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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04778904
Recruitment Status : Recruiting
First Posted : March 3, 2021
Last Update Posted : March 3, 2021
Sponsor:
Information provided by (Responsible Party):
Vaccitech Limited

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Hepatitis B Biological: ChAdOx1-HBV Biological: MVA-HBV Biological: Nivolumab Phase 1 Phase 2

Detailed Description:

This is a multi-centre study conducted in 64 participants, who will each be administered 2 vaccine injections (IM) on Day 0 and Day 28 as follows:

Group 1: MVA-HBV + MVA-HBV Group 2: ChAdOx1-HBV + MVA-HBV Group 3: ChAdOx1-HBV + MVA-HBV + nivolumab (IV infusion) Group 4: ChAdOx1-HBV + nivolumab + MVA-HBV + nivolumab

Participants are randomised to treatment as the groups are initiated with a 1:1:1:1 allocation. 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 64 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Participants are randomised to the four treatment groups, as the groups are initiated. Allocation to the groups is 1:1:1:1.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : December 22, 2020
Estimated Primary Completion Date : June 22, 2022
Estimated Study Completion Date : September 22, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Nivolumab

Arm Intervention/treatment
Experimental: Group 1 (MVA-HBV)
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
Modified Vaccinia Ankara-vectored Hepatitis B virus vaccine

Experimental: Group 2 (ChAdOx1-HBV, MVA-HBV)
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
Chimpanzee Adenovirus Oxford 1-vectored Hepatitis B virus vaccine

Biological: MVA-HBV
Modified Vaccinia Ankara-vectored Hepatitis B virus vaccine

Experimental: Group 3 (ChAdOx1-HBV, MVA-HBV and nivolumab)
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
Chimpanzee Adenovirus Oxford 1-vectored Hepatitis B virus vaccine

Biological: MVA-HBV
Modified Vaccinia Ankara-vectored Hepatitis B virus vaccine

Biological: Nivolumab
Human immunoglobulin G4 monoclonal antibody
Other Name: Opdivo 10mg/ml concentrate for solution for infusion

Experimental: Group 4 (ChAdOx1-HBV and nivolumab, MVA-HBV and nivolumab)
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
Chimpanzee Adenovirus Oxford 1-vectored Hepatitis B virus vaccine

Biological: MVA-HBV
Modified Vaccinia Ankara-vectored Hepatitis B virus vaccine

Biological: Nivolumab
Human immunoglobulin G4 monoclonal antibody
Other Name: Opdivo 10mg/ml concentrate for solution for infusion




Primary Outcome Measures :
  1. The incidence of participants with Treatment-Emergent Adverse Events (TEAEs) and ≥Grade 3 study vaccine-related adverse events following study vaccination [ Time Frame: From each study vaccination for the following 27 days ]

    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).


  2. The incidence of participants with Treatment-Emergent Adverse Events (TEAEs) and ≥Grade 3 study vaccine-related adverse events following study vaccination with nivolumab [ Time Frame: From each study vaccination with nivolumab for the following 27 days ]

    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.


  3. The incidence of participants with Adverse Events of Special Interest (AESIs) [ Time Frame: From study admission (the signature of informed consent) to the end of the study (Month 9) ]

    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.


  4. The incidence of participants with Treatment-Emergent Adverse Events (TEAEs) within each study group [ Time Frame: From each study vaccination for the following 27 days ]
    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.

  5. Incidence of participants with potentially clinically significant laboratory signs within each treatment group as assessed by the Investigator [ Time Frame: Baseline, Day7, Day28, Day35, Month 3, Month 6, Month 9 ]

    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.


  6. Incidence of participants with potentially clinically significant vital signs within each treatment group as assessed by the Investigator [ Time Frame: Baseline, Day7, Day28, Day35, Month 3, Month 6, Month 9 ]

    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.


  7. Number of participants with worst changes from baseline in laboratory hematology parameters [ Time Frame: Baseline, Day7, Day28, Day35, Month 3, Month 6, Month 9 ]

    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.


  8. Number of participants with worst changes from baseline in laboratory biochemistry parameters [ Time Frame: Baseline, Day7, Day28, Day35, Month 3, Month 6, Month 9 ]

    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.


  9. Number of participants with worst changes from baseline in laboratory urinalysis parameters [ Time Frame: Baseline, Day7, Day28, Day35, Month 3, Month 6, Month 9 ]

    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.


