Gut Microbiota in Patients With Haematological Malignancies Undergoing CAR-T Cell Therapy: A Randomized Phase II Trial Comparing Standard of Care Versus a Restrictive Antibiotic Strategy
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 150
- 试验地点
- 1
- 主要终点
- Gut Microbiota Alpha Diversity at Day 28
研究概览
简要总结
The purpose of the CARMic study is to investigate whether a restrictive, microbiome-sparing antibiotic strategy can better preserve the gut microbiota in patients undergoing chimeric antigen receptor T-cell (CAR-T) therapy without compromising infectious safety.
This is a randomized, open-label Phase II trial enrolling 150 adults with large B-cell lymphoma or multiple myeloma who are scheduled to receive standard-of-care CAR-T therapy. Participants will be randomly assigned in a 1:1 ratio to either a restrictive antibiotic strategy based on ceftazidime and/or ciprofloxacin or an unrestricted standard-of-care antibiotic strategy. The assigned strategy will apply from randomization until 28 days after CAR-T-cell infusion. Antibiotic treatment may be modified or broadened at any time when clinically indicated.
The primary question is whether the restrictive antibiotic strategy results in greater gut microbial diversity 28 days after CAR-T-cell infusion compared with standard-of-care antibiotic treatment. Gut microbial diversity will be assessed in stool samples using the Shannon diversity index.
The study will also compare infections, antibiotic exposure, adherence to the assigned strategy, CAR-T-related toxicities, treatment response, relapse, progression-free survival, and overall survival between the two groups. Changes in gut microbiota composition and in blood and stool metabolomic and proteomic profiles will be evaluated over time. Blood and stool samples will be collected at randomization, around the time of CAR-T-cell infusion, 28 days after infusion, and at the end-of-treatment evaluation approximately 3-6 months after infusion.
详细描述
CAR-T-cell therapy is associated with substantial exposure to antibacterial agents because patients frequently develop fever, neutropenia, and suspected or confirmed infections during the peri-infusion period. Broad-spectrum antibacterial agents, particularly those with extended anaerobic activity, may cause marked disruption of the intestinal microbiota. Retrospective studies have associated peri-CAR-T antibiotic exposure and reduced gut microbial diversity with inferior treatment response, increased toxicity, and shorter survival. However, these associations may be affected by confounding related to infection severity, disease status, and other clinical factors. Prospective randomized evidence is therefore needed to determine whether a microbiome-sparing antibacterial strategy can preserve gut microbial diversity while remaining clinically feasible and safe.
In the restrictive-strategy group, intravenous ceftazidime will be used as initial empirical antibacterial treatment when antibacterial therapy is clinically indicated. Oral ciprofloxacin may be used as protocol-defined step-down treatment after adequate infection control and clinical stabilization. Ciprofloxacin may also be used as antibacterial prophylaxis when prophylaxis is clinically indicated and there is no suspected ongoing infection. Ciprofloxacin will not be used as initial empirical monotherapy for suspected infection.
A switch from intravenous ceftazidime to oral ciprofloxacin may be considered when the participant is clinically stable; fever and other clinical signs of infection have resolved or clearly improved; no microbiologically documented infection or suspected infectious focus requires alternative or additional coverage; any identified pathogen is susceptible to ciprofloxacin; oral absorption is considered reliable; and there is no known colonization or previous infection with a fluoroquinolone-resistant pathogen that would make ciprofloxacin inappropriate.
Participant safety takes priority over adherence to the restrictive strategy. The treating physician may modify or broaden antibacterial treatment at any time in response to clinical deterioration, persistent or recurrent fever, microbiological findings, suspected resistance, organ-specific infection, or a need for additional Gram-positive, anaerobic, or other antimicrobial coverage. All decisions to modify or escalate treatment and the reasons for doing so will be recorded. In the standard-of-care group, antibacterial prophylaxis and treatment will be selected according to local clinical practice without protocol-defined restrictions.
The biological effects of the two strategies will be characterized through longitudinal collection of stool and blood samples. Samples will be obtained at randomization, around the time of CAR-T-cell infusion, at day 28 after infusion, and at the end-of-treatment evaluation approximately 3-6 months after infusion. Stool samples will be used to assess microbial diversity, community composition, and the relative abundance of selected bacterial taxa. Blood and stool samples will also be used for exploratory metabolomic analyses, including microbiota-associated metabolites such as short-chain fatty acids, tryptophan-derived metabolites, secondary bile acids, and other immunomodulatory metabolites, depending on assay coverage. Blood proteomic profiles will be explored in relation to microbiota changes, antibacterial exposure, toxicity, and clinical outcomes.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Supportive Care
- 盲法
- None
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
- •Age 18 years or older. Relapsed or refractory large B-cell lymphoma according to the current World Health Organization classification, or relapsed or refractory multiple myeloma according to the current International Myeloma Working Group classification.
- •Eligible for treatment with a CAR-T-cell product authorized in the European Union and recommended for reimbursement by the Danish Medicines Council.
