SYN-004 Safety and Tolerability in Allo-HCT Subjects

Study Overview
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Brief Summary
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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

Detailed Description
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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. The study will consist of two periods: the Treatment Period and the Follow-up Period. The Treatment Period will be defined as the time from first dose of study drug until the last dose. For participants who do not meet criteria for early discontinuation, study drug will be continued for 72 hours after last dose of MER, PIP/TAZO, or FEP. The Follow-up Period begins after cessation of study drug dosing and is split into three parts: Part A: up to 30 days after study drug was discontinued Part B: from end of Part A to day +180 after HCT Part C: from end of Part B to day +365 after HCT Patients enrolled in the study will receive conditioning and HCT according to their treatment plan. Fever and time of antibiotic start will be defined per local standard of care of patients. Cessation of antibiotic therapy and/or changes to antibiotic therapy will be at the discretion of the treating physician. All participants will be evaluated as outlined in the Schedule of Assessments. At predetermined points during the study as outlined in the SOA, blood samples, urine samples, fecal swabs, and fecal samples will be collected for the indicated analyses.

Official Title
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Phase 1b/2a Evaluation of the Safety and Tolerability of SYN-004 in Adult Allogeneic Hematopoietic Cell Transplantation (Allo-HCT) Recipients

Conditions
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121121000119106, Acute Graft-versus-host Reaction Following Bone Marrow Transplant (Disorder)

Intervention / Treatment
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* Biological: SYN-004, Ribaxamase or Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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). Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo + IV Meropenem<br>Placebo, oral administration, 4 times per day (q6h), beginning on day +1 after HCT until 72-hours after completion of IV Meropenem (MER) | Biological: SYN-004, Ribaxamase or Placebo<br>* SYN-004 is an oral formulation of a recombinant class-A beta-lactamase that hydrolyzes the beta-lactam ring of susceptible antibiotics that are excreted into the intestines<br>|
| Active Comparator: SYN-004 + IV Meropenem<br>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) | Biological: SYN-004, Ribaxamase or Placebo<br>* SYN-004 is an oral formulation of a recombinant class-A beta-lactamase that hydrolyzes the beta-lactam ring of susceptible antibiotics that are excreted into the intestines<br>|
| Placebo Comparator: Placebo + IV Piperacillin/Tazobactam<br>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) | Biological: SYN-004, Ribaxamase or Placebo<br>* SYN-004 is an oral formulation of a recombinant class-A beta-lactamase that hydrolyzes the beta-lactam ring of susceptible antibiotics that are excreted into the intestines<br>|
| Active Comparator: SYN-004 + IV Piperacillin/Tazobactam<br>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) | Biological: SYN-004, Ribaxamase or Placebo<br>* SYN-004 is an oral formulation of a recombinant class-A beta-lactamase that hydrolyzes the beta-lactam ring of susceptible antibiotics that are excreted into the intestines<br>|
| Placebo Comparator: Placebo + IV Cefepime<br>Placebo, oral administration, 4 times per day (q6h), beginning on day +1 after HCT until 72-hours after completion of IV Cefepime (FEP) | Biological: SYN-004, Ribaxamase or Placebo<br>* SYN-004 is an oral formulation of a recombinant class-A beta-lactamase that hydrolyzes the beta-lactam ring of susceptible antibiotics that are excreted into the intestines<br>|
| Active Comparator: SYN-004 + Cefepime<br>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) | Biological: SYN-004, Ribaxamase or Placebo<br>* SYN-004 is an oral formulation of a recombinant class-A beta-lactamase that hydrolyzes the beta-lactam ring of susceptible antibiotics that are excreted into the intestines<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SYN-004 systemic absorption | Assess potential SYN-004 systemic absorption (if any) by measuring SYN-004 plasma concentrations | No more than 28 days | 
| Systemic antibiotic concentrations | 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 | Up to 8 hours after IV administration of antibiotic | 
| Bacteremia | 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 | Daily during treatment, and weekly until 30 days after discontinuation of SYN-004 or Placebo | 
| Bacterial intestinal infections | 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 | Daily during treatment, and weekly until 30 days after discontinuation of SYN-004 or Placebo | 
| Grade 3 or 4 adverse events | Assess tolerability of SYN-004 and grade 3 or 4 adverse events up to 30 days after the last dose of SYN-004 | Up to 30 days after the last dose of SYN-004 or Placebo | 
| Overall survival | Overall survival at 30 days after last dose of SYN-004 | Up to 30 days after the last dose of SYN-004 or Placebo | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| First line failure of PIP/TAZO or FEP | Assess the number of study participants who fail first line PIP/TAZO or FEP therapy and require second line therapy with another antibiotic | Up to 30 days after the last dose of SYN-004 or Placebo | 
| Gut microbiome protection | Assess the ability of SYN-004 to protect the gut microbiome (defined by alterations from baseline in bacterial community composition, metabolic potential of the microbiome, and antibiotic resistome) in study participants treated with PIP/TAZO or FEP, and confirm lack of protection in study participants treated with MER at up to 30 days after last dose of SYN-004 (and up to 180 days after HCT) | Up to 30 days after the last dose of SYN-004 or Placebo, and up to 180 days after HCT | 
| Urine concentrations of 3-indoxyl sulfate | Assess urine concentrations of 3-indoxyl sulfate as a biomarker of fecal levels of Clostridium and Enterococcus species up to 30 days after last dose of SYN-004 (and 180 days after HCT) | Up to 30 days after the last dose of SYN-004 or Placebo, and up to 180 days after HCT | 
| Impact on immunosuppressant dosing | Assess impact of SYN-004 on immunosuppressant dosing and levels obtained through routine care up to 30 days after last dose of SYN-004 (and 180 days after HCT) | Up to 30 days after the last dose of SYN-004 or Placebo, and up to 180 days after HCT |