A Study of NKTR-358 in Participants With Systemic Lupus Erythematosis (SLE)

• ClinicalTrials.gov Identifier: NCT03556007
• Recruitment Status: Completed
• First Posted: June 14, 2018
• Last Update Posted: October 9, 2019
• Sponsor: Nektar Therapeutics
• Collaborator: Eli Lilly and Company
• Information provided by (Responsible Party): Nektar Therapeutics

Study Description

Brief Summary:

The main purpose of this study is to evaluate the safety and tolerability of a study drug known as NKTR-358 in participants with SLE. The study will last about 79 days for each participant.

Condition or disease	Intervention/treatment	Phase
Systemic Lupus Erythematosus	Drug: NKTR-358; Drug: Placebo	Phase 1

Detailed Description:

NKTR-358 is a potential first-in-class therapeutic that may address an underlying immune system imbalance in patients with many autoimmune conditions. It targets the interleukin (IL-2) receptor complex in the body in order to stimulate proliferation of inhibitory immune cells known as regulatory T cells. By activating these cells, NKTR-358 may act to bring the immune system back into balance.

This study will evaluate the safety, tolerability, PK, and immunologic effects of multiple doses of NKTR-358 in patients with minimal to moderate SLE. The effects on SLE disease activity will also be evaluated. SLE patients will be randomized to receive multiple SC doses of NKTR-358 or receive placebo. After receiving the last dose of NKTR-358 or placebo, patients will be followed for an additional 50 days to evaluate safety, PK, PD, and preliminary efficacy.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Basic Science
• Official Title: A Phase 1, Double-blind, Randomized, Placebo-controlled, Ascending Multiple-dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneous NKTR-358 in Patients With Systemic Lupus Erythematosus
• Actual Study Start Date: May 1, 2018
• Actual Primary Completion Date: August 29, 2019
• Actual Study Completion Date: August 29, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: NKTR-358; SLE patients in each cohort will receive multiple subcutaneous doses of NKTR-358.	Drug: NKTR-358; NKTR-358 drug product is a sterile liquid for subcutaneous injection that will be diluted with sterile 0.9% Sodium Chloride solution for Injection (USP) prior to administration.
Placebo Comparator: Placebo; SLE patients in each cohort will receive the Placebo comparator.	Drug: Placebo; The placebo dosing solution is 0.9% Sodium Chloride for Injection (USP).

Outcome Measures

Primary Outcome Measures :

1. Safety and Tolerability of NKTR-358 - number of subjects experiencing adverse events [ Time Frame: Informed consent until last study visit (approximately 79 days after first dose of study drug) ]
   Safety and tolerability of NKTR-358 as assessed through collection of adverse events, serious adverse events, change in vital signs (body temperature, blood pressure, heart rate, rate of breathing and oxygen in blood); ECG; laboratory evaluations (hematology, chemistry, liver function and urine analysis).

Secondary Outcome Measures :

