possibly related to study

  As judged by the core team, blinded to treatment arm; any time from study treatment administration until 28 days after the administration. (Pneumonitis is Category A, B, or C)

  Measured through Day 28

• Frequency of HIV-1 Gag-specific CD8 T-cells by intracellular staining for interferon (IFN)-gamma at baseline and after treatment (through Day 28)

  Measured through Day 28

• HIV-1 RNA by single copy assay (SCA) at baseline and after treatment (through Day 28)

  Measured through Day 28

Secondary Outcomes (16)

• PK parameters from non-compartmental analysis (area under curve [AUC], Cmax, V, Tmax, CL/F, t1/2)

  Measured through Week 48

• Exploratory pharmacodynamic parameters (Emax, EC50)

  Measured through Week 48

• HIV-1 DNA at baseline and after treatment

  Measured through Week 48

• Programmed cell death 1 ligand 1 (PD-L1) receptor occupancy

  Measured through Week 48

• Proportion of total and HIV-1 gag-specific CD8 T-cells expressing programmed cell death 1 (PD-1), PD-L1, and other exhaustion markers

  Measured through Week 48

Study Arms (8)

Cohort 1A: single dose 0.3 mg/kg BMS-936559

EXPERIMENTAL

Participants will receive 0.3 mg/kg of BMS-936559, administered as a single infusion once at study entry.

Drug: BMS-936559

Cohort 1B: single dose placebo for BMS-936559

PLACEBO COMPARATOR

Participants will receive placebo for BMS-936559, administered as a single infusion once at study entry.

Drug: Placebo for BMS-936559

Cohort 2A: single dose 1 mg/kg BMS-936559

EXPERIMENTAL

Participants will receive 1 mg/kg of BMS-936559, administered as a single infusion once at study entry.

Drug: BMS-936559

Cohort 2B: single dose placebo for BMS-936559

PLACEBO COMPARATOR

Participants will receive placebo for BMS-936559, administered as a single infusion once at study entry.

Drug: Placebo for BMS-936559

Cohort 3A: single dose 3 mg/kg BMS-936559

EXPERIMENTAL

Participants will receive 3 mg/kg of BMS-936559, administered as a single infusion once at study entry.

Drug: BMS-936559

Cohort 3B: single dose placebo for BMS-936559

PLACEBO COMPARATOR

Participants will receive placebo for BMS-936559, administered as a single infusion once at study entry.

Drug: Placebo for BMS-936559

Cohort 4A: single dose 10 mg/kg BMS-936559

EXPERIMENTAL

Participants will receive 10 mg/kg of BMS-936559, administered as a single infusion once at study entry.

Drug: BMS-936559

Cohort 4B: single dose placebo for BMS-936559

PLACEBO COMPARATOR

Participants will receive placebo for BMS-936559, administered as a single infusion once at study entry.

Drug: Placebo for BMS-936559

Interventions

BMS-936559 DRUG

0.3 mg/kg, 1 mg/kg, 3 mg/kg, or 10 mg/kg of BMS-936559, depending on which cohort participants are enrolled in, administered as an intravenous (IV) infusion

Cohort 1A: single dose 0.3 mg/kg BMS-936559; Cohort 2A: single dose 1 mg/kg BMS-936559; Cohort 3A: single dose 3 mg/kg BMS-936559; Cohort 4A: single dose 10 mg/kg BMS-936559

Placebo for BMS-936559 DRUG

Sodium chloride for injection 0.9%, USP, administered as an IV infusion

Cohort 1B: single dose placebo for BMS-936559; Cohort 2B: single dose placebo for BMS-936559; Cohort 3B: single dose placebo for BMS-936559; Cohort 4B: single dose placebo for BMS-936559

