PHASE II SINGLE-CENTER, RANDOMIZED, OPEN-LABEL, PROSPECTIVE, STUDY TO DETERMINE THE IMPACT OF SERIAL PROCALCITONIN

Study Overview
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Brief Summary
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This phase II trial studies the effect of imipenem-relebactam in treating patients with cancer who have a fever due to low white blood cell counts (febrile neutropenia). In this study, imipenem-relebactam will be compared to the standard-of-care treatment (cefepime, meropenem, or piperacillin/tazobactam) for the treatment of febrile neutropenia. Imipenem-relebactam is used to treat infections. Giving imipenem-relebactam may help to control febrile neutropenia in patients with cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the efficacy of imipenem, cilastatin sodium, and relebactam monohydrate (imipenem-relebactam) plus vancomycin, daptomycin or linezolid versus (vs) standard of care (SOC) plus vancomycin, daptomycin or linezolid as empiric therapy in febrile neutropenic adults with cancer with respect to favorable clinical response at end of inpatient intravenous therapy (EOIV) in the modified intent-to-treat (MITT) analysis set. II. To evaluate the safety and tolerability of imipenem-relebactam plus vancomycin, daptomycin, or linezolid compared with SOC plus vancomycin, daptomycin or linezolid as empiric therapy in febrile neutropenic adults with cancer. SECONDARY OBJECTIVES: I. To evaluate the efficacy of imipenem-relebactam plus vancomycin, daptomycin or linezolid compared with SOC plus vancomycin < daptomycin or linezolid as empiric therapy in febrile neutropenic adults with cancer with respect to the following: Ia. Favorable clinical response at EOIV in the mMITT and clinically evaluable (CE) analysis sets. Ib. Favorable clinical response at time of clinical response (TOC) (ie, 21 to 28 days after start of intravenous [IV] therapy) and late follow-up (LFU) (ie, 35 to 42 days after start of IV therapy) in the MITT analysis set. Ic. Favorable clinical response by baseline Gram-negative pathogen at EOIV, TOC, and LFU in the mMITT and CE analysis sets. Id. Favorable microbiological response by patient and by baseline Gram-negative pathogen at EOIV, TOC, and LFU in the mMITT and ME analysis sets. Ie. Infection-related mortality rate at TOC and LFU in the MITT and mMITT analysis sets. If. 30-day all-cause mortality rate in the MITT and mMITT analysis sets. II. To evaluate the role of procalcitonin (PCT) in promoting antimicrobial stewardship resulting in the switch of most patients from the broad spectrum agents (Imipenem/Relebactam & SOC) to a more simplified IV or oral antibiotic therapy in 48-72 hours. OUTLINE: Patients are randomized to 1 of 2 groups. GROUP I (TREATMENT): Patients receive imipenem intravenously (IV), cilastatin IV, and relebactam IV over 30-60 minutes once every 6 hours (q6h) for 2 days for a minimum of 8 doses. Patients may also receive gram-positive therapy at the discretion of the primary team or emergency center physician consisting of vancomycin IV q12h or linezolid IV or orally (PO) q12h. Patients may continue to receive imipenem IV, cilastatin IV, and relebactam IV over 30-60 minutes for up to 14 days if clinically indicated by the assessment of the treating physician. GROUP II (STANDARD OF CARE): Patients receive cefepime IV q8h for a minimum of 6 doses, meropenem IV q8h for a minimum of 6 doses, or piperacillin/tazobactam IV q6h for a minimum of 8 doses. Patients may also receive gram-positive therapy at the discretion of the primary team or emergency center physician consisting of vancomycin IV q12h or linezolid IV or PO q12h. Patients in both groups may receive other additional therapy (double-gram negative therapy) consisting of tobramycin IV q24h, amikacin IV q24h, ciprofloxacin IV q8h, minocycline q12h, tigecycline on days 1-2 q12h, doxycycline q12h, and/or bactrim. After at least 48 hours of gram-negative antimicrobial therapy, patients may be allowed to switch to PO or IV therapy such as linezolid PO, ampicillin, amoxicillin, amoxicillin/clavulanate PO, minocycline PO, ciprofloxacin PO, levofloxacin PO, cefpodoxime PO, trimethoprim/sulfamethoxazole PO, ceftriaxone IV, ertapenem IV, daptomycin IV and/or vancomycin IV for outpatient or home administration as clinically indicated. While in the hospital, patients undergo the collection of blood samples daily for 2 weeks, and urine samples every 2 days for up to 2 weeks. After completion of study treatment, patients are followed up at 2, 21-28, and 35-42 days.

