First-In-Human Study of ChAdOx1-HBV & MVA-HBV Vaccines (VTP-300) for Chronic HBV

Study Overview
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Brief Summary
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This is an open-label study to determine the safety, tolerability and immunogenicity of ChAdOx1-HBV and MVA-HBV vaccines, with or without nivolumab, in patients with chronic HBV who are virally suppressed with oral anti-viral therapies.

Detailed Description
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This is a multi-centre study conducted in 52 participants, who will each be administered 2 vaccine injections (IM) on Day 0 and Day 28 as follows: Group 1: MVA-HBV + MVA-HBV (now closed) Group 2: ChAdOx1-HBV + MVA-HBV Group 3: ChAdOx1-HBV + MVA-HBV + nivolumab (IV infusion) Group 4: ChAdOx1-HBV + nivolumab + MVA-HBV + nivolumab (now closed) Participants are randomised to treatment as the groups are initiated with a 1:1:1:1 allocation. Version 6.0 of the study protocol has closed Groups 1 and 4 to further randomisation; recruitment will now be in a 1:1 ratio between Groups 2 and 3 only. A sentinel participant is dosed in Group 1, with further participants in Group 1 only being dosed at least 48h later. Group 2 is initiated following a Day 7 safety assessment of the first 6 participants in Group 1. Groups 3 and 4 are initiated following a Day 7 safety assessment of the first 6 participants in Group 2. The primary objective of the study is to determine the safety and reactogenicity of the treatment regimens; this will be assessed by analysis of the incidence and severity of (serious) adverse events and any changes in laboratory values and vital signs. The secondary objectives of the study are the determination of the immunogenicity of the ChAdOx1-HBV and MVA-HBV vaccines and the impact of PD-blockade, as well as the effect on HBV markers; these are assessed by measurements of the magnitude and avidity of HBV-specific CD4+ and CD8+ T cells and the magnitude of HBV markers. Following first vaccination, participants remain in the study for 9 months and attend clinic visits for vaccination and assessments on Days 0, 7, 28, 35 and Months, 3, 6 and 9.

Official Title
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A Phase 1b/2a, Open-Label Study to Evaluate the Safety, Tolerability and Immunogenicity of VTP-300 With or Without Nivolumab in Participants With Chronic Hepatitis B Infection

Conditions
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Hepatitis B

Intervention / Treatment
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* Biological: ChAdOx1-HBV
* Biological: MVA-HBV
* Biological: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult males or females aged ≥18 to ≤65 years at screening (according to country/local regulations) BMI ≤32kg/m2 Able to provide informed consent indicating they understand the purpose of, and procedures required, for the study and are willing to participate If female, willing not to become pregnant up to 8 weeks after last dose of study vaccine and up to 5 months after the last dose of nivolumab If female: Not pregnant or breast feeding and one of the following: Of non-childbearing potential (i.e. women who have had a hysterectomy or tubal ligation or are post menopausal, as defined by no menses in ≥1 year and without an alternative medical cause) Of childbearing potential but agrees to practice highly effective contraception for 4 weeks prior to study vaccine and 8 weeks after study vaccine and 5 months after the last dose of nivolumab. Highly effective methods of contraception include one or more of the following: (i) Male partner who is sterile (medically effective vasectomy) prior to the female participant's entry into the study and is the sole sexual partner for the female participant (ii) Combined (oestrogen and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral intravaginal transdermal (iii) Progestogen-only hormonal contraception associated with inhibition of ovulation: oral injectable implantable (iv) An intrauterine device (v) Bilateral tubal occlusion Documented evidence of chronic HBV infection (e.g. HBsAg positive ≥6 months with detectable HBsAg levels at screening) Receipt of only either entecavir, tenofovir (tenofovir alafenamide fumarate or tenofovir disoproxil fumarate), or besifovir for at least 12 months before screening Virally suppressed (HBV-DNA viral load < 40 IU/mL for ≥ 1 year) HBsAg levels <4000 IU/mL Exclusion Criteria: Presence of any significant acute or chronic, uncontrolled medical/psychiatric illness Hepatitis C virus (HCV) antibody positive. HIV antibody positive Co-infection with hepatitis D virus Documented cirrhosis or advanced fibrosis indicated by a