A Phase IIB Clinical Trial of the Multitargeted Recombinant Adenovirus 5 (CEA/MUC1/Brachyury) Vaccines (TRI-AD5) and IL-15 Superagonist N-803 in Lynch Syndrome
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 186
- 试验地点
- 22
- 主要终点
- Cumulative incidence rate of the composite endpoint of adenomas (tubular, tubulovillous and serrated), advanced adenomas and colon cancer
研究概览
简要总结
This phase IIb trial tests whether Tri-Ad5 in combination with N-803 works to prevent colon and other cancers in participants with Lynch syndrome. Each of the three injections in Tri-Ad5 vaccine contain a different substance that is in precancer and cancer cells. Injecting these substances may cause the immune system to develop a defense against cancer that recognizes and destroys any precancer and cancer cells that produce these proteins in the future. N-803 may increase immune responses to other vaccines. Giving Tri-Ad5 in combination with immune enhancing N-803 may lower the chance of developing colon and other cancers in participants with Lynch syndrome.
详细描述
PRIMARY OBJECTIVE:
I. To evaluate if the combination of trivalent adenovirus-5 (Tri-Ad5) vaccines and IL-15 superagonist nogapendekin alfa inbakicept (N-803) reduces the incidence of colorectal neoplasms in patients with Lynch syndrome (LS).
SECONDARY OBJECTIVES:
I. To evaluate the safety and tolerability of the Tri-Ad5 vaccines + N-803 in combination.
II. To correlate clinical factors such as use of aspirin and non-steroidal anti-inflammatory drugs (NSAID), smoking and alcohol intake with immune responses.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants with LS defined as one of the following:
- •Mutation positive: MLH1, MSH2/EPCAM and MSH6 genotypes with prior history of ≥1 colorectal neoplasms** (tubular or tubulovillous adenoma[s] or sessile serrated polyps/adenomas/lesion[s] or traditional serrated adenoma[s]), and/or colorectal cancer[s] (but no active cancer for 6 months) OR
- •PMS2 genotype with prior history of colon cancer(s) (but no active cancer for 6 months)
- •Note: Should be confirmed by pathology report or letter from endoscopist to participant
- •Participants must have at least part of the descending/sigmoid colon and/or rectum intact
- •Participants must be at least 6 months from any cancer-directed treatment (such as surgical resection, chemotherapy, immunotherapy or radiation). Ongoing adjuvant endocrine therapy is allowed
- •Participants >= 18 years will be enrolled. Because the risk of LS related cancers is very low in participants < 18 years of age, children and adolescents are excluded from this study
- •Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
- •Leukocytes >= 3,000/microliter
- •Absolute neutrophil count >= 1,500/microliter
- •Platelets >= 100,000/microliter
- •Total bilirubin =< institutional upper limit of normal
- •Note: Higher bilirubin levels (<= 3 mg/dL) can be allowed if due to a known benign liver condition, i.e. Gilbert's
- •Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 x institutional upper limit of normal
- •Creatinine =< institutional upper limit of normal or estimated glomerular filtration rate (eGFR) >= 60 ml/min/1.73m^2
- •The effects of the Tri-Ad5 vaccines and N-803 on the developing human fetus at the recommended therapeutic dose are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately
- •Ability to understand and the willingness to sign a written informed consent document
- •Participants must be willing and able to space coronavirus disease (COVID) vaccines at least 2 weeks prior to and 2 weeks after receipt of study agent
排除标准
- •History of organ allograft or other history of immunodeficiency
- •Known human immunodeficiency virus (HIV) with CD4 count < 540, hepatitis B virus (HBV), or hepatitis C virus (HCV) infection. Subjects with laboratory evidence of cleared HBV and HCV infection will be permitted. Poorly controlled HIV may prevent an adequate immune response to the vaccine and will be an exclusion criterion
- •Subjects requiring systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 3 months of vaccination
- •Participants may not be receiving any other investigational agents
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to adenovirus-based vaccines and N-803
- •Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirements
- •Pregnant women are excluded from this study because of the unknown effects of the vaccine and N-803 on the fetus. Because there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with the vaccine plus N-803, breastfeeding should be discontinued if the mother is treated with the vaccine plus N-803
- •History of untreated thrombotic disorders
- •Participants who experienced severe side effects or allergic reactions to previous adenovirus-based vaccines (such as Johnson and Johnson COVID vaccine) will be excluded
- •History of atrial fibrillation
- •History of gastrointestinal hemorrhage and intracranial hemorrhage
研究组 & 干预措施
Arm I (Tri-Ad5, N-803)
Participants receive Tri-Ad5 SC and N-803 SC at weeks 0, 4, 8, and 52. Participants also undergo SOC colonoscopy with biopsy at baseline and at 52 and 104 weeks. Participants undergo blood sample collection throughout the study.