1. Pharmacokinetics (PK): Area Under the Drug Concentration - Time Curve from Zero to the end of dosing interval (i.e, 14 days past each dose) (AUC[0-day 14]) of NKTR-358 [ Time Frame: Baseline until 14 days after last dose (approximately 43 days after first dose of study drug) ]
   PK measurement of AUC 0-Day 14
2. PK: Maximum Observed Drug Concentration (Cmax) of NKR-358 after first and last dose [ Time Frame: Baseline until last study visit (approximately 79 days after first dose of study drug) ]
   PK: Measurement of Cmax
3. PK: Time to maximum plasma concentration (Tmax) of NKTR-358 [ Time Frame: Baseline until last study visit (approximately 79 days after first dose of study drug) ]
   PK: Measurement of tmax
4. PK: Time to decrease in concentration of NKTR 358 by half (T1/2) due to elimination [ Time Frame: Baseline until last study visit (approximately 79 days after first dose of study drug) ]
   PK: Measurement of t1/2
5. Pharmacodynamics (PD): Measurement of change in number of regulatory T cells (Tregs) and subsets of Tregs in blood [ Time Frame: Baseline until last study visit (approximately 79 days after first dose of study drug) ]
6. PD: Measurement activity of Tregs [ Time Frame: Baseline until last study visit (approximately 79 days after first dose of study drug) ]
7. PD: Measurement of change in number of subsets of conventional T cells (Tcons) in blood [ Time Frame: Baseline until last study visit (approximately 79 days after first dose of study drug) ]
8. PD: Measurement of change in number of natural killer cells (NK cells) in blood [ Time Frame: Baseline until last study visit (approximately 79 days after first dose of study drug) ]
9. PD: Measurement of cytokines in blood. [ Time Frame: Baseline until last study visit (approximately 79 days after first dose of study drug) ]
10. Change in Disease Activity (SLEDAI): Urine; Measurement of hematuria, pyuria, urinary casts, creatinine, protein [ Time Frame: Baseline until last study visit (approximately 79 days after first dose of study drug) ]
11. Change in Disease Activity (SLEDAI): Blood: Measurement of anti-dsDNA, complement, white blood cells and platelets [ Time Frame: Baseline until last study visit (approximately 79 days after first dose of study drug) ]
12. Change in Disease Activity (Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)): Physical Examination [ Time Frame: Baseline until last study visit (approximately 79 days after first dose of study drug) ]
13. Change in Disease Activity (Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)): Urine analysis [ Time Frame: Baseline until last study visit (approximately 79 days after first dose of study drug) ]
14. Change in Disease Activity (Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)): Blood analysis [ Time Frame: Baseline until last study visit (approximately 79 days after first dose of study drug) ]
15. Change in Disease Activity (Cutaneous Lupus Erythematosus Disease Area Severity Index (CLASI)): Evaluation of skin on the body [ Time Frame: Baseline until last study visit (approximately 79 days after first dose of study drug) ]
16. Change in Disease Activity (Cutaneous Lupus Erythematosus Disease Area Severity Index (CLASI)): Evaluation of mucous membrane [ Time Frame: Baseline until last study visit (approximately 79 days after first dose of study drug) ]
17. Change in Disease Activity (Cutaneous Lupus Erythematosus Disease Area Severity Index (CLASI)): Evaluation of scalp [ Time Frame: Baseline until last study visit (approximately 79 days after first dose of study drug) ]
18. Change in Disease Activity (Cutaneous Lupus Erythematosus Disease Area Severity Index (CLASI)): Evaluation of hair loss [ Time Frame: Baseline until last study visit (approximately 79 days after first dose of study drug) ]
19. Change in Disease Activity (Joint score): Evaluation of tender joints in the body [ Time Frame: Baseline until last study visit (approximately 79 days after first dose of study drug) ]
20. Change in Disease Activity (Joint score): Evaluation of swollen joints in the body [ Time Frame: Baseline until last study visit (approximately 79 days after first dose of study drug) ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Willing and able to give written informed consent and comply with study procedures and requirements.
• Body mass index (BMI) between 18.0 and 32.0 (kg/m2).
• Systolic blood pressure between 90 to 140 millimeters of mercury (mm Hg), diastolic blood pressure between 50 to 90 mm Hg, and resting heart rate between 40 to 100 beats per minute.
• Diagnosis of adult SLE according to the 1997 ACR classification criteria for at least 6 months prior to signing the informed consent form (ICF).
• Minimal to moderate SLE disease activity (active SLE clinical disease is not required for enrollment into the study and patients with severe SLE clinical disease activity, based on the evaluation of the investigator, should be excluded).
• If a patient is taking oral prednisone (or prednisone equivalent) for their SLE, the dose must be ≤ 10 mg/day for a minimum of 8 weeks prior to screening. In addition, the dose of oral prednisone or prednisone equivalent the patient is taking must be stable for a minimum of 2 weeks prior to screening.

• If a patient is taking any of the medications below for their SLE, the medication must have been administered for a minimum of 12 weeks prior to signing the ICF, and at a stable dose for a minimum of 8 weeks prior to signing the ICF:

  • Azathioprine ≤ 200 mg/day
  • Antimalarial (e.g., chloroquine, hydroxychloroquine, quinacrine)
  • Mycophenolate mofetil ≤ 2 g/day or mycophenolic acid ≤ 1.44 g/day
  • Oral, SC, or intramuscular methotrexate ≤ 15 mg/week
• Willing and able to participate in the study for a duration of up to 4 months.
• Willing and able to abstain from participating in another clinical study for a duration of up to 4 months.
• Female subjects will be non-pregnant, non-lactating, and either postmenopausal for at least 2 years, or surgically sterile for at least 3 months, or will agree to use double barrier contraception from period prior to study enrollment until 5 months following the last dose received; women of child-bearing potential must have a negative serum β- hCG test at screening and randomization prior to administration of investigational product.
• Male subjects with female partners of childbearing potential must agree to use double barrier contraception during the study (until 5 months following the last dose received). Sperm donation is also restricted during the time-frame that males must be using double barrier contraception. This criterion may be waived for male subjects who have had a vasectomy > 6 months prior to enrollment.

