A Multicenter Phase 1b Randomized, Placebo-controlled, Blinded Study to Evaluate the Safety, Tolerability and Efficacy of Microbiome Study Intervention Administration in Combination With Anti-PD-1 Therapy in Adult Patients With Unresectable or Metastatic Melanoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 14
- 试验地点
- 7
- 主要终点
- Percentage of Patients With Adverse Events (AEs)
研究概览
简要总结
This study is designed to evaluate the safety and tolerability of treatment with oral microbiome study intervention (SER-401) or matching placebo in combination with anti-programmed cell death 1 (anti-PD-1) therapy (nivolumab) in participants with unresectable or metastatic melanoma. The study also intends to assess clinical outcomes, the impact of microbiome study intervention administration on the microbiome profile, and its association with clinical and immunological outcomes.
详细描述
This is a Phase 1b, multicenter, randomized, placebo-controlled, blinded study in adult participants with anti-PD-1 therapy naïve, unresectable or metastatic melanoma to evaluate the safety and tolerability of SER-401, or matching placebo in combination with anti-PD-1 therapy (nivolumab). Prior to initiating microbiome study intervention and nivolumab, participants will undergo an antibiotic or antibiotic placebo treatment lead-in to prime the gut microbiome for engraftment of the oral microbiome study intervention. Study intervention groups will be assessed for safety, changes in the microbiome, changes in the percentage of tumoral CD8 T cells, and antitumor activity. Participants must have measurable disease that can be biopsied and consent to baseline and on-treatment biopsies, as well as stool and blood biomarker collection throughout the study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
Participants will be randomly assigned in a 2:1 ratio to oral microbiome study intervention or matching placebo. Nivolumab will be administered open-label as standard of care to all groups. Investigators, site personnel, and participants will remain blinded to the assignment of microbiome study intervention throughout the course of the study. Select Sponsor personnel, including but not limited to the Medical Monitor, Clinical Scientists, Biostatistician, and Patient Safety, will be unblinded to treatment assignment for ongoing safety monitoring.
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
- •Participant must be willing to provide a baseline stool sample.
- •Histologically-confirmed Stage IV cutaneous melanoma or Stage III cutaneous, acral or mucosal melanoma that is judged inoperable. Participants with a history of uveal melanoma are not eligible.
- •Measurable disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1; ie, defined as at least 1 lesion that can be accurately measured in at least 1 dimension [longest diameter to be recorded] with a minimum size of ≥ 10 mm by computerized tomography [CT] scan or caliper measurement on clinical exam or ≥ 20 mm by chest X-ray).
- •Malignant lymph nodes must be ≥ 15 mm in short axis when assessed by CT scan to be considered pathologically enlarged and measurable.
- •Participants must have at least one measurable lesion by RECIST and a separate lesion amenable to biopsy that has not been previously irradiated.
- •i. Participants must be willing to undergo a newly-obtained core needle or incisional biopsy at baseline (prior to antibiotic or antibiotic placebo administration). Fine needle aspiration is not acceptable.
- •Participants must be willing to undergo tumor biopsy on treatment.
- •Prior adjuvant or neoadjuvant melanoma therapy is permitted if completed at least 6 weeks prior to randomization and all related AEs have either returned to baseline or stabilized.
- •Prior anti-CTLA-4 therapy in the adjuvant setting is allowed if completed at least 12 weeks prior to the first dose of anti-PD-1.
排除标准
- •Participants who require hemodialysis.
- •Participants with a history of another cancer in the last 5 years, except for: a) curatively resected non-melanoma skin cancer; b) curatively treated cervical carcinoma in situ; c) localized prostate cancer not requiring systemic therapy; and c) other primary tumors with no known active disease present that, in the opinion of the Investigator and the Sponsor, will not affect participant outcome in the setting of the current diagnosis.
- •Any known, untreated brain metastases. Participants with brain metastases are eligible if these have been treated, and provided:
- •Brain metastases must be stable (image-documented) 4 weeks after completion of treatment for brain metastases and require treatment with less than 10 mg/day prednisone equivalent for at least 2 weeks prior to study intervention administration.
- •Neurological symptoms should be absent or returned to baseline.
- •Prior checkpoint inhibitor therapy with anti-PD-1 or anti-PD-L1 in the adjuvant setting.
- •a. Exception: Participants with stage 3 or 4 cutaneous melanoma status post-resection who have received up to one year of adjuvant anti-PD-1 therapy who have recurred > 6 months after their last dose of anti-PD-1 therapy are eligible.
