Phase 1b/2a Evaluation of the Safety and Tolerability of SYN-004 in Adult Allogeneic Hematopoietic Cell Transplantation (Allo-HCT) Recipients
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 36
- 试验地点
- 1
- 主要终点
- SYN-004 systemic absorption
研究概览
简要总结
Study Objectives:
- To evaluate the safety and tolerability of oral SYN-004 in adult allogeneic HCT (allo-HCT) recipients who develop fever after conditioning therapy and are treated with IV β-lactam antibiotics meropenem (MER), piperacillin tazobactam (PIP/TAZO), or cefepime (FEP).
- To evaluate potential absorption of oral SYN-004 into the systemic circulation of allo-HCT recipients and potential SYN-004-mediated alterations to systemic levels and efficacy of IV MER, PIP/TAZO or FEP.
- To evaluate potential protective effects of SYN-004 on the intestinal microbiome of allo-HCT recipients treated with IV MER, PIP/TAZO or FEP.
- To obtain preliminary information on potential therapeutic benefits and patient outcomes of SYN-004 in allo-HCT recipients treated with IV MER, PIP/TAZO or FEP
详细描述
Study Design:
This is a single-center, placebo controlled, double blinded Phase 1b/2a study to assess the safety, tolerability and potential efficacy of orally administered SYN-004 in adult allo-HCT recipients. Participants will be randomized 2:1 to SYN-004 or placebo in blocks of three, stratified in three cohorts based on study assigned antibiotic (MER, piperacillin/tazobactam [PIP/TAZO], FEP) to be administered if the treating clinicians determine initiation of broad-spectrum antibiotics is indicated. As such, there will be six groups based on antibiotic cohort and randomized assignment of study drug:
Group 1: Placebo + IV MER (n=4) (MER control). Group 2: SYN-004 + IV MER (n=8) (MER treatment). Group 3: Placebo + IV PIP/TAZO (n=4) (PIP/TAZO control). Group 4: SYN-004 + IV PIP/TAZO (n=8) (PIP/TAZO treatment). Group 5: Placebo + IV FEP (n=4) (FEP control). Group 6: SYN-004 + IV FEP (n=8) (FEP treatment). Study-assigned antibiotics will be dosed as follows (adjusted for renal function as needed): MER 1 gram every 8 hours, PIP/TAZO 4.5 grams every 6 hours, FEP 1 gram every 8 hours. SYN-004 treated participants (Groups 2, 4 and 6) will be compared to control participants who receive placebo (Groups 1, 3 and 5, respectively). The study will be conducted in stages, commencing with Groups 1 and 2 who will be assigned to receive MER if antibiotics are indicated. MER is the first cohort because anti-infective efficacy of MER is not anticipated to be affected if SYN-004 is absorbed systemically. Accrual for Groups 3 and 4 (PIP/TAZO cohort) will begin only after review of the data from Groups 1 and 2 by the Data and Safety Monitoring Committee (DSMC) and agreement to proceed. PIP/TAZO is the next cohort because TAZO is a beta-lactamase inhibitor. As such, in the unlikely event of SYN-004 systemic absorption, TAZO systemic concentrations should be sufficient to inhibit any absorbed SYN-004. Accrual for the FEP cohort will begin after approval by the DSMC's review of results from groups 3 and 4.
Patients planned to receive an allo-HCT will be eligible for enrollment in the study and can be enrolled anytime from when it is known they will undergo HCT until day +1 after HCT (day of study drug start). Written informed consent will be obtained by all patients. To count towards the enrollment goal of 36 participants, a study participant must receive at least 80% of scheduled study drug doses from initiation of study assigned antibiotics through the second antibiotic pharmacokinetic assessment (7-9 days of concomitant study drug and study assigned antibiotic). Additional participants will be enrolled to replace participants who do not meet criteria to count towards the goal study enrollment until the goal enrollment is achieved.
This Phase 1b/2a study will use the SYN-004 dosing regimen (150 mg, PO, q6h) used in previous Phase 1 and Phase 2 clinical trials in healthy volunteers and patents with LRTIs. The first dose of study drug will be administered at day +1 after HCT and will be continued until Criteria for Discontinuation of Study Drug are met.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Prevention
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
Double-blinding by randomization schedule
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 provides written informed consent.
- •Male or female patients ≥18 years undergoing myeloablative allo-HCT for a hematologic malignancy or myeloproliferative disorder.
- •Participant is able to ingest the SYN-004 dosage form (size 0 hard capsule).
排除标准
- •Allergy(ies) to MER, PIP, TAZO, or FEP.
- •History of allergy to SYN-004 or its components.
- •Admitted for HCT and started on MER, PIP/TAZO, or FEP prior to enrollment in the present study.
- •Currently enrolled in another interventional clinical study or received an investigational drug or device within 30 days or within a time period consistent with a washout period of 5 half-lives before signing the Informed Consent Form, whichever is longer.
- •Recipients of umbilical cord blood transplantation.
