Safety and Immunotherapeutic Activity of Cemiplimab in Participants With HBV on Suppressive Antiviral Therapy: A Phase I/II Ascending Multiple Dose Study
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 试验地点
- 15
- 主要终点
- Number of participants who experienced any targeted safety event that is related to study treatment
研究概览
简要总结
The purpose of this study is to evaluate the safety and immunotherapeutic activity of cemiplimab in participants with hepatitis B virus (HBV) on suppressive antiviral therapy.
详细描述
The study consists of up to three cemiplimab dose cohorts (n=10 participants each). The cohorts will open sequentially, based on the safety of the previous cohort. Cohort 1 will open first to examine the lowest dose. When Cohort 1 participants have completed study week 18 visit and there are no safety concerns, Cohort 2 will open for enrollment. A similar assessment will be conducted with Cohort 2 to make a decision on opening Cohort 3. In each cohort, participants enter the study 6 weeks prior to initiation of treatment. The 6-week lead-in period is followed by a 6-week treatment period where two infusions of cemiplimab are administered 6 weeks apart, at study weeks 6 and 12.
The total study duration per participant is 90 weeks, including 78 weeks of follow-up after the treatment period. Study visit schedule includes visits at entry, and weeks 6, 7, 8, 10, 12, 13, 14, 16, 17, 18, 22, 24, 30, 36, 54, 72 and 90. Evaluations include: a medical and medication history; assessment of HBV antiviral therapy adherence; physical exam; blood, urine, and fecal collection; rectal swab; liver biopsy and fine needle aspiration; and optional leukapheresis.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Chronic HBV infection (defined as hepatitis B surface antigen [HBsAg] positive).
- •Receiving treatment at the time of study entry and for ≥12 months prior to study entry with HBV-active nucleos(t)ides, with tenofovir- or entecavir-containing therapy: tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), TDF/emtricitabine (FTC), TAF/FTC, or entecavir.
- •Ability and willingness of participant to provide informed consent.
- •Ability and willingness of participant to continue HBV antiviral therapy throughout the study.
- •Weight ≥40 kg and <200 kg.
- •Evidence of limited or no evidence of fibrosis (F0-F2) by liver biopsy or non-invasive alternative, as defined in the study protocol.
- •The following laboratory values obtained within 60 days prior to study entry:
- •HBV DNA level <20 IU/mL
- •Documentation of hepatitis B e antigen (HBeAg) status (positive or negative)
- •Hemoglobin ≥14.0 g/dL for male, ≥12.0 g/dL for female participants
- •Platelets ≥150,000/mm^3
- •Absolute neutrophil count (ANC) >1500/mm^3
- •International normalized ratio (INR) ≤1.1
- •Albumin ≥3.5 g/dL
- •Creatinine Clearance ≥60 mL/min, as calculated by the Cockcroft-Gault equation
- •NOTE: A calculator for the Cockcroft-Gault equation is available on the Data Management Center (DMC) website at www.fstrf.org.
- •Aspartate aminotransferase (AST) serum glutamic:oxaloacetic transaminase (SGOT) <1.25 x ULN
- •ALT serum glutamic:pyruvic transaminase (SGPT) <1.25 x ULN
- •Direct bilirubin ≤1.0 x ULN
- •AM cortisol >10 mcg/dL and <ULN
- •NOTE A: Female participants on estrogen-containing oral contraception or other exogenous estrogen treatment may repeat the AM cortisol as part of screening to determine eligibility. AM cortisol should be drawn prior to 12 noon or per local lab requirements.
- •NOTE B: Participants with a low cortisol level that was drawn after 10:00 AM may repeat the AM cortisol as part of screening to determine eligibility.
- •Normal creatinine phosphokinase (CPK) level
- •Thyroid stimulating hormone (TSH) and free thyroxine (T4) level within normal limits
- •Fasting blood glucose <126 mg/dL
- •Interferon-gamma release assay (IGRA) for tuberculosis (TB) with negative results within 90 days prior to study entry, OR prior positive TB IGRA or positive purified protein derivative (PPD) skin test with documented evidence of completed prophylaxis treatment.
- •HCV antibody negative result within one year prior to study entry; or if the participant is HCV antibody positive, an unquantifiable HCV RNA result (< lower limit of quantification [LLOQ], either target detected, or target not detected) within 60 days prior to study entry.
- •Documentation of completion of SARS-CoV-2 vaccine series and up-to-date additional or booster immunizations, as recommended by local country guidance
- •Participants of reproductive potential, a negative urine or serum pregnancy test at screening, and again within 48 hours prior to study entry by any US clinic or laboratory that has CLIA certification or its equivalent, or is using a point of care (POC)/ CLIA-waived test, or at any Network-approved non-US laboratory or clinic that operates in accordance with GCLP and participates in appropriate EQA programs
- •All participants must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, oocyte donation, in vitro fertilization).