- •Other prior systemic treatment (ie, anticancer chemotherapy, immunotherapy, or investigational agents) for unresectable or metastatic melanoma EXCEPT:
- •Prior BRAF-targeted therapy (ie, BRAF or BRAF-MEK) in the metastatic setting is allowed if completed at least 4 weeks prior to the first dose of anti-PD-
- •Prior anti-CTLA 4 therapy in the adjuvant setting are allowed if completed at least 12 weeks prior to the first dose of anti-PD-
- •History of active inflammatory bowel disease (eg, active Crohn's disease or ulcerative colitis) with diarrhea OR major gastrointestinal surgery (not including appendectomy or cholecystectomy) within 3 months of enrollment (ie, signed informed consent for the study), OR any history of total colectomy or bariatric surgery (bariatric surgery which does not disrupt the gastrointestinal lumen, ie, restrictive procedures such as banding, are permitted).
- •Any diagnosis of autoimmune disease. Participants with Type I diabetes mellitus, hypothyroidism only requiring hormone replacement, adrenal insufficiency on replacement dose steroids, skin disorders (such as vitiligo, psoriasis or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
- •a. Participants with controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible.
- •Has a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study intervention administration or has a contrast allergy requiring premedication with corticosteroids. Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
- •History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (ie, bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest CT scan.
- •a. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
- •Has a transplanted organ or has undergone allogeneic bone marrow transplant.
- •Has received a live vaccine within 30 days prior to first dose. Participants must not receive live, attended influenza vaccine (eg, FluMist) within 30 days prior to Cycle 1, Day 1 or at any time during the study and 100 days after last dose of nivolumab.
- •Has used antibiotics within 30 days prior to randomization or has planned or required need for antibiotic prophylaxis for more than 24 consecutive hours during the course of the study.
研究组 & 干预措施
SER-401 Matching Placebo/ Nivolumab
Participants will undergo a 4-day lead-in pretreatment with antibiotic placebo, then matching placebo for SER-401 and nivolumab (480 mg) treatment.
干预措施: Placebo for antibiotic (Drug)
SER-401 Matching Placebo/ Nivolumab
Participants will undergo a 4-day lead-in pretreatment with antibiotic placebo, then matching placebo for SER-401 and nivolumab (480 mg) treatment.
干预措施: Nivolumab (Drug)
SER-401 Matching Placebo/ Nivolumab
Participants will undergo a 4-day lead-in pretreatment with antibiotic placebo, then matching placebo for SER-401 and nivolumab (480 mg) treatment.
干预措施: Matching Placebo for SER-401 (Drug)
SER-401/ Nivolumab
Participants will undergo a 4-day lead-in pretreatment with antibiotic (vancomycin) to prime the gut microbiome for engraftment of the oral microbiome study intervention, then SER-401 and nivolumab treatment.
干预措施: Vancomycin pretreatment (Drug)
SER-401/ Nivolumab
Participants will undergo a 4-day lead-in pretreatment with antibiotic (vancomycin) to prime the gut microbiome for engraftment of the oral microbiome study intervention, then SER-401 and nivolumab treatment.
干预措施: Nivolumab (Drug)
SER-401/ Nivolumab
Participants will undergo a 4-day lead-in pretreatment with antibiotic (vancomycin) to prime the gut microbiome for engraftment of the oral microbiome study intervention, then SER-401 and nivolumab treatment.
干预措施: SER-401 (Drug)
结局指标
主要结局
Percentage of Patients With Adverse Events (AEs)
时间窗: Up to 2 years
Investigators recorded AEs during each participant interaction. Symptoms were evaluated by the Investigator using the CTCAE version 5.0. This system grades AEs on a 1 to 5 scale: Grades 1 and 2 indicate mild to moderate events; Grade 3 denotes severe events; Grades 4 and 5 signify life-threatening or fatal outcomes. A treatment-emergent adverse event (TEAE) is defined as any event that either occurs after the initiation of study intervention, having been absent at baseline, or, if present at baseline, appears to have worsened in severity or frequency, regardless of its relation to the intervention. Adverse events deemed 'Possibly', 'Probably', or 'Definitely' related to the intervention were labeled as treatment-related adverse events (TRAE).
次要结局
- Progression-free Survival (PFS)(Up to 2 years)
- Disease Control Rate (DCR)(Up to week 52)
- Mean Change From Baseline in the Number of Newly Appearing Spore-forming Species(Up to 2 years)
- Objective Response Rate (ORR)(Up to week 52)
- Overall Survival (OS)(Up to 2 years)
- Duration of Response(Up to 2 years)
- Absolute Change in the Percentage of CD8 Cells in Tumor Tissue From Baseline at Cycle 2.(At cycle 2 (each cycle is 28 days))