liver biopsy within 6 months prior to screening (Metavir activity grade A3 and stages F3 and F4; Ishak stages 4-6). In the absence of a documented liver biopsy, either 1 of the following (not both): Screening Fibroscan with a result > 9 kilopascals (kPa) (or the equivalent) within ≤ 6 months of screening, OR Screening FibroTest >0.48 and aspartate aminotransferase (AST) to platelet ratio index (APRI) of >1. ALT >3 x upper limit of normal (ULN), international normalized ratio (INR) >1.5 unless the participant was stable on an anticoagulant regimen affecting INR, albumin <3.5 g/dL, direct bilirubin >1.5 x ULN, platelet count < 100,000/microlitre. A history of liver decompensation (e.g. ascites, encephalopathy or variceal haemorrhage) Prior hepatocellular carcinoma Chronic liver disease of a non-HBV aetiology History or evidence of autoimmune disease or known immunodeficiency of any cause Presence of active infection Evidence of interstitial lung disease, active pneumonitis, myocarditis, or a history of myocarditis Past history of thyroid disorder or abnormal thyroid function at screening that is still active and uncontrolled Prolonged therapy with immunomodulators (e.g. corticosteroids such as prednisone > 10 mg/day) or biologics (e.g. monoclonal antibodies, IFN) within 3 months of screening Receipt of immunoglobulin or other blood products within 3 months prior to enrolment Receipt of any investigational drug or vaccine within 3 months prior to screening Receipt of any adenoviral-based vaccine within 3 months prior to administration of ChAdOx1-HBV on Day 0, or plan to receive an adenoviral-based vaccine within 3 months after Day 0 Receipt of any live vaccines within 30 days prior to screening Receipt of any inactivated vaccines within 14 days prior to screening, History of severe hypersensitivity or anaphylactic reactions likely to be exacerbated by any component of the vaccine or nivolumab Malignancy within 5 years prior to screening with the exception of specific cancers that are cured by surgical resection (e.g. except basal cell skin carcinoma of the skin and cervical carcinoma). Participants under evaluation for possible malignancy are not eligible Current alcohol or substance abuse judged by the Investigator to potentially interfere with participant safety and compliance Significant cardiac disease or unstable uncontrolled cardiac disease Any laboratory test which is abnormal, and which is deemed by the Investigator to be clinically significant Cytotoxic agents, other anti HBV or traditional herbal medicines which, in the opinion of the Investigator, may have activity against HBV within the previous 6 months prior to randomization Any other finding that, in the opinion of the Investigator, deems the participant unsuitable for the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Interventional Model Description: Participants are randomised to the four treatment groups, as the groups are initiated. Allocation to the groups is 1:1:1:1. Version 6.0 of the study protocol has closed Groups 1 and 4 to further randomisation; recruitment will now be in a 1:1 ratio between Groups 2 and 3 only.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 (MVA-HBV)<br>Day 0: MVA-HBV 1 x 10^8 pfu IM injection Day 28: MVA-HBV 1 x 10^8 pfu IM injection | Biological: MVA-HBV<br>* Modified Vaccinia Ankara-vectored Hepatitis B virus vaccine<br>|
| Experimental: Group 2 (ChAdOx1-HBV, MVA-HBV)<br>Day 0: ChAdOx1-HBV 1 x 2.5 10^10 vp IM injection Day 28: MVA-HBV 1 x 10^8 pfu IM injection | Biological: ChAdOx1-HBV<br>* Chimpanzee Adenovirus Oxford 1-vectored Hepatitis B virus vaccine<br>Biological: MVA-HBV<br>* Modified Vaccinia Ankara-vectored Hepatitis B virus vaccine<br>|
| Experimental: Group 3 (ChAdOx1-HBV, MVA-HBV and nivolumab)<br>Day 0: ChAdOx1-HBV 1 x 2.5 10^10 vp IM injection Day 28: MVA-HBV 1 x 10^8 pfu IM injection + nivolumab 0.3 mg/kg IV infusion | Biological: ChAdOx1-HBV<br>* Chimpanzee Adenovirus Oxford 1-vectored Hepatitis B virus vaccine<br>Biological: MVA-HBV<br>* Modified Vaccinia Ankara-vectored Hepatitis B virus vaccine<br>Biological: Nivolumab<br>* Human immunoglobulin G4 monoclonal antibody<br>* Other names: Opdivo 10mg/ml concentrate for solution for infusion;|