Official Title
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An Investigator Initiated, Phase IV Single-Center, Randomized, Open-Label, Prospective Study to Determine the Impact of Serial Procalcitonin on Improving Antimicrobial Stewardship and on the Efficacy, Safety, and Tolerability of Imipenem - Relebactam Plus Vancomycin or Linezolid Versus Standard of Care Antipseudomonal Beta-Lactams Plus Vancomycin or Linezolid as Empiric Therapy in Febrile Neutropenic Adults With Cancer

Conditions
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Hematopoietic and Lymphoid Cell Neoplasm, Malignant Solid Neoplasm

Intervention / Treatment
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* Drug: Cefepime
* Drug: Imipenem/cilastatin-relebactam
* Drug: Daptomycin
* Drug: Linezolid
* Drug: Meropenem
* Drug: Piperacillin-Tazobactam
* Drug: Vancomycin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has provided written informed consent, and has the willingness and ability to comply with all study procedures >= 18 years old Patients with neutropenic fever who have existing malignancy or have undergone hematopoietic stem cell transplantation Neutropenic fever is defined as the presence of neutropenia defined by: Absolute neutrophil count (ANC) < 500 cells/mm3 or has an ANC that is expected to decrease to < 500 cells/mm^3 within 48 hours of trial entry and fever defined as: Single oral temperature measurement of > 101 degree Fahrenheit (F) (38.3 degree Celsius [C]) or a temperature of > 100.4 degree F (38.0 degree C) sustained over a 1- hour period Requires hospitalization for IV empiric antibiotic therapy If female: Not breastfeeding Agrees to not attempt to become pregnant during the study. Is surgically sterile or at least 2-years postmenopausal, or if of childbearing potential, has negative screening serum or urine pregnancy test within 5 days If of childbearing potential (including being < 2 years postmenopausal), is willing to practice sexual abstinence or use an effective dual form of contraception with her partner (eg, 2 barrier methods, barrier method plus hormonal method) during treatment and up 28 days post treatment Exclusion Criteria: History of any hypersensitivity or allergic reaction to any cephalosporin antibiotic or carbapenem Fever suspected to be caused by a noninfectious cause (eg, fever related to drug or blood product administration) Confirmed fungal infection (eg, Pneumocystis jirovecii etiology in patients with pneumonia) that justifies adding additional empiric antimicrobial therapy (eg, antifungals) Confirmed viral infection that justifies adding additional empiric antiviral therapy (eg, ganciclovir, foscarnet) Evidence of significant hepatic impairment (any of the following): Known acute viral hepatitis Alanine aminotransferase (ALT) level > 5 times the upper limit of normal (x upper limit of normal [ULN]). Total bilirubin > 3 x ULN unless isolated hyperbilirubinemia is directly related to the acute infection or due to known Gilbert disease Manifestations of end-stage liver disease, such as ascites or hepatic encephalopathy Known to be human immunodeficiency virus positive Severely impaired renal function, defined as creatinine clearance (CrCl) =< 30 mL/min estimated by the Cockcroft-Gault formula Expected requirement for hemodialysis while on study therapy Received > 24 hours of IV antibacterial therapy (with study drugs) within 72 hours of the initiation of inpatient IV study drug for treatment of suspected infection. Antibiotic prophylaxis and oral antibiotics is allowed. Prophylactic use of antiviral or antifungal medication is permitted Past or current history of epilepsy or seizure disorder; exception: well-documented febrile seizure of childhood Evidence of immediately life-threatening disease, progressively fatal disease, or life expectancy of 3 months or less (eg, moribund or with shock unresponsive to fluid replacement) Unable or unwilling to adhere to the study-specified procedures and restrictions Any condition that would make the patient, in the opinion of the Investigator, unsuitable for the study (eg, would place a patient at risk or compromise the quality of the data Participation in any other ongoing imipenem-relebactam trial