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 assay. More information on this criterion is available in the protocol.
• Receiving a stable cART regimen containing at least three agents (not including ritonavir if less than a 200 mg total daily dose) with no changes in the components of their antiretroviral therapy for at least 90 days prior to study entry. NOTE: One of the agents must include an integrase inhibitor, a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a boosted protease inhibitor (PI).
• CD4 cell count greater than or equal to 350 cells/mm\^3 obtained within 90 days prior to study entry at any U.S. laboratory that has a clinical laboratory improvement amendments (CLIA) certification or its equivalent
• Plasma HIV-1 RNA below detected limit obtained by Food and Drug Administration (FDA)-approved assays (limit of detection: 75, 50, 40, or 20) for greater than or equal to 2 years on cART. Participants must have at least one documented HIV-1 RNA less than the limit of detection 12-24 months prior to screening and one HIV-1 RNA less than the limit of detection within 12 months prior to screening. NOTE: A single unconfirmed plasma HIV-1 RNA greater than the limit of detection but less than 1,000 copies/mL is allowed if followed by HIV-1 RNA below detectable limits, but none in the 6 months prior to screening.
• Plasma HIV-1 RNA level of less than 40 copies/mL obtained by the Abbott m2000 assay or less than 20 copies/mL by the Roche Taqman v2.0 assay within 90 days prior to entry. The protocol team should be notified as soon as possible if the HIV-1 RNA level is above the limit of detection for either assay.
• Plasma HIV-1 RNA greater than or equal to 0.4 copies/mL by single copy assay (SCA) within 120 days prior to entry
• The following laboratory values obtained within 60 days prior to entry by any U.S. laboratory that has a CLIA certification or its equivalent:
• Absolute neutrophil count (ANC) greater than or equal to 1,000 cells/mm\^3
• Hemoglobin greater than or equal to 14.0 g/dL for men and greater than or equal to 12.0 g/dL for women
• Platelet count greater than or equal to 75,000/mm\^3
• Creatinine clearance greater than or equal to 50 mL/min estimated by the Cockcroft-Gault equation. NOTE: A program for calculating creatinine clearance by the Cockcroft-Gault method is available on www.fstrf.org.
• Alanine aminotransferase (ALT) (SGPT) less than or equal to 2.5 times upper limit of normal (ULN)
• A.M. cortisol within normal limits
• Fasting blood sugar within normal limits
• Total bilirubin less than or equal to 1.6 x ULN. NOTE: If the participant is on an atazanavir-containing therapy then a direct bilirubin should be measured instead of the total bilirubin and must be less than or equal to 1.0 mg/dL.

You may not qualify if:

• History of HIV-related opportunistic infections within the last 5 years. More information on this criterion is available in the protocol.
• Current chronic, acute, or recurrent bacterial, fungal, or viral (other than HIV) infections that are serious, in the opinion of the site investigator, and required systemic therapy within 30 days prior to entry
• 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, or sarcoidosis. More information on this criterion is available in the protocol.
• Previous ocular treatment with silicone oil tamponade (for complex retinal detachment)
• Intraocular surgery within 90 days prior to entry or the anticipated need for intraocular surgery during the course of the study
• Intraocular laser or cryotherapy within 90 days prior to entry or the anticipated need for intraocular laser or cryotherapy during the course of the study
• Evidence on eye exam of active or previous ocular inflammation or uveitis
• Previous history of serious ocular trauma (e.g., penetrating trauma of the eye)
• Severe cataract or other ocular abnormality that precludes adequate examination of the posterior chamber and fundus
• Immune deficiency other than HIV
• Breastfeeding
• Known allergy/sensitivity or any hypersensitivity to components of BMS-936559 (anti-PD-L1) 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
• Acute or serious illness, in the opinion of the site investigator, requiring systemic treatment 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 glucocorticoid doses, defined as prednisone less than or equal to 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 inhaled or topical corticosteroids will not be excluded.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (5)

University of Colorado Hospital CRS

Aurora, Colorado, 80045, United States

Location

Washington University Therapeutics (WT) CRS

St Louis, Missouri, 63110-1010, United States

Location

Chapel Hill CRS

Chapel Hill, North Carolina, 27599, United States

Location

Cincinnati Clinical Research Site

Cincinnati, Ohio, 45219, United States

Location

Vanderbilt Therapeutics (VT) CRS

Nashville, Tennessee, 37204, United States

Location

Related Publications (1)

• Gay CL, Bosch RJ, Ritz J, Hataye JM, Aga E, Tressler RL, Mason SW, Hwang CK, Grasela DM, Ray N, Cyktor JC, Coffin JM, Acosta EP, Koup RA, Mellors JW, Eron JJ; AIDS Clinical Trials 5326 Study Team. Clinical Trial of the Anti-PD-L1 Antibody BMS-936559 in HIV-1 Infected Participants on Suppressive Antiretroviral Therapy. J Infect Dis. 2017 Jun 1;215(11):1725-1733. doi: 10.1093/infdis/jix191.

  PMID: 28431010 DERIVED

MeSH Terms

Conditions

HIV Infections

Interventions

BMS-936559

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Study Officials

• Joseph Eron Jr., MD

  University of North Carolina, Chapel Hill

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 3, 2014
• First Posted: January 7, 2014
• Study Start: June 1, 2014
• Primary Completion: November 1, 2015
• Study Completion: November 1, 2015
• Last Updated: November 5, 2021

Record last verified: 2016-10

Locations

US (5)