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

Phase 2

Completed

Conditions: Hematopoietic and Lymphoid Cell Neoplasm
Malignant Solid Neoplasm

Interventions: Drug: Imipenem/Cilastatin/Relebactam
Drug: Cefepime
Drug: Vancomycin
Drug: Meropenem
Drug: Daptomycin
Drug: Piperacillin-Tazobactam
Drug: Linezolid

Registration Number: NCT04983901

Lead Sponsor: M.D. Anderson Cancer Center

Brief Summary: 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: PRIMARY OBJECTIVES:

I. 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.

OUTLINE: Patients are randomized to 1 of 2 groups.

GROUP I (TREATMENT): Patients receive imipenem/cilastatin/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/cilastatin/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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 100

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 > 100.4 degree F (38.0 degree C).
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 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 > 36 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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group I (imipenem, cilastatin, relebactam)	Imipenem/Cilastatin/Relebactam	Patients receive imipenem/cilastatin/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/cilastatin/relebactam IVover 30-60 minutes for up to 14 days if clinically indicated by the assessment of the treating physician.
Group I (imipenem, cilastatin, relebactam)	Daptomycin	Patients receive imipenem/cilastatin/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/cilastatin/relebactam IVover 30-60 minutes for up to 14 days if clinically indicated by the assessment of the treating physician.
Group I (imipenem, cilastatin, relebactam)	Vancomycin	Patients receive imipenem/cilastatin/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/cilastatin/relebactam IVover 30-60 minutes for up to 14 days if clinically indicated by the assessment of the treating physician.
Group I (imipenem, cilastatin, relebactam)	Linezolid	Patients receive imipenem/cilastatin/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/cilastatin/relebactam IVover 30-60 minutes for up to 14 days if clinically indicated by the assessment of the treating physician.
Group II (cefepime, meropenem, piperacillin/tazobactam)	Cefepime	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.
Group II (cefepime, meropenem, piperacillin/tazobactam)	Meropenem	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.
Group II (cefepime, meropenem, piperacillin/tazobactam)	Piperacillin-Tazobactam	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.
Group II (cefepime, meropenem, piperacillin/tazobactam)	Vancomycin	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.
Group II (cefepime, meropenem, piperacillin/tazobactam)	Daptomycin	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.
Group II (cefepime, meropenem, piperacillin/tazobactam)	Linezolid	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.

Primary Outcome Measures

Name	Time	Method
Clinical Outcome in the MITT Analysis Set at EOIV.	Within 72 hours after administration of the last dose of inpatient IV study drug.	The primary efficacy outcome is favorable clinical response of the patients in the MITT (Modified Intent-To-Treat) Analysis Set at end of inpatient intravenous therapy (EOIV). The clinical outcome has three categories: Favorable clinical response, Clinical failure, and Indeterminate.