干预措施: Colonoscopy (Procedure)
Arm II (placebo)
Participants receive placebo SC at weeks 0, 4, 8, and 52. Participants also undergo SOC colonoscopy with biopsy at baseline and at 52 and 104 weeks. Participants undergo blood sample collection throughout the study.
干预措施: Questionnaire Administration (Other)
Safety phase I (Tri-Ad5)
Participants receive Tri-Ad5 SC at weeks 0, 4, 8, and 52. Participants also undergo SOC colonoscopy with biopsy at baseline and at 52 weeks and 104 weeks. Participants undergo blood sample collection throughout the study.
干预措施: Adenovirus 5 CEA/MUC1/Brachyury Vaccine Tri-Ad5 (Biological)
Arm I (Tri-Ad5, N-803)
Participants receive Tri-Ad5 SC and N-803 SC at weeks 0, 4, 8, and 52. Participants also undergo SOC colonoscopy with biopsy at baseline and at 52 and 104 weeks. Participants undergo blood sample collection throughout the study.
干预措施: Nogapendekin Alfa (Drug)
Arm II (placebo)
Participants receive placebo SC at weeks 0, 4, 8, and 52. Participants also undergo SOC colonoscopy with biopsy at baseline and at 52 and 104 weeks. Participants undergo blood sample collection throughout the study.
干预措施: Biospecimen Collection (Procedure)
Arm II (placebo)
Participants receive placebo SC at weeks 0, 4, 8, and 52. Participants also undergo SOC colonoscopy with biopsy at baseline and at 52 and 104 weeks. Participants undergo blood sample collection throughout the study.
干预措施: Colonoscopy (Procedure)
Arm I (Tri-Ad5, N-803)
Participants receive Tri-Ad5 SC and N-803 SC at weeks 0, 4, 8, and 52. Participants also undergo SOC colonoscopy with biopsy at baseline and at 52 and 104 weeks. Participants undergo blood sample collection throughout the study.
干预措施: Adenovirus 5 CEA/MUC1/Brachyury Vaccine Tri-Ad5 (Biological)
Arm I (Tri-Ad5, N-803)
Participants receive Tri-Ad5 SC and N-803 SC at weeks 0, 4, 8, and 52. Participants also undergo SOC colonoscopy with biopsy at baseline and at 52 and 104 weeks. Participants undergo blood sample collection throughout the study.
干预措施: Biospecimen Collection (Procedure)
Arm I (Tri-Ad5, N-803)
Participants receive Tri-Ad5 SC and N-803 SC at weeks 0, 4, 8, and 52. Participants also undergo SOC colonoscopy with biopsy at baseline and at 52 and 104 weeks. Participants undergo blood sample collection throughout the study.
干预措施: Biopsy Procedure (Procedure)
Safety phase I (Tri-Ad5)
Participants receive Tri-Ad5 SC at weeks 0, 4, 8, and 52. Participants also undergo SOC colonoscopy with biopsy at baseline and at 52 weeks and 104 weeks. Participants undergo blood sample collection throughout the study.
干预措施: Biospecimen Collection (Procedure)
Safety phase I (Tri-Ad5)
Participants receive Tri-Ad5 SC at weeks 0, 4, 8, and 52. Participants also undergo SOC colonoscopy with biopsy at baseline and at 52 weeks and 104 weeks. Participants undergo blood sample collection throughout the study.
干预措施: Biopsy Procedure (Procedure)
Safety phase I (Tri-Ad5)
Participants receive Tri-Ad5 SC at weeks 0, 4, 8, and 52. Participants also undergo SOC colonoscopy with biopsy at baseline and at 52 weeks and 104 weeks. Participants undergo blood sample collection throughout the study.