- •When participating in sexual activity that could lead to pregnancy, participants must agree to use at least two reliable forms of contraceptive simultaneously, over the time period of 36 weeks following study entry (to include time period up to 6 months after last infusion). Such methods include:
- •Condoms (male or female) with or without a spermicidal agent
- •Diaphragm or cervical cap with spermicide
- •Intrauterine device (IUD)
- •Tubal ligation
- •Hormone-based contraceptive
- •NOTE: Providers and participants should be advised that not all contraceptive choices listed above can prevent HBV transmission. Study participants who are sexually active with HBV negative or unknown HBV serostatus partners should be advised that they need to consider effective strategies to reduce the risk of HBV transmission and meet the requirement for effective contraception during their participation in the study. Study participants should discuss contraceptive choices and HBV risk-reduction methods with their health care provider.
- •Participants who are not of reproductive potential (women who have been post-menopausal for at least 24 consecutive months or have undergone hysterectomy and/or bilateral oophorectomy or salpingectomy or men who have documented azoospermia) are eligible without requiring the use of contraceptives. Acceptable documentation of menopause or sterilization is specified below.
- •Written or oral documentation communicated by clinician or clinician's staff of one of the following:
- •Physician report/letter
- •Operative report or other source documentation in the patient record (a laboratory report of azoospermia is required to document successful vasectomy)
- •Discharge summary
- •Follicle stimulating hormone-release factor (FSH) measurement elevated into the menopausal range as established by the reporting laboratory
- •Intention to comply with the dosing instructions for study drug administration and ability to complete the study schedule of assessments.
- •Exclusion Criteria
- •Any malignancy within the 5 years prior to study entry or current malignancy requiring cytotoxic therapy.
- •NOTE: A history of non-melanoma skin cancer (e.g., basal cell carcinoma or squamous cell skin cancer) at any time is not exclusionary.
- •Current chronic, acute, or recurrent bacterial, fungal, or viral (other than HBV) infections that are serious, in the opinion of the site investigator, and that required systemic therapy within 30 days prior to study entry.
- •Prior history of or active autoimmune disorders including but not limited to inflammatory bowel diseases, scleroderma, severe psoriasis, myocarditis, uveitis, pneumonitis, systemic lupus erythematosus, rheumatoid arthritis, optic neuritis, myasthenia gravis, adrenal insufficiency, hypothyroidism and/or hyperthyroidism, autoimmune thyroiditis, hypophysitis, multiple sclerosis, or sarcoidosis.
- •NOTE: For questions related to the definition of autoimmune disorders, sites should contact the team per the study protocol.
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排除标准
- 未提供
结局指标
主要结局
Number of participants who experienced any targeted safety event that is related to study treatment
时间窗: From Week 6 to Week 18
Targeted safety events include: * Hepatic encephalopathy * Ascites * Grade 2 or higher ALT elevation with INR greater than 1.5 or direct bilirubin greater than 1.5, unless occurring as part of HBeAg or HBsAg seroconversion to anti-HBe or anti-HBs or greater than 1 log decline in quantitative HBsAg with ALT resolution to Grade 1 or less within 60 days of elevation. * Non-hepatic AE of Grade 3 or higher * Adrenal insufficiency or adrenal crisis, confirmed, Grades 1-3 * Myocarditis, Grades 1-3 * Pneumonitis, Grades 2-3 * Infusion-related reaction, Grade 3 * Rash, Grade 3 * Uveitis, Grades 1-3 * Immune mediated hyper- or hypothyroidism, Grades 2-3 * Colitis, Grade 3 or higher * Myositis, Grades 2-3 * Immune-mediated hepatitis * Death DAIDS AE Grading Table (V2.1) is used.
Number of participants who discontinue treatment and/or study which is related to any adverse event
时间窗: From Week 6 to Week 18
Attributed to any adverse event as reported by the site
Number of participants with any AE
时间窗: From entry to Week 90
Study protocol requires reporting of all targeted events (listed in Primary Outcome Measure 1 above), all Grade 1 or higher AEs, and any AE that occurs during the infusion or within 24 hours after infusion. DAIDS AE Grading Table (V2.1) is used.
次要结局
- Number of participants with detectable HBsAg(Entry and Weeks 6, 12, 18, 36, 54, 72, Week 90)
- Number of participants with anti-HBs conversion from negative (at study Week 6) to positive at a subsequent visit(Weeks 6, 12, 18, 36, 54, 72, 90)
- Change in quantitative HBsAg from pre-treatment(Entry and Weeks 6, 8, 12, 14, 18, 24, 36, 54, 72, 90)
- Change in quantitative HBeAg from pre-treatment(Entry and Weeks 6, 12, 18, 36, 54, 72, 90)
- Number of participants with anti-HBe conversion from negative (at study Week 6) to positive at a subsequent visit(Entry and Weeks 6, 12, 18, 36, 54, 72, 90)
- Detection of hepatitis B core-related antigen (HBcrAg)(Entry and Weeks 6, 8, 12, 14, 18, 24, 36, 54, 72,90)