Clinical trial NCT03565315: Phase I Study to Evaluate a Human Monoclonal Antibody (MAb) 10E8VLS Administered Alone or Concurrently With MAb VRC07-523LS Via Subcutaneous Injection in Healthy Adults
Official title: VRC 610: Phase I Safety and Pharmacokinetics Study to Evaluate a Human Monoclonal Antibody (MAB) VRC-HIVMAB095-00-AB (10E8VLS) Administered Alone or Concurrently With MAB VRC-HIVMAB075-00-AB (VRC07-523LS) Via Subcutaneous Injection in Healthy Adults
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Healthy Adult Immune Response
Keywords: HIV Prevention
Broadly Neutralizing Monoclonal Antibodies
First in Human Study
Anti-Drug Antibody Response to 10E8VLS or VRC07-523LS
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2018-06-21
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: PREVENTION

Brief summary: Background:

Human immunodeficiency virus (HIV) infection is a serious disease. There is no cure or vaccine to prevent infection. Using antibodies might be a good way to treat or prevent HIV. Antibodies are naturally made by the body to fight germs. Researchers want to test if two antibodies made artificially in a lab can help to prevent HIV infection. The antibodies are 10E8VLS and VRC07-523LS.

Objective:

To see if 10E8VLS and VRC07-523LS are safe and well-tolerated and how long they stay in the blood.

Eligibility:

Healthy adults ages 18-60

Design:

Volunteers were screened in another protocol.

Participants were enrolled in 1 of 4 groups:

Group 1 participants were enrolled to receive 1 dose of 10E8VLS.

Group 2 participants were enrolled to receive 3 doses of 10E8VLS.

Group 3 participants were enrolled to receive 1 dose of both 10E8VLS and VRC07-523LS.

Group 4 participants were enrolled to receive 3 doses of both 10E8VLS and VRC07-523LS.

Participants in Groups 1 and 3 were expected to be enrolled about 13 visits over 24 weeks.

Participants in Groups 2 and 4 were expected to be enrolled about 26 visits over 48 weeks.

Participants were weighed before each dose. Women may have had a pregnancy test. Participants had blood collected.

A small needle injected each dose into fatty tissue of the belly, upper arm, or thigh. Participants received between 1 and 8 injections per dose depending on their weight. Heavier participants received more injections.

Participants received a ruler and thermometer. They checked their temperature for 3 days after injection(s) and measured any redness, swelling, or bruising at the injection site.

At non-injection visits, participants had blood drawn and were checked for health changes or problems.

Detailed description: VRC 610:

A Phase I Safety and Pharmacokinetics Study to Evaluate a Human Monoclonal Antibody (MAB) VRC-HIVMAB095-00-AB (10E8VLS) Administered Alone or Concurrently with MAB VRC-HIVMAB075-00-AB (VRC07-523LS) Via Subcutaneous Injection in Healthy Adults

Study Design:

This first-in-human, open-label study evaluated MAb 10E8VLS (VRC-HIVMAB095-00-AB) administered alone or concurrently (i.e., at the same visit) with MAb VRC07-523LS (VRC-HIVMAB075-00-AB) in healthy adults ages 18 to 60. The primary hypothesis was that administrations of 10E8VLS alone and concurrently with VRC07-523LS will be well-tolerated in healthy adults. A secondary hypothesis was that both broadly neutralizing monoclonal antibodies (bNAbs) will be detectable in human sera with a definable half-life.

Product Description:

The 10E8VLS and VRC07-523LS bNAbs target the HIV-1 envelope at distinct epitopes: 10E8VLS recognizes the membrane proximal external region (MPER) and proximal viral membrane lipid of gp41, while VRC07-523LS recognizes the CD4 binding site of gp120. Both antibodies are human in origin, contain two amino acid modifications within the C-terminus of the heavy chain constant region designed to improve antibody half-life in vivo, and were developed by the VRC/NIAID/NIH. The 10E8VLS and VRC07-523LS bNAbs were manufactured under current Good Manufacturing Practice (cGMP) regulations at the VRC Pilot Plant operated under contract by the Vaccine Clinical Materials Program (VCMP), Leidos Biomedical Research, Inc., Frederick, MD.

The 10E8VLS drug product was supplied at a concentration of 100 mg/mL in a sterile, aqueous, buffered solution of 5.25 mL in single-use 10 mL glass vials. The VRC07-523LS drug product was supplied at a concentration of 100 mg/mL in an isotonic, sterile solution of 6.25 mL in single-use 10 mL glass vials. Each drug product was prepared for administration in separate syringes.

Participants:

Healthy adults, 18-60 years of age.

Study Plan:

This open-label study included 4 dosing regimens of either 10E8VLS (5 mg/kg) administered alone or 10E8VLS (5 mg/kg) and VRC07-523LS (5 mg/kg). All injections were administered by the subcutaneous (SC) route. For Groups 1 and 2, 10E8VLS was to be administered once or three-times at 12-week intervals. For Groups 3 and 4, 10E8VLS and VRC07-523LS were to be administered once or three-times at 12-week intervals, respectively. Enrollment began with Groups 1 and 2, followed by Groups 3 and 4.

VRC 610 Study Schema:

* Group 1; Study Product: 10E8VLS; Planned Participants per Group: 3; Dose Administered SC: 5 mg/kg; Day 0
* Group 2; Study Product: 10E8VLS; Planned Participants per Group: 3; Dose Administered SC: 5 mg/kg; Day 0, Week 12\*, Week 24\*
* Group 3 (a,b); Study Product: 10E8VLS+VRC07-523LS; Planned Participants per Group: 5; Dose Administered SC: 5 mg/kg of each MAb; Day 0
* Group 4 (a,b); Study Product: 10E8VLS+VRC07-523LS; Planned Participants per Group: 5; Dose Administered SC: 5 mg/kg of each MAb; Day 0, Week 12\*, Week 24\*
* Total Planned Participants = 16
* Total Actual Participants = 9 (c)

(\*)Participants received only one product administration on Day 0 because of the voluntary study pause and termination by Investigational New Drug (IND) Sponsor/Principal Investigator (PI) decision.

1. Enrollment into Group 3 and 4 commenced after positive protocol safety review team (PSRT) review of safety data from Groups 1 and 2
2. 10E8VLS and VRC07-523LS were provided in separate syringes and administered at the same visit.
3. The expected enrollment was 16 participants; however, enrollment was voluntarily paused by the IND Sponsor/PI and the study ultimately stopped after several Grade 2 and Grade 3 redness local reactogenicity reactions were observed at 10E8VLS injection sites.

Study Duration:

Study participation was expected to be approximately 24 weeks for participants in Groups 1 and 3, and 48 weeks for participants in Groups 2 and 4. Participants in the repeat-dose groups (2 and 4) were converted to a modified schedule per protocol. Study participation for all participants was approximately 24 weeks after Day 0 product administration.

Eligibility criteria: * INCLUSION CRITERIA:

  1. Willing and able to complete the informed consent process.
  2. 18 to 60 years of age.
  3. Based on history and examination, in good general health and without history of any of the conditions listed in the exclusion criteria.
  4. Willing to have blood samples collected, stored indefinitely, and used for research purposes.
  5. Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process.
  6. Screening laboratory criteria within 84 days prior to enrollment must meet the following criteria:
* White blood cell count (WBC): 2,500-12,000/mm\^3.
* WBC differential: Within institutional normal range or accompanied by the Principal Investigator (PI) or designee approval.
* Platelets: 125,000 - 400,000/mm\^3.
* Hemoglobin: Within institutional normal range or accompanied by PI or designee approval.
* Creatinine: less than or equal to 1.1 x Upper Limit of Normal (ULN).
* Aspartate aminotransferase (AST): less than or equal to 1.25 x ULN
* Alanine aminotransferase (ALT): less than or equal to 1.25 x ULN.
* Negative for HIV infection by an FDA approved method of detection.
* Negative for Hepatitis B core antibody (HBcAb) and Hepatitis C virus antibody (HCV Ab).

Female-Specific Criteria:

7. If a woman is of reproductive potential and sexually active with a male partner, then she agrees to use an effective means of birth control from the time of study enrollment until the last study visit, or to be monogamous with a partner who has had a vasectomy.

8. Negative Beta-HCG (human chorionic gonadotropin) pregnancy test (urine or serum) on day of enrollment for women presumed to be of reproductive potential.

* EXCLUSION CRITERIA:

  1. Woman who is breast-feeding, or planning to become pregnant during the study.
  2. Prior receipt of licensed or investigational monoclonal antibody.
  3. Weight \> 115 kg.
  4. Any history of a severe allergic reaction with generalized urticaria, angioedema or anaphylaxis within the 2 years prior to enrollment that has a reasonable risk of recurrence during the study.
  5. Hypertension that is not well controlled.
  6. Receipt of any investigational study agent within 28 days prior to enrollment.
  7. Any other chronic or clinically significant condition that in the opinion of investigator would jeopardize the safety or rights of the volunteer including (but not limited to): diabetes mellitus type I/II, chronic hepatitis; OR clinically significant forms of drug or alcohol abuse, asthma, autoimmune disease, psychiatric disorders, heart disease, or cancer.

Primary outcomes:
measure: Number of Participants Reporting Local Reactogenicity Signs and Symptoms Within 3 Days of Product Administration
timeFrame: 3 days after product administration
measure: Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms Within 3 Days of Product Administration
timeFrame: 3 days after product administration
measure: Number of Participants With One or More Unsolicited Non-Serious Adverse Events
timeFrame: Up to 24 weeks after product administration
measure: Number of Participants With Serious Adverse Events
timeFrame: Up to 24 weeks after product administration
Secondary outcomes:
measure: Maximum Observed Serum Concentration (Cmax) of 10E8VLS Administered Alone or Concurrently With VRC07-523LS
timeFrame: Up to 24 weeks after product administration
measure: Time to Reach Maximum Observed Serum Concentration (Tmax) of 10E8VLS Administered Alone or Concurrently With VRC07-523LS
timeFrame: Up to 24 weeks after product administration
measure: Area Under the Curve (AUC0-28D) of 10E8VLS Administered Alone or Concurrently With VRC07-523LS
timeFrame: Administration (0h) up to 28 days after product administration
measure: 4 Week Mean Serum Concentration of 10E8VLS Administered Alone or Concurrently With VRC07-523LS
timeFrame: Administration (0h) up to 28 days after product administration
measure: Clearance Rate of 10E8VLS Administered Alone or Concurrently With VRC07-523LS
timeFrame: Administration (0h) up to 28 days after product administration
measure: Overall Half-Life (T1/2) of 10E8VLS Administered Alone or Concurrently With VRC07-523LS
timeFrame: Administration (0h) up to 28 days after product administration
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Institute of Allergy and Infectious Diseases (NIAID)
name: Martin R Gaudinski, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Huang J, Ofek G, Laub L, Louder MK, Doria-Rose NA, Longo NS, Imamichi H, Bailer RT, Chakrabarti B, Sharma SK, Alam SM, Wang T, Yang Y, Zhang B, Migueles SA, Wyatt R, Haynes BF, Kwong PD, Mascola JR, Connors M. Broad and potent neutralization of HIV-1 by a gp41-specific human antibody. Nature. 2012 Nov 15;491(7424):406-12. doi: 10.1038/nature11544. Epub 2012 Sep 18.
citation: Kwon YD, Georgiev IS, Ofek G, Zhang B, Asokan M, Bailer RT, Bao A, Caruso W, Chen X, Choe M, Druz A, Ko SY, Louder MK, McKee K, O'Dell S, Pegu A, Rudicell RS, Shi W, Wang K, Yang Y, Alger M, Bender MF, Carlton K, Cooper JW, Blinn J, Eudailey J, Lloyd K, Parks R, Alam SM, Haynes BF, Padte NN, Yu J, Ho DD, Huang J, Connors M, Schwartz RM, Mascola JR, Kwong PD. Optimization of the Solubility of HIV-1-Neutralizing Antibody 10E8 through Somatic Variation and Structure-Based Design. J Virol. 2016 Jun 10;90(13):5899-5914. doi: 10.1128/JVI.03246-15. Print 2016 Jul 1.