| Experimental: Group 4 (ChAdOx1-HBV and nivolumab, MVA-HBV and nivolumab)<br>Day 0: ChAdOx1-HBV 1 x 2.5 10^10 vp IM injection + nivolumab 0.3 mg/kg IV infusion Day 28: MVA-HBV 1 x 10^8 pfu IM injection + nivolumab 0.3 mg/kg IV infusion | Biological: ChAdOx1-HBV<br>* Chimpanzee Adenovirus Oxford 1-vectored Hepatitis B virus vaccine<br>Biological: MVA-HBV<br>* Modified Vaccinia Ankara-vectored Hepatitis B virus vaccine<br>Biological: Nivolumab<br>* Human immunoglobulin G4 monoclonal antibody<br>* Other names: Opdivo 10mg/ml concentrate for solution for infusion;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of participants with Treatment-Emergent Adverse Events (TEAEs) and ≥Grade 3 study vaccine-related adverse events following study vaccination | The incidence of TEAEs and and ≥Grade 3 study vaccine-related adverse events will be based on the number and percentage of participants with events and number of events. TEAEs are defined as all adverse events occurring after study vaccine administration; they will be further categorised by Seriousness, Severity (i.e. ≥ Grade 3) and Causality. Seriousness of the TEAEs is assessed according to the published FDA criteria (2016). Severity of the TEAEs will be graded according to the FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adults and Volunteers Enrolled in Preventative Vaccine Trials, 2007 (70 FR 22664). | From each study vaccination for the following 27 days | 
| The incidence of participants with Treatment-Emergent Adverse Events (TEAEs) and ≥Grade 3 study vaccine-related adverse events following study vaccination with nivolumab | The incidence of TEAEs and ≥Grade 3 study vaccine-related adverse events will be based on the number and percentage of participants with events and number of events. TEAEs are defined as all adverse events occurring after study vaccine administration with nivolumab (Groups 3 and 4); they are further categorised by Seriousness, Severity (i.e. ≥ Grade 3) according to FDA Guidance 70 FR 22664 and Causality. | From each study vaccination with nivolumab for the following 27 days | 
| The incidence of participants with Adverse Events of Special Interest (AESIs) | The incidence of AESIs will be based on the number and percentage of participants with events and number of events. AESIs specific to this study include pneumonitis, grade 3 or 4 diarrhoea, diabetes, thyroid diseases, colitis, nephritis, immune-related endocrinopathies, myocarditis, immune-related skin conditions, or other unspecified immune-related adverse reactions. | From study admission (the signature of informed consent) to the end of the study (Month 9) | 
| The incidence of participants with Treatment-Emergent Adverse Events (TEAEs) within each study group | The incidence of TEAEs will be based on the number and proportion of participants with events and number of events and will be calculated for each of the four study groups. | From each study vaccination for the following 27 days | 
| Incidence of participants with potentially clinically significant laboratory signs within each treatment group as assessed by the Investigator | The incidence of participants will be based upon the number and proportion of patients in each treatment group with clinically significant laboratory signs (haematology and biochemistry, including liver function tests) as assessed by the investigator. All laboratory signs will be reported in SI units. If any laboratory sign is considered to be clinically significant i.e. outside laboratory normal reference range, the severity of this sign will be assessed according to the FDA Guidance for Industry 70 FR 22664. Absolute change, change from baseline and worst change for each participant will be calculated. The incidence of participants with treatment-emergent, clinically significant laboratory signs and laboratory signs of Grade 3-4 severity will be calculated for each treatment group at each time point. | Baseline, Day7, Day28, Day35, Month 3, Month 6, Month 9 | 
| Incidence of participants with potentially clinically significant vital signs within each treatment group as assessed by the Investigator | The incidence of participants will be based upon the number and proportion of patients in each treatment group with clinically significant vital signs. Vital signs will be considered to be potentially clinically significant if they respectively fall below or above the relevant upper and lower limits. The incidence of participants with treatment-emergent, clinically significant vital signs will be calculated for each treatment group at each time point. | Baseline, Day7, Day28, Day35, Month 3, Month 6, Month 9 | 
| Number of participants with worst changes from baseline in laboratory hematology parameters | Hematology laboratory values will be evaluated according to the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (FDA). For all hematology parameters, changes from baseline of at least two severity grades will be calculated for each timepoint at which the laboratory test is conducted throughout the study. The number of participants showing shifts of at least two severity grades (as worst change from baseline for each hematology parameter) will be presented within shift tables. | Baseline, Day7, Day28, Day35, Month 3, Month 6, Month 9 | 