  10. Number of participants with worst changes from baseline in vital signs parameters (heart rate, systolic blood pressure, diastolic blood pressure and temperature) [ Time Frame: Baseline, Day7, Day28, Day35, Month 3, Month 6, Month 9 ]

    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.



Secondary Outcome Measures :
  1. Magnitude and avidity of HBV-specific CD4+ and magnitude of CD 8+ T cells induced by each treatment regimen [ Time Frame: Baseline, Day7, Day28, Day35, Month 3, Month 6, Month 9 ]

    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.


  2. Percentage of Participants with Reduction in HBsAg titre [ Time Frame: Baseline, Day7, Day28, Day35, Month 3, Month 6, Month 9 ]
    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.

  3. Percentage of Participants with HBsAg and HBeAg Loss [ Time Frame: Baseline, Day7, Day28, Day35, Month 3, Month 6, Month 9 ]

    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.


  4. Percentage of Participants with HBsAg Seroconversion [ Time Frame: Baseline and Month 9 ]

    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.


  5. Percentage of Participants with HBeAg Seroconversion [ Time Frame: Baseline and Month 9 ]

    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.


  6. Percentage of Participants with Reduction of Hepatitis B DNA [ Time Frame: Baseline, Day 35, Month 3 and Month 9 ]
    Quantitative DNA analysis will be conducted on samples of PBMCs. Changes from baseline will be calculated for each vaccine and for each treatment group.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Adult males or females aged ≥18 to ≤65 years at screening (according to country/local regulations)
  2. BMI ≤32kg/m2
  3. Able to provide informed consent indicating they understand the purpose of, and procedures required, for the study and are willing to participate
  4. 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
  5. 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

  6. Documented evidence of chronic HBV infection (e.g. HBsAg positive ≥6 months with detectable HBsAg levels at screening)
  7. Receipt of only either entecavir, tenofovir (tenofovir alafenamide fumarate or tenofovir disoproxil fumarate), or besifovir for at least 12 months before screening
  8. Virally suppressed (HBV-DNA viral load < 40 IU/mL for ≥ 1 year)
  9. HBsAg levels <4000 IU/mL

Exclusion Criteria:

  1. Presence of any significant acute or chronic, uncontrolled medical/psychiatric illness
  2. Hepatitis C virus (HCV) antibody positive.
  3. HIV antibody positive
  4. Co-infection with hepatitis D virus
  5. Documented cirrhosis or advanced fibrosis indicated by a liver biopsy within 6 months prior to screening.

    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.
  6. 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.
  7. A history of liver decompensation (e.g. ascites, encephalopathy or variceal haemorrhage)
  8. Prior hepatocellular carcinoma
  9. Chronic liver disease of a non-HBV aetiology
  10. History or evidence of autoimmune disease or known immunodeficiency of any cause
  11. Presence of active infection
  12. Evidence of interstitial lung disease, active pneumonitis, myocarditis, or a history of myocarditis
  13. History of thyroid disorder or abnormal thyroid function at screening
  14. 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
  15. Receipt of immunoglobulin or other blood products within 3 months prior to enrolment
  16. Receipt of any investigational drug or vaccine within 3 months prior to screening
  17. Any history of receipt of any non-oral adenoviral vaccine
  18. Receipt of any live vaccines within 30 days prior to screening
  19. Receipt of any inactivated vaccines within 14 days prior to screening,
  20. History of severe hypersensitivity or anaphylactic reactions likely to be exacerbated by any component of the vaccine or nivolumab
  21. 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
  22. Current alcohol or substance abuse judged by the Investigator to potentially interfere with participant safety and compliance
  23. Significant cardiac disease or unstable uncontrolled cardiac disease
  24. Any laboratory test which is abnormal, and which is deemed by the Investigator to be clinically significant
  25. 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
  26. Any other finding that, in the opinion of the Investigator, deems the participant unsuitable for the study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04778904


Contacts
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Contact: Tom Evans, MD +44 01865 818808 enquiries@vaccitech.co.uk