Secondary Outcome Measures

Name	Time	Method
Clinical Outcome in the CE Analysis Set at EOIV.	Within 72 hours after administration of the last dose of inpatient IV study drug.	The secondary efficacy outcome is favorable clinical response of the patients in the CE (Clinically Evaluable) Analysis Set at end of inpatient intravenous therapy (EOIV). The clinical outcome has three categories: Favorable clinical response, Clinical failure, and Indeterminate.
Clinical Outcome in the MITT Analysis Set at LFU.	35 to 42 days after the start of inpatient IV study drug.	The secondary efficacy outcome is favorable clinical response of the patients in the MITT (Modified Intent-To-Treat) Analysis Set at late follow-up (LFU). The clinical outcome has three categories: Clinical cure, Clinical failure, and Indeterminate.
30-Day All-cause Mortality in the MITT Analysis Set.	30 days after the last dose of inpatient IV study drug.	The secondary efficacy outcome is 30-day all-cause mortality of the patients in the MITT (Modified Intent-To-Treat) Analysis Set.
Clinical Outcome in the ME Analysis Set at LFU.	35 to 42 days after the start of inpatient IV study drug.	The secondary efficacy outcome is favorable clinical response of the patients in the ME (Microbiologically Evaluable) Analysis Set at late follow-up (LFU). The clinical outcome has three categories: Clinical cure, Clinical failure, and Indeterminate.
Microbiological Outcome in the mMITT Analysis Set at EOIV.	Within 72 hours after administration of the last dose of inpatient IV study drug.	The secondary efficacy outcome is favorable microbiological response of the patients in the mMITT (Microbiological Modified Intent-To-Treat) Analysis Set at end of inpatient intravenous therapy (EOIV). The microbiological response outcome has five categories: Persistence, eradication, presumed eradication, presumed persistence, and Indeterminate.
Microbiological Outcome in the mMITT Analysis Set at TOC.	21 to 28 days after the start of inpatient IV study drug.	The secondary efficacy outcome is favorable microbiological response of the patients in the mMITT (Microbiological Modified Intent-To-Treat) Analysis Set at test-of-cure (TOC). The microbiological response outcome has five categories: Persistence, eradication, presumed eradication, presumed persistence, and Indeterminate.
Clinical Outcome in the mMITT Analysis Set at EOIV.	Within 72 hours after administration of the last dose of inpatient IV study drug.	The secondary efficacy outcome is favorable clinical response of the patients in the mMITT (Microbiological Modified Intent-To-Treat) Analysis Set at end of inpatient intravenous therapy (EOIV). The clinical outcome has three categories: Favorable clinical response, Clinical failure, and Indeterminate.
Clinical Outcome in the CE Analysis Set at LFU.	35 to 42 days after the start of inpatient IV study drug.	The secondary efficacy outcome is favorable clinical response of the patients in the CE (Clinically Evaluable) Analysis Set at late follow-up (LFU). The clinical outcome has three categories: Clinical cure, Clinical failure, and Indeterminate.
Clinical Outcome in the MITT Analysis Set at TOC.	21 to 28 days after the start of inpatient IV study drug.	The secondary efficacy outcome is favorable clinical response of the patients in the MITT (Modified Intent-To-Treat) Analysis Set at test-of-cure (TOC). The clinical outcome has three categories: Clinical cure, Clinical failure, and Indeterminate.
Clinical Outcome in the CE Analysis Set at TOC.	21 to 28 days after the start of inpatient IV study drug.	The secondary efficacy outcome is favorable clinical response of the patients in the CE (Clinically Evaluable) Analysis Set at test-of-cure (TOC). The clinical outcome has three categories: Clinical cure, Clinical failure, and Indeterminate.
Clinical Outcome in the ME Analysis Set at TOC.	21 to 28 days after the start of inpatient IV study drug.	The secondary efficacy outcome is favorable clinical response of the patients in the ME (Microbiologically Evaluable) Analysis Set at test-of-cure (TOC). The clinical outcome has three categories: Clinical cure, Clinical failure, and Indeterminate.
Microbiological Outcome in the mMITT Analysis Set at LFU.	35 to 42 days after the start of inpatient IV study drug.	The secondary efficacy outcome is favorable microbiological response of the patients in the mMITT (Microbiological Modified Intent-To-Treat) Analysis Set at late follow-up (LFU). The microbiological response outcome has five categories: Persistence, eradication, presumed eradication, presumed persistence, and Indeterminate.
Infection-related Mortality in the MITT Analysis Set at LFU.	35 to 42 days after the start of inpatient IV study drug.	The secondary efficacy outcome is infection-related mortality of the patients in the MITT (Modified Intent-To-Treat) Analysis Set at late follow-up (LFU).
Clinical Outcome in the mMITT Analysis Set at TOC.	21 to 28 days after the start of inpatient IV study drug.	The secondary efficacy outcome is favorable clinical response of the patients in the mMITT (Microbiological Modified Intent-To-Treat) Analysis Set at test-of-cure (TOC). The clinical outcome has three categories: Clinical cure, Clinical failure, and Indeterminate.
Clinical Outcome in the mMITT Analysis Set at LFU.	Pateints in mMITT (Microbiological Modified Intent-To-Treat) Analysis Set	The secondary efficacy outcome is favorable clinical response of the patients in the mMITT (Microbiological Modified Intent-To-Treat) Analysis Set at late follow-up (LFU). The clinical outcome has three categories: Clinical cure, Clinical failure, and Indeterminate.
Clinical Outcome in the ME Analysis Set at EOIV.	Within 72 hours after administration of the last dose of inpatient IV study drug.	The secondary efficacy outcome is favorable clinical response of the patients in the ME (Microbiologically Evaluable) Analysis Set at end of inpatient intravenous therapy (EOIV). The clinical outcome has three categories: Favorable clinical response, Clinical failure, and Indeterminate.
Microbiological Outcome in the ME Analysis Set at EOIV.	Within 72 hours after administration of the last dose of inpatient IV study drug.	The secondary efficacy outcome is favorable microbiological response of the patients in the ME (Microbiologically Evaluable) Analysis Set at end of inpatient intravenous therapy (EOIV). The microbiological response outcome has five categories: Persistence, eradication, presumed eradication, presumed persistence, and Indeterminate.
Microbiological Outcome in the ME Analysis Set at TOC.	21 to 28 days after the start of inpatient IV study drug.	The secondary efficacy outcome is favorable microbiological response of the patients in the ME (Microbiologically Evaluable) Analysis Set at test-of-cure (TOC). The microbiological response outcome has five categories: Persistence, eradication, presumed eradication, presumed persistence, and Indeterminate.
Microbiological Outcome in the ME Analysis Set at LFU.	35 to 42 days after the start of inpatient IV study drug.	The secondary efficacy outcome is favorable microbiological response of the participants in the ME (Microbiologically Evaluable) Analysis Set at late follow-up (LFU). The microbiological response outcome has five categories: Persistence, eradication, presumed eradication, presumed persistence, and Indeterminate.
Infection-related Mortality in the mMITT Analysis Set at LFU.	35 to 42 days after the start of inpatient IV study drug.	The secondary efficacy outcome is Infection-related mortality of the patients in the mMITT (Microbiological Modified Intent-To-Treat) Analysis Set at late follow-up (LFU).
Infection-related Mortality in the MITT Analysis Set at TOC.	21 to 28 days after the start of inpatient IV study drug.	The secondary efficacy outcome is infection-related mortality of the patients in the MITT (Modified Intent-To-Treat) Analysis Set at test-of-cure (TOC).
Infection-related Mortality in the mMITT Analysis Set at TOC.	21 to 28 days after the start of inpatient IV study drug.	The secondary efficacy outcome is Infection-related mortality of the participants in the mMITT (Microbiological Modified Intent-To-Treat) Analysis Set at test-of-cure (TOC).
30-Day All-cause Mortality in the mMITT Analysis Set.	30 days after the last dose of inpatient IV study drug.	The secondary efficacy outcome is 30-day all-cause mortality of the patients in the mMITT (Microbiological Modified Intent-To-Treat) Analysis Set.