| Number of participants with worst changes from baseline in laboratory biochemistry parameters | Biochemistry laboratory values will be evaluated according to the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (FDA). For all biochemistry parameters, changes from baseline of at least two severity grades will be calculated for each timepoint at which the laboratory test is conducted throughout the study. The number of participants showing shifts of at least two severity grades (as worst change from baseline for each biochemistry parameter) will be presented within shift tables. | Baseline, Day7, Day28, Day35, Month 3, Month 6, Month 9 | 
| Number of participants with worst changes from baseline in laboratory urinalysis parameters | Urinalysis laboratory values will be evaluated according to the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (FDA). For all urinalysis parameters, changes from baseline of at least two severity grades will be calculated for each timepoint at which the laboratory test is conducted throughout the study. The number of participants showing shifts of at least two severity grades (as worst change from baseline for each urinalysis parameter) will be presented within shift tables. | Baseline, Day7, Day28, Day35, Month 3, Month 6, Month 9 | 
| Number of participants with worst changes from baseline in vital signs parameters (heart rate, systolic blood pressure, diastolic blood pressure and temperature) | Worst change is defined as the lowest and highest post-baseline values for heart rate (bradycardia, tachycardia) and systolic blood pressure (hypotension, hypertension), and as the highest post-baseline values for diastolic blood pressure (hypertension) and temperature (fever). For all vital signs measurements, changes from baseline will be calculated for each timepoint at which the vital sign measurement is conducted throughout the study. The number of participants showing worst change from baseline for the vital signs parameters overall will be presented within shift tables. | Baseline, Day7, Day28, Day35, Month 3, Month 6, Month 9 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Magnitude and avidity of HBV-specific CD4+ and magnitude of CD 8+ T cells induced by each treatment regimen | This will be determined from samples of Peripheral Blood Mononuclear Cells (PBMCs) using a multi-parameter index (CD4+ magnitude; CD4+ avidity; CD8+ magnitude) derived by the laboratory. The index will be calculated by the laboratory at each timepoint for each treatment group and and change from Baseline at all time points will be presented. | Baseline, Day7, Day28, Day35, Month 3, Month 6, Month 9 | 
| Percentage of Participants with Reduction in HBsAg titre | This will be determined from samples of PBMCs. The percentage of participants with a HBsAg loss >0.5 log10 and >1.0 log10 will be determined for each vaccine and for each treatment group. | Baseline, Day7, Day28, Day35, Month 3, Month 6, Month 9 | 
| Percentage of Participants with HBsAg and HBeAg Loss | This will be determined from samples of PBMCs. The proportion of participants infected with HBsAg-positive virus at baseline who develop Hepatitis B surface antigen antibody will be determined for each vaccine and for each treatment group. The proportion of participants infected with HBeAg-positive virus at baseline who develop Hepatitis B e-antigen antibody will be determined for each vaccine and for each treatment group. | Baseline, Day7, Day28, Day35, Month 3, Month 6, Month 9 | 
| Percentage of Participants with HBsAg Seroconversion | This will be determined from samples of PBMCs. The proportion of participants infected with HBsAg-positive virus at baseline who become HBsAg negative will be determined for each vaccine and for each treatment group. The proportion of participants infected with HBeAg-positive virus at baseline who become HBeAg negative will be determined for each vaccine and for each treatment group. The times to seroconversion will be calculated in months. | Baseline and Month 9 | 
| Percentage of Participants with HBeAg Seroconversion | This will be determined from samples of PBMCs. The proportion of participants infected with HBeAg-positive virus at baseline who become HBeAg negative will be determined for each vaccine and for each treatment group. The times to seroconversion will be calculated in months. | Baseline and Month 9 | 
| Percentage of Participants with Reduction of Hepatitis B DNA | Quantitative DNA analysis will be conducted on samples of PBMCs. Changes from baseline will be calculated for each vaccine and for each treatment group. | Baseline, Day 35, Month 3 and Month 9 |