None listed
Conditions
Brief summary
Given the low rate of HBsAg loss with currently available therapies and the treatment burden associated with life-long treatment to maintain viral suppression, there is a need to identify new therapies that may provide durable HBsAg loss with a finite treatment duration. The primary objective of this study is to evaluate the safety, tolerability and efficacy of novel HBV combination regimens in association with an oral nucleotide (NUC) HBV polymerase inhibitor for the treatment of CHB subjects. In addition, this study will evaluate changes in HBV specific immune responses following administration of study treatment (nivolumab±ledipasvir/sofosbuvir or nivolumab±GS-9688). This Phase 1b study will be conducted in virally-suppressed CHB subjects to minimize safety risks and maximize efficacy benefits associated with study treatment(s). Because they have stable viral suppression on treatment with an oral antiviral medication, these subjects generally have lower levels of HBV virions and proteins, including HBsAg, within the serum as well as lower expression of HBV antigens within infected hepatocytes. This lower antigen burden enhances the safety profile of immune stimulating approaches to CHB treatment (e.g. nivolumab and/or GS-9688). In addition, a virally suppressed population may have a higher chance of response to immune modulatory therapies (e.g. nivolumab and/or GS-9688) as suggested by the observation that immune responsiveness of chronic HBV patients is improved in patients who are on chronic suppressive antiviral therapy. To further maximize safety in this study, all subjects will be closely monitored during the study and only subjects with sufficient hepatic reserve will be included.
Interventions
Approximately 36 virally-suppressed, chronic hepatitis B (CHB) infected subjects, currently being treated with a commercially available nucleos(t)ide (NUC), may be enrolled and assigned into a cohort. Subjects will remain on their current commercially available NUC(s) therapy for the entire duration of the study.
Cohorts 1-3 will be enrolled sequentially and receive:
Cohort 1 (n = 12): Nivolumab 0.3 mg/kg IV once every 4 weeks for 12 weeks (total 3 doses)
Cohort 2 (n=12): Ledipasvir/sofosbuvir
Approximately 36 virally-suppressed, chronic hepatitis B (CHB) infected subjects, currently being treated with a commercially available nucleos(t)ide (NUC), may be enrolled and assigned into a cohort. Subjects will remain on their current commercially available NUC(s) therapy for the entire duration of the study. Cohorts 1-3 will be enrolled sequentially and receive: Cohort 1 (n = 12): Nivolumab 0.3 mg/kg IV once every 4 weeks for 12 weeks (total 3 doses) Cohort 2 (n=12): Ledipasvir/sofosbuvir (90 mg/400 mg) tablet orally administered once daily for 12 weeks, followed by Ledipasvir/sofosbuvir tablet orally administered once daily plus nivolumab 0.3 mg/kg IV once every 4 weeks for 12 weeks (total 3 doses) Cohort 2 will be enrolled after Cohort 1 has completed enrollment. Prior to administration of nivolumab in Cohort 2, safety of 12 Weeks of nivolumab in at least 10 subjects will have been demonstrated in Cohort 1. Safety data review of 12 weeks of nivolumab will be completed by the Medical Monitor. Cohort 3 (n=12): GS-9688 3 mg (2 x 1.5 mg tablets) orally administered on the same day once a week for 12 weeks (total 12 doses), plus Nivolumab 0.3 mg/kg IV once every 4 weeks for 12 weeks (total 3 doses). On the days when nivolumab is to be administered, the scheduled weekly dose of GS-9688 is to be administered on the same day. Cohort 3 will be enrolled after Cohorts 1 and 2 have completed enrollment. Safety in Cohort 1 of nivolumab alone will have been demonstrated prior to enrollment of Cohort 3. Cohort 3 will initially enroll a sentinel group of 3 subjects that will complete at least 4 weeks of combination treatment. After demonstration of safety of 4 weeks of combination treatment in the first 3 subjects, enrollment of the remaining 9 subjects will commence. Safety data review of 4 weeks of GS-9688 plus nivolumab will be completed by the Medical Monitor. For Cohorts 1-3, all subjects will complete 24 weeks of follow up after completion of study treatment(s). The investigator will maintain an accurate inventory of all study drug(s). Each dose of the study drug(s) administered at the study center will be administered by qualified study center staff. The dose of study drug(s) administered to subjects in the clinic under the supervision of staff will be accurately recorded, which indicates the date and quantity of each dosage formulation dispensed to individual subjects. Used and unused study drug supplies, including empty containers, are to be returned to the shipping facility from which it came for destruction following drug accountability and drug inventory reconciliation.