Locations
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Korea, Republic of
Pusan National University Hospital Not yet recruiting
Busan, Korea, Republic of, 492421
Contact: Jeong Heo, MD    +82-51-240-7078    dusrn121233@gmail.com   
Contact: Seung Hee Park       dusrn121233@gmail.com   
Kyungpook National University Hospital Not yet recruiting
Daegu, Korea, Republic of, 41944
Contact: Won Young Tak, MD    +82-53-200-6943    sukyung0830@hanmail.net   
Contact: Choi Sukyung       sukyung0830@hanmail.net   
Keimyung University Dongsan Hospital Not yet recruiting
Daegu, Korea, Republic of, 42601
Contact: Byoung Kuk Jang, MD    +82-53-258-6680    llllbm1010@gmail.com   
Contact: Seung Hyo Woo       llllbm1010@gmail.com   
Yonsei University College of Medicine Not yet recruiting
Seoul, Korea, Republic of, 03722
Contact: Sang Hoon Ahn, MD    +82-2-2228-5633    NAV152@yuhs.ac   
Contact: SeoHyeon Choi       NAV152@yuhs.ac   
Asan Medical Centre Not yet recruiting
Seoul, Korea, Republic of, 05505
Contact: Young-Suk Lim, MD    +82-2-3210-7198    jhlee22@amc.seoul.kr   
Contact: Jaehee Lee       jhlee22@amc.seoul.kr   
The Catholic University of Korea Seoul Saint Mary's Hospital Not yet recruiting
Seoul, Korea, Republic of, 06591
Contact: Seung Kew Yoon, MD    +82-2-2258-2077    soon@catholic.ac.kr   
Contact: Young Soon Kim       soon@catholic.ac.kr   
Taiwan
Buddhist Tzu Chi Medical Foundation Not yet recruiting
Dalin, Chia-Yi County, Taiwan, 62247
Contact: Kuo-Chih Tseng, MD    886-5-2648000 ext 3240    yitinghe0912@gmail.com   
Contact: Yi-Ting He       yitinghe0912@gmail.com   
E-Da Hospital Not yet recruiting
Kaohsiung City, Yan-chao District, Taiwan, 82445
Contact: Gin-Ho Lo, MD    886-7-615-0011 ext 5007    ed107482@edah.org.tw   
Contact: Hui-Chen Lin       ed107482@edah.org.tw   
Changhua Christian Hospital Recruiting
Changhua City, Taiwan, 50006
Contact: Wei-Wen Su, MD    +886-4-7238595 ext 3935    135065@cch.org.tw   
Contact: Yuan-I Fan       135065@cch.org.tw   
Chia-Yi Christian Hospital Recruiting
Chiayi City, Taiwan, 60002
Contact: Chi-Yi Chen, MD    +86-5-276-5041 ext 2535    cych01290@gmail.com   
Contact: Yi-Lin Lu       cych01290@gmail.com   
Hualien Tzu Chi Hospital Not yet recruiting
Hualien City, Taiwan, 970
Contact: Chi-Tan Hu, MD    +886-3-8561825 ext 17602    mfwu@tzuchi.com.tw   
Contact: Ming-Fen Wu       mfwu@tzuchi.com.tw   
Kaohsiung Medical University Chung-Ho Memorial Hospital Recruiting
Kaohsiung, Taiwan, 807
Contact: Wan-Long Chuang, MD    +886-916-892-601    s0932841038@gmail.com   
Contact: Ya-Wen Liu       s0932841038@gmail.com   
United Kingdom
The Pennine Acute Hospitals NHS Trust Not yet recruiting
Manchester, Lancaster, United Kingdom, M8 5RB
Contact: Andrew Ustianowski, MD    +44-161-918-4649      
Contact: Gabriella Lindergard       gabriella.lindergard@pat.nhs.uk   
Nottingham University Hospitals NHS Trust Not yet recruiting
Nottingham, Notts, United Kingdom, NG7 2UH
Contact: Stephen Ryder    +44-115-924-9924 ext 83711      
Contact: Matthew Barnes       matthew.barnes@nuh.nhs.uk   
King's College Hospital NHS Foundation Trust Not yet recruiting
London, United Kingdom, SE5 9RS
Contact: Kaushik Agarwal, MD    +44-20-3299-7622      
Contact: Adam Hossen       adam.hossen-mamode@nhs.net   
Sponsors and Collaborators
Vaccitech Limited
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Responsible Party: Vaccitech Limited
ClinicalTrials.gov Identifier: NCT04778904    
Other Study ID Numbers: HBV-002
2020-000190-25 ( EudraCT Number )
First Posted: March 3, 2021    Key Record Dates
Last Update Posted: March 3, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Hepatitis B
Hepatitis
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Hepadnaviridae Infections
DNA Virus Infections
Nivolumab
Antineoplastic Agents, Immunological
Antineoplastic Agents