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I (imipenem, cilastatin, relebactam)<br>Patients receive imipenem IV, cilastatin IV, and relebactam IV over 30-60 minutes q6h for 2 days for a minimum of 8 doses. Patients may also receive gram-positive therapy at the discretion of the primary team or emergency center physician consisting of vancomycin IV q12h or linezolid IV or PO q12h. Patients may continue to receive imipenem IV, cilastatin IV, and relebactam IV over 30-60 minutes for up to 14 days if clinically indicated by the assessment of the treating physician. | Drug: Imipenem/cilastatin-relebactam<br>* Given IV<br>* Other names: RECARBRIO™;Drug: Daptomycin<br>* Given IV<br>* Other names: LY146032;Drug: Linezolid<br>* Given IV or PO<br>* Other names: Zyvox;Drug: Vancomycin<br>* Given IV<br>|
| Active Comparator: Group II (cefepime, meropenem, piperacillin/tazobactam)<br>Patients receive cefepime IV q8h for a minimum of 6 doses, meropenem IV q8h for a minimum of 6 doses, or piperacillin/tazobactam IV q6h for a minimum of 8 doses. Patients may also receive gram-positive therapy at the discretion of the primary team or emergency center physician consisting of vancomycin IV q12h or linezolid IV or PO q12h. | Drug: Cefepime<br>* Given IV<br>Drug: Daptomycin<br>* Given IV<br>* Other names: LY146032;Drug: Linezolid<br>* Given IV or PO<br>* Other names: Zyvox;Drug: Meropenem<br>* Given IV<br>* Other names: SM-7338;Drug: Piperacillin-Tazobactam<br>* Given IV<br>* Other names: Zosyn;Drug: Vancomycin<br>* Given IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical response | The investigator will consider the entirety of the patient's clinical course and current status, including an evaluation of infection signs and symptoms (eg, fever, neutropenia), radiological findings (if applicable), and physical examination in order to classify the patient's clinical response at end of inpatient intravenous therapy (EOIV). The investigator could rely on physical exam performed by a professionally trained physician or health professional licensed to perform physical examinations. The investigator will use the serial procalcitonin (PCT) levels drawn at baseline and at 48-72 hours as an adjunct to the clinical judgement to guide antibiotic therapy and prevent unnecessary prolonged therapy with broad spectrum agents (imipenem/relebactam & standard of care [SOC]). | Up to 42 days | 
| Incidence of adverse events | Treatment-emergent adverse event (TEAEs), serious adverse events (SAEs), deaths, and discontinuations due to AEs will be summarized by treatment group, system organ class and preferred term according to the Medical Dictionary for Regulatory Activities, type, frequency, relationship to study therapy, and severity. Safety summaries will be presented using the Safety Analysis Set, according to the treatment actually received. Descriptive statistics of observed results and the change from baseline will be presented for clinical laboratory results and vital signs. The incidence of potentially clinically significant (PCS) laboratory results will be summarized. A list of all TEAEs/SAEs that resulted in deaths will also be generated. The changes in clinical laboratory parameters and vital sign parameters in the Safety Analysis Set at each study visit that assessments will be performed. | Up to 42 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical response | The investigator's assessment of clinical response at EOIV, time of clinical response (TOC), and late follow-up (LFU) will be used to determine the secondary clinical efficacy endpoints. | Up to 42 days | 
| Microbiological response | A patient's microbiological response at EOIV, TOC, and LFU will be determined programmatically based on individual outcomes for each baseline pathogen. | Up to 42 days |