干预措施: Colonoscopy (Procedure)
Safety phase I (Tri-Ad5)
Participants receive Tri-Ad5 SC at weeks 0, 4, 8, and 52. Participants also undergo SOC colonoscopy with biopsy at baseline and at 52 weeks and 104 weeks. Participants undergo blood sample collection throughout the study.
干预措施: Questionnaire Administration (Other)
Safety phase II (Tri-Ad5 , N-803)
Participants receive Tri-Ad5 SC and N-803 SC at weeks 0, 4, 8, and 52. Participants also undergo SOC colonoscopy with biopsy at baseline and at 52 weeks and 104 weeks. Participants undergo blood sample collection throughout the study.
干预措施: Questionnaire Administration (Other)
Safety phase II (Tri-Ad5 , N-803)
Participants receive Tri-Ad5 SC and N-803 SC at weeks 0, 4, 8, and 52. Participants also undergo SOC colonoscopy with biopsy at baseline and at 52 weeks and 104 weeks. Participants undergo blood sample collection throughout the study.
干预措施: Nogapendekin Alfa (Drug)
Safety phase II (Tri-Ad5 , N-803)
Participants receive Tri-Ad5 SC and N-803 SC at weeks 0, 4, 8, and 52. Participants also undergo SOC colonoscopy with biopsy at baseline and at 52 weeks and 104 weeks. Participants undergo blood sample collection throughout the study.
干预措施: Adenovirus 5 CEA/MUC1/Brachyury Vaccine Tri-Ad5 (Biological)
Arm II (placebo)
Participants receive placebo SC at weeks 0, 4, 8, and 52. Participants also undergo SOC colonoscopy with biopsy at baseline and at 52 and 104 weeks. Participants undergo blood sample collection throughout the study.
干预措施: Biopsy Procedure (Procedure)
Arm II (placebo)
Participants receive placebo SC at weeks 0, 4, 8, and 52. Participants also undergo SOC colonoscopy with biopsy at baseline and at 52 and 104 weeks. Participants undergo blood sample collection throughout the study.
干预措施: Placebo Administration (Drug)
Arm I (Tri-Ad5, N-803)
Participants receive Tri-Ad5 SC and N-803 SC at weeks 0, 4, 8, and 52. Participants also undergo SOC colonoscopy with biopsy at baseline and at 52 and 104 weeks. Participants undergo blood sample collection throughout the study.
干预措施: Questionnaire Administration (Other)
Safety phase II (Tri-Ad5 , N-803)
Participants receive Tri-Ad5 SC and N-803 SC at weeks 0, 4, 8, and 52. Participants also undergo SOC colonoscopy with biopsy at baseline and at 52 weeks and 104 weeks. Participants undergo blood sample collection throughout the study.
干预措施: Biopsy Procedure (Procedure)
Safety phase II (Tri-Ad5 , N-803)
Participants receive Tri-Ad5 SC and N-803 SC at weeks 0, 4, 8, and 52. Participants also undergo SOC colonoscopy with biopsy at baseline and at 52 weeks and 104 weeks. Participants undergo blood sample collection throughout the study.
干预措施: Biospecimen Collection (Procedure)
Safety phase II (Tri-Ad5 , N-803)
Participants receive Tri-Ad5 SC and N-803 SC at weeks 0, 4, 8, and 52. Participants also undergo SOC colonoscopy with biopsy at baseline and at 52 weeks and 104 weeks. Participants undergo blood sample collection throughout the study.
干预措施: Colonoscopy (Procedure)
结局指标
主要结局
Cumulative incidence rate of the composite endpoint of adenomas (tubular, tubulovillous and serrated), advanced adenomas and colon cancer
时间窗: At 104 weeks
Will be compared between the two arms using a stratified Cochran-Mantel-Haenszel test where the randomization stratification factors will be included as strata. The cumulative events rates will be reported for each study arm along with the corresponding two-sided 95% confidence intervals.
次要结局
- Incidence of adverse events(Up to 104 weeks)
- Association of clinical factors with immune responses(At 104 weeks)
- Incidence of extracolonic neoplasms(At 104 weeks)
- Participants' behavior and experience(At baseline, 12 weeks and 52 weeks)