- •Underlying condition requiring HCT is not in remission (per International Working Group definitions), except for myelodysplastic syndrome and lymphoma, as long as these conditions are chemotherapy responsive.
- •Creatinine clearance <60 mL/min/1.73 m² by Cockroft-Gault calculation.
- •Cardiac ejection fraction <50%.
- •Cirrhosis, bilirubin >1.5x upper limit of normal, or AST/ALT >2.5x upper limit of normal.
- •History of veno-occlusive disease (VOD) or hepatic sinusoidal obstructive syndrome (SOS).
- •DLCO and/or FEV1 ≤80% of normal.
- •Chronic HIV or HBV infection.
- •Invasive fungal infection not responding to treatment at time of HCT.
- •Known active bacterial or viral infection at time of HCT.
- •CDI in the preceding 6 months.
- •Unable to comply with study protocol as determined by primary investigator.
- •Active gastrointestinal (GI) bleeding at time of HCT.
- •Prior colectomy or short gut syndrome.
- •Pregnant or breast feeding.
研究组 & 干预措施
Placebo + IV Meropenem
Placebo, oral administration, 4 times per day (q6h), beginning on day +1 after HCT until 72-hours after completion of IV Meropenem (MER)
干预措施: SYN-004, Ribaxamase or Placebo (Biological)
SYN-004 + IV Meropenem
SYN-004, oral administration, 150mg, 4 times per day (q6h), beginning on day +1 after HCT until 72-hours after completion of IV Meropenem (MER)
干预措施: SYN-004, Ribaxamase or Placebo (Biological)
Placebo + IV Piperacillin/Tazobactam
Placebo, oral administration, 4 times per day (q6h), beginning on day +1 after HCT until 72-hours after completion of IV Piperacillin/Tazobactam (PIP/TAZO)
干预措施: SYN-004, Ribaxamase or Placebo (Biological)
SYN-004 + IV Piperacillin/Tazobactam
SYN-004, oral administration, 150mg, 4 times per day (q6h), beginning on day +1 after HCT until 72-hours after completion of IV Piperacillin/Tazobactam (PIP/TAZO)
干预措施: SYN-004, Ribaxamase or Placebo (Biological)
Placebo + IV Cefepime
Placebo, oral administration, 4 times per day (q6h), beginning on day +1 after HCT until 72-hours after completion of IV Cefepime (FEP)
干预措施: SYN-004, Ribaxamase or Placebo (Biological)
SYN-004 + Cefepime
SYN-004, oral administration, 150mg, 4 times per day (q6h), beginning on day +1 after HCT until 72-hours after completion of IV Cefepime (FEP)
干预措施: SYN-004, Ribaxamase or Placebo (Biological)
结局指标
主要结局
SYN-004 systemic absorption
时间窗: No more than 28 days
Assess potential SYN-004 systemic absorption (if any) by measuring SYN-004 plasma concentrations
Grade 3 or 4 adverse events
时间窗: Up to 30 days after the last dose of SYN-004 or Placebo
Assess tolerability of SYN-004 and grade 3 or 4 adverse events up to 30 days after the last dose of SYN-004
Systemic antibiotic concentrations
时间窗: Up to 8 hours after IV administration of antibiotic
Assess potential effects of SYN-004 on systemic antibiotic concentrations by measuring MER, PIP and FEP plasma levels and determining the area under the curve for antibiotic concentrations and time (T) of antibiotic concentration above the minimum inhibitory concentration (MIC) (T\>MIC) using the Clinical and Laboratory Standards Institute (CLSI) MIC susceptibility breakpoint for Enterobacteriaceae and Pseudomonas aeruginosa for each individual participant
Overall survival
时间窗: Up to 30 days after the last dose of SYN-004 or Placebo
Overall survival at 30 days after last dose of SYN-004
Bacteremia
时间窗: Daily during treatment, and weekly until 30 days after discontinuation of SYN-004 or Placebo
Assess the incidence of blood stream infections (bacteremia) with an organism susceptible to MER, PIP/TAZO or FEP while receiving SYN-004 concurrent with the antibiotic the organism is susceptible to, wherein the bacteremia is attributable to a clinical infection with adequate source control (if applicable) and unrelated to a device
Bacterial intestinal infections
时间窗: Daily during treatment, and weekly until 30 days after discontinuation of SYN-004 or Placebo
Assess the incidence and severity of bacterial intestinal infections other than CDI (such as typhlitis, neutropenic enterocolitis or diverticulitis) while on study drug and study assigned antibiotic
次要结局
- Urine concentrations of 3-indoxyl sulfate(Up to 30 days after the last dose of SYN-004 or Placebo, and up to 180 days after HCT)
- Impact on immunosuppressant dosing(Up to 30 days after the last dose of SYN-004 or Placebo, and up to 180 days after HCT)
- First line failure of PIP/TAZO or FEP(Up to 30 days after the last dose of SYN-004 or Placebo)
- Gut microbiome protection(Up to 30 days after the last dose of SYN-004 or Placebo, and up to 180 days after HCT)