- •A clinical decision to proceed with CAR-T-cell therapy has been made jointly by the participant and the treating physician.
- •Written informed consent to participate in the trial.
排除标准
- •Pregnancy or breastfeeding. Psychiatric illness or other condition that may interfere with the ability to understand or comply with the trial requirements.
- •Clinical signs of an uncontrolled serious infection. Severe colitis. Previous allergic reaction to cephalosporins or ciprofloxacin. Participants with a known allergy to other beta-lactam antibiotics, including penicillins, may be enrolled provided that they do not have a known allergy to cephalosporins.
研究组 & 干预措施
Standard-of-Care Antibiotic Strategy
Participants will receive antibacterial prophylaxis and treatment according to unrestricted local standard-of-care practice from randomization until day 28 after CAR-T-cell infusion. Selection, modification, escalation, and duration of antibacterial treatment will be determined by the treating physician according to clinical findings, microbiological results, and local guidelines.
干预措施: Standard-of-Care Antibiotic Strategy (Other)
Restrictive Antibiotic Strategy
Participants will follow a protocol-defined restrictive antibacterial strategy from randomization until day 28 after CAR-T-cell infusion. Intravenous ceftazidime will be used as initial empirical antibacterial treatment when clinically indicated. Oral ciprofloxacin may be used as step-down therapy following adequate infection control and clinical stabilization or as antibacterial prophylaxis when clinically indicated in the absence of suspected ongoing infection. Antibacterial treatment may be modified or broadened at any time when clinically required.
干预措施: ciprofloxacin (Drug)
Restrictive Antibiotic Strategy
Participants will follow a protocol-defined restrictive antibacterial strategy from randomization until day 28 after CAR-T-cell infusion. Intravenous ceftazidime will be used as initial empirical antibacterial treatment when clinically indicated. Oral ciprofloxacin may be used as step-down therapy following adequate infection control and clinical stabilization or as antibacterial prophylaxis when clinically indicated in the absence of suspected ongoing infection. Antibacterial treatment may be modified or broadened at any time when clinically required.
干预措施: ceftazidime (Drug)
结局指标
主要结局
Gut Microbiota Alpha Diversity at Day 28
时间窗: Day 28 after CAR-T-cell infusion (±3 working days)
Gut microbiota alpha diversity measured by the Shannon diversity index in a stool sample collected at day 28 after CAR-T-cell infusion. The Shannon index quantifies within-sample microbial diversity by incorporating both microbial richness and evenness. The treatment effect will be expressed as the adjusted mean difference in the Shannon diversity index between the restrictive antibiotic strategy and the standard-of-care antibiotic strategy, calculated as restrictive strategy minus standard of care. A positive difference favors the restrictive strategy.
次要结局
- Longitudinal Gut Microbiota Alpha Diversity(From randomization through the end-of-treatment evaluation, approximately 3-6 months after CAR-T-cell infusion)
- Gut Microbiota Beta Diversity(From randomization through the end-of-treatment evaluation, approximately 3-6 months after CAR-T-cell infusion)
- Relative Abundance of Predefined Beneficial Bacterial Taxa(From randomization through the end-of-treatment evaluation, approximately 3-6 months after CAR-T-cell infusion)
- Infectious Complications(Randomization to CAR-T-cell infusion; day 0-28; and day 29-90 after infusion)
- Total Systemic Antibacterial Exposure(From randomization through day 28 after CAR-T-cell infusion)
- Exposure to Broad-Spectrum Antibiotics With Extended Anaerobic Coverage(From randomization through day 28 after CAR-T-cell infusion)
- Cytokine Release Syndrome(From CAR-T-cell infusion through day 28)
- Immune Effector Cell-Associated Neurotoxicity Syndrome(From CAR-T-cell infusion through day 28)
- Immune Effector Cell-Associated Hematotoxicity(From CAR-T-cell infusion through day 90)
- Clinical Response in Large B-Cell Lymphoma(At the end-of-treatment evaluation, approximately 3-6 months after CAR-T-cell infusion)
- Clinical Response in Multiple Myeloma(At the end-of-treatment evaluation, approximately 3-6 months after CAR-T-cell infusion)
- Relapse at 1 Year(One year after CAR-T-cell infusion)
- Progression-Free Survival(From CAR-T-cell infusion through 24 months)
- Overall Survival(From CAR-T-cell infusion through 24 months)
- Adherence to the Assigned Antibiotic Strategy(From randomization through day 28 after CAR-T-cell infusion)
- Modification or Escalation of Antibacterial Treatment(From randomization through day 28 after CAR-T-cell infusion)
- Blood and Stool Metabolomic Profiles(From randomization through the end-of-treatment evaluation, approximately 3-6 months after CAR-T-cell infusion)
- Blood Proteomic Profiles(From randomization through the end-of-treatment evaluation, approximately 3-6 months after CAR-T-cell infusion)