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

  • STATUS
    Recruiting
  • End date
    Jan 31, 2024
  • participants needed
    100
  • sponsor
    M.D. Anderson Cancer Center
Updated on 25 October 2022
cancer
cell transplantation
neutropenia

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.

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 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.

Details
Condition Hematopoietic and Lymphoid Cell Neoplasm, Malignant Solid Neoplasm
Treatment linezolid, Vancomycin, Daptomycin, cefepime, Meropenem, Piperacillin-tazobactam, Imipenem/cilastatin-relebactam
Clinical Study IdentifierNCT04983901
SponsorM.D. Anderson Cancer Center
Last Modified on25 October 2022

Eligibility

Yes No Not Sure

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
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