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

An Investigator Initiated, Phase II 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-Cilastatin-Relebactam Plus/Minus Vancomycin Or Linezolid Versus Standard Of Care Antipseudomonal Beta-Lactams Plus/Minus Vancomycin Or Linezolid As Empiric Therapy In Febrile Neutropenic Adults With Cancer

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.

Study Overview

• Status: Completed
• Conditions: Hematopoietic and Lymphoid Cell Neoplasm; Malignant Solid Neoplasm
• Intervention / Treatment: Drug: Cefepime; Drug: Meropenem; Drug: Piperacillin-Tazobactam; Drug: Daptomycin; Drug: Linezolid; Drug: Vancomycin; Drug: Imipenem/Cilastatin/Relebactam

Detailed Description

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/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.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group II (cefepime, meropenem, 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.	Drug: Cefepime; Given IV; Drug: Meropenem; Given IV; Other Names: Meropenem Trihydrate; Merrem I.V.; SM-7338; Drug: Piperacillin-Tazobactam; Given IV; Other Names: Zosyn; PIPER/TAZO; Piperacillin/Tazobactam; Drug: Daptomycin; Given IV; Other Names: Cubicin; LY146032; Drug: Linezolid; Given IV or PO; Other Names: Zyvox; Drug: Vancomycin; Given IV
Experimental: Group I (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.	Drug: Daptomycin; Given IV; Other Names: Cubicin; LY146032; Drug: Linezolid; Given IV or PO; Other Names: Zyvox; Drug: Vancomycin; Given IV; Drug: Imipenem/Cilastatin/Relebactam; Given IV; Other Names: RECARBRIO™

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Outcome in the MITT Analysis Set at EOIV.	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.	Within 72 hours after administration of the last dose of inpatient IV study drug.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Outcome in the mMITT Analysis Set at EOIV.	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.	Within 72 hours after administration of the last dose of inpatient IV study drug.
Clinical Outcome in the CE Analysis Set at EOIV.	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.	Within 72 hours after administration of the last dose of inpatient IV study drug.
Clinical Outcome in the MITT Analysis Set at TOC.	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.	21 to 28 days after the start of inpatient IV study drug.
Clinical Outcome in the MITT Analysis Set at LFU.	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.	35 to 42 days after the start of inpatient IV study drug.
Clinical Outcome in the mMITT Analysis Set at TOC.	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.	21 to 28 days after the start of inpatient IV study drug.
Clinical Outcome in the mMITT Analysis Set at LFU.	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.	Pateints in mMITT (Microbiological Modified Intent-To-Treat) Analysis Set
Clinical Outcome in the CE Analysis Set at TOC.	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.	21 to 28 days after the start of inpatient IV study drug.
Clinical Outcome in the CE Analysis Set at LFU.	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.	35 to 42 days after the start of inpatient IV study drug.
Clinical Outcome in the ME Analysis Set at EOIV.	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.	Within 72 hours after administration of the last dose of inpatient IV study drug.
Clinical Outcome in the ME Analysis Set at TOC.	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.	21 to 28 days after the start of inpatient IV study drug.
Clinical Outcome in the ME Analysis Set at LFU.	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.	35 to 42 days after the start of inpatient IV study drug.
Microbiological Outcome in the mMITT Analysis Set at EOIV.	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.	Within 72 hours after administration of the last dose of inpatient IV study drug.
Microbiological Outcome in the mMITT Analysis Set at TOC.	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.	21 to 28 days after the start of inpatient IV study drug.
Microbiological Outcome in the mMITT Analysis Set at LFU.	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.	35 to 42 days after the start of inpatient IV study drug.
Microbiological Outcome in the ME Analysis Set at EOIV.	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.	Within 72 hours after administration of the last dose of inpatient IV study drug.
Microbiological Outcome in the ME Analysis Set at TOC.	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.	21 to 28 days after the start of inpatient IV study drug.
Microbiological Outcome in the ME Analysis Set at LFU.	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.	35 to 42 days after the start of inpatient IV study drug.
Infection-related Mortality in the MITT Analysis Set at TOC.	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).	21 to 28 days after the start of inpatient IV study drug.
Infection-related Mortality in the MITT Analysis Set at LFU.	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).	35 to 42 days after the start of inpatient IV study drug.
Infection-related Mortality in the mMITT Analysis Set at TOC.	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).	21 to 28 days after the start of inpatient IV study drug.
Infection-related Mortality in the mMITT Analysis Set at LFU.	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).	35 to 42 days after the start of inpatient IV study drug.
30-Day All-cause Mortality in the MITT Analysis Set.	The secondary efficacy outcome is 30-day all-cause mortality of the patients in the MITT (Modified Intent-To-Treat) Analysis Set.	30 days after the last dose of inpatient IV study drug.
30-Day All-cause Mortality in the mMITT Analysis Set.	The secondary efficacy outcome is 30-day all-cause mortality of the patients in the mMITT (Microbiological Modified Intent-To-Treat) Analysis Set.	30 days after the last dose of inpatient IV study drug.

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Issam I Raad, M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• MD Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): September 14, 2021
• Primary Completion (Actual): October 6, 2023
• Study Completion (Actual): October 6, 2023

Study Registration Dates

• First Submitted: July 21, 2021
• First Submitted That Met QC Criteria: July 21, 2021
• First Posted (Actual): July 30, 2021

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: February 14, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Protease Inhibitors; Anti-Bacterial Agents; Protein Synthesis Inhibitors; beta-Lactamase Inhibitors; Vancomycin; Linezolid; Imipenem; Relebactam; Cilastatin; Meropenem; Daptomycin; Piperacillin; Tazobactam; Piperacillin, Tazobactam Drug Combination; Cefepime
• Other Study ID Numbers: 2020-0074 (Other Identifier: M D Anderson Cancer Center); NCI-2021-01957 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No