Sponsors
Gilead Sciences, Inc
Study design
Allocation
Non-randomised trial
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1) Must have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures 2) Adult male and non-pregnant, non-lactating female subjects, 18-65 years of age inclusive based on the date of the Screening visit 3) Documented evidence of chronic HBV infection (e.g. HBsAg positive for more than 6 months) with detectable HBsAg levels at Screening 4) Have been on a commercially available HBV nucleos(t)ide treatment(s) (tenofovir alafenamide, tenofovir disoproxil fumurate, entecavir, adefovir, lamivudine, telbivudine, either as single agents or in combination) with no change in regimen for 3 months prior to screening. 5) Have a historic HBV DNA <69 IU/mL, measured at least once at local laboratory, 3 or more months prior to screening 6) HBV DNA < 20 IU/mL by central laboratory at Screening 7) Screening ECG without clinically significant abnormalities and with QTcF interval (QT corrected using Fridericia’s formula) =< 450 msec for males and =< 470 msec for females. 8) Females of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline prior to enrollment 9) Male and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception 10) Must be willing and able to comply with all study requirements
Exclusion criteria
1) Extensive bridging fibrosis or cirrhosis as defined clinically by any one of the following: a) Metavir >= 3 or Ishak fibrosis score >= 4 by a liver biopsy within 3 years of screening, or, in the absence of an appropriate liver biopsy, either: b) Screening FibroTest score of > 0.48 and APRI > 1 by central laboratory, or c) Historic FibroScan with a result > 9 kPa within =< 1 year of screening If liver biopsy is available, the liver biopsy result supersedes (b) and/or (c, if available) If an appropriate liver biopsy is not available, fibrosis will be evaluated by (b) and/or (c, if available). In the event of discordance between (b) and (c), the FibroScan results will take precedence. 2) Subjects meeting any of the following laboratory parameters at screening: a) Hemoglobin < 12 g/dL (for males) or <11 g/dL (for females) b) White Blood cell count < 2500 cells/mm3 c) Neutrophil count < 1500 cell/mm3 (or < 1000 cell/mm3 if considered a physiological variant in a subject of African descent) d) ALT > 3x ULN e) INR > ULN unless the subject is stable on an anticoagulant regimen affecting INR f) Albumin < 3.5 g/dL g) Direct bilirubin >1.5x ULN h) Platelet Count < 100,000/uL i) Positive autoantibodies, defined as any one or more of the following: i) Antinuclear antibodies (ANA) >1:80 ii) Smooth muscle antibodies (anti-SMA) >1:80 iii) Antimitochondrial antibodies (AMA) >1:40 iv) Anti-thyroid peroxidase (anti-TPO) >1:40 j) Estimated creatinine clearance (CrCl) < 60 mL/min (using the Cockcroft-Gault method) based on serum creatinine and actual body weight as measured at the screening evaluation 3) Co-infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatitis D virus (HDV). Subjects who are HCV Ab or HDV Ab positive, but have a documented negative HCV RNA or HDV RNA, respectively, are eligible. 4) Current or prior history of hepatocellular carcinoma (HCC) (e.g. as evidenced by prior imaging) or screening alpha-fetoprotein (AFP) >= 50 ng/mL without imaging to rule out HCC 5) Current or prior history of clinical hepatic decompensation (e.g. ascites, encephalopathy, or variceal hemorrhage). 6) Malignancy within 5 years prior to screening, with the exception of specific cancers that are cured by surgical resection (e.g. basal cell skin cancer). Subjects under evaluation for possible malignancy are not eligible 7) Significant cardiovascular, ophthalmological, pulmonary, or neurological disease in the opinion of the investigator 8) Diagnosis of any autoimmune disease (e.g., systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, pneumonitis, autoimmune hepatitis, sarcoidosis, psoriasis of greater than mild severity, autoimmune uveitis, autoimmune nephritis, thyroiditis), poorly controlled diabetes mellitus, significant psychiatric illness, severe chronic obstructive pulmonary disease (COPD), hemoglobinopathy, retinal disease, or are immunosuppressed 9) Chronic liver disease of a non-HBV etiology (e.g. Wilson’s disease, hemochromatosis, alpha-1-antitrypsin deficiency, cholangitis), except for non-alcoholic fatty liver disease 10) Received solid organ or bone marrow transplant 11) Received prolonged therapy with immunomodulators (e.g. corticosteroids) or biologics (e.g. monoclonal antibody, interferon, nivolumab) within 3 months of screening 12) Have received inactivated vaccinations (e.g. injectable influenza or pneumococcal) within 4 weeks prior to randomization or received live vaccinations within 4 weeks prior to screening pneumococcal] are allowed) 13) Use of another investigational agent within 90 days of screening, unless allowed by the Sponsor 14) Current alcohol or substance abuse judged by the investigator to potentially interfere with subject compliance 15) Known hypersensitivity to study drug or formulation excipients 16) Women who are breastfeeding, pregnant or who wish to become pregnant during the course of the study 17) Female subjects unwilling to refrain from egg donation and in vitro fertilization during and until at least 30 days after the last study drug dose or 5 months after last dose of nivolumab, if administered. 18) Male subjects unwilling to refrain from sperm donation during and until at least 90 days after the last study drug dose 19) Use of any prohibited concomitant medications 20) Believed by the Study Investigator to be inappropriate for study participation for any reason not otherwise listed.
Outcome results
None listed