Exclusion Criteria:

Medical Conditions:

• Current active bacterial, viral, or fungal infection.
• Evidence of significant hematologic dysfunction
• Evidence of significant liver or kidney dysfunction
• History of, or current diagnosis of, a clinically significant non SLE-related vasculitis syndrome.
• Active severe or unstable neuropsychiatric SLE.
• Active severe SLE-driven renal disease or history of severe active lupus nephritis with persisting proteinuria levels greater than 0.5 g/24 hours.
• Diagnosis (within 1 year of signing the ICF) of mixed connective tissue disease or any history of overlap syndromes of SLE.
• History of, or current, inflammatory joint or skin disease other than SLE.
• History of any non-SLE disease that has required treatment with oral or parenteral corticosteroids for more than 2 weeks within the last 24 weeks prior to signing the ICF.
• Active TB on the basis of positive medical history or chest radiograph (OR) evidence of latent TB or by positive (or persistently indeterminate) Quantiferon-TB Gold or T-Spot test.
• Known history of a primary immunodeficiency, splenectomy, or any underlying condition that predisposes the patient to infection.
• Confirmed positive serology for hepatitis B, hepatitis C (anti-HCV), or a positive result for HIV antibody screen.
• Any severe herpes infection at any time prior to screening per judgement of the investigator.
• History of opportunistic infection requiring hospitalization or intravenous antimicrobial treatment within 3 years prior to randomization.
• History of major surgery within 12 weeks of screening or will require major surgery during the study.
• Clinically significant electrocardiographic abnormalities
• History of any significant cardiovascular disease (e.g., myocardial infarction, congestive heart failure, uncontrolled hypertension, cerebrovascular accident), thrombotic episode, or any severe non-SLE medical illness within the previous 1 year.

• History of cancer, apart from:

  • Squamous or basal cell carcinoma of the skin that has been successfully treated
  • Cervical cancer in situ that has been successfully treated

Medications:

• Receipt of any investigational product (small molecule or biologic agent) within 4 weeks or 5 half-lives prior to signing of the ICF, whichever is greater.
• Receipt of belimumab in 6 months prior to screening.
• History of treatment with rituximab or ocrelizumab (or other B cell depleting agent) within 6 months prior to screening. For patients who received their last treatment with rituximab or ocrelizumab more than 6 months earlier, evidence of significant and persisting low B cell levels in blood
• History of cytotoxic medications (e.g., cyclophosphamide) within preceding 12 months.
• Receipt of any intra-articular, intramuscular, or IV glucocorticoids within 6 weeks prior to screening.
• Receipt of blood products within 6 months prior to screening.

General:

• Receipt of blood products within 6 months prior to screening and donation of blood or plasma to a blood bank or for a clinical study (except for screening of this study) within 28 days prior to screening.
• Subjects who have a history of organ or bone marrow transplant.

Contacts and Locations

Locations

United States, Alabama

Investigator Site - Anniston

Anniston, Alabama, United States, 36207

United States, California

Investigator Site - La Jolla

La Jolla, California, United States, 92037

United States, Florida

Investigator Site - Clearwater

Clearwater, Florida, United States, 33765

Investigator Site - Orlando

Orlando, Florida, United States, 32806

Investigator Site-Tampa

Tampa, Florida, United States, 33603

United States, New York

Investigator Site - Great Neck

Great Neck, New York, United States, 11021

United States, North Carolina

Investigator Site- Wilmington

Wilmington, North Carolina, United States, 28401

United States, Ohio

Investigator Site - Middleburg Heights

Middleburg Heights, Ohio, United States, 44130

United States, Pennsylvania

Investigator Site - Duncansville

Duncansville, Pennsylvania, United States, 16635

United States, Tennessee

Investigator Site - Jackson

Jackson, Tennessee, United States, 38305

Investigator Site - Memphis

Memphis, Tennessee, United States, 38119

United States, Texas

Investigator Site - Austin

Austin, Texas, United States, 78745

Investigator Site - Dallas

Dallas, Texas, United States, 75231

Investigator Site - Mesquite

Mesquite, Texas, United States, 75150

Sponsors and Collaborators

Nektar Therapeutics

Eli Lilly and Company

More Information

• Responsible Party: Nektar Therapeutics
• ClinicalTrials.gov Identifier: NCT03556007 History of Changes
• Other Study ID Numbers: 17-358-02
• First Posted: June 14, 2018
• Last Update Posted: October 9, 2019
• Last Verified: October 2019

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

Keywords provided by Nektar Therapeutics:

T regulatory cells

Additional relevant MeSH terms:

Lupus Erythematosus, Systemic; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases