CMV CTLs in Neonates With CMV Infection

Official title

A Phase II Open-Label Randomized Study of Anti-Viral Antibiotic Therapy With and Without Familial (Maternal) Cytomegalovirus (CMV) Cytotoxic T Lymphocytes (CTLs) in Neonates With Moderate/Severe Maternal Acquired CMV Infection

Overview

Patients with moderate or severe CMV disease less than 21 days old who have a maternal donor who has a CMV response to the peptivators will be screened. All patients will receive treatment with valganciclovir or ganciclovir. There is a safety run in with treatment with CMV CTLs in cohort 1 and if found to be safe, will proceed to cohort 2 for randomization to receive antiviral therapy with or without CMV CTLs. Funding source: FDA OOPD

Detailed description

Given the vulnerability and poor outcomes of preterm neonates and neonates in general to viral infection, including the need for prolonged antiviral therapy for 6 or more months to achieve just modest improvements in sensorineural functions, CMV CTL therapy offers a promising alternative. CMV CTL treatment will build on the hosts innate immune capacity to create a more effective and permanent defense against collateral injury arising from CMV infections.

Patients who meet all inclusion/exclusion criteria with a maternal donor who meet all donor criteria will be enrolled onto study.

Cohort 1 is a safety run-in; the first 3 patients enrolled will be treated with anti-viral and CMV CTLs. The external DSMB will review the data from the first patient, and if there are no adverse events or dose-limiting toxicities observed, approve patient 2, and then 3, 28 days after the prior patients last CTL infusion. Assuming there are no adverse events in any of the first 3 patients, the study will proceed to Cohort 2.

Cohort 2 will be randomized 1:1 to either anti-viral treatment alone or anti-viral treatment plus CMV CTLs.

Patients who are randomized to receive CMV CTLs will get their first infusion on Day 0. If the patient fails to achieve a CR, they may receive one infusion every 2 weeks up to 5 maximum CMV CTL infusions as long as there are no DLTs or AEs observed

Interventions

• Biological CMV Cytotoxic T-Lymphocytes
  Patients will receive maternal CMV CTLs on day 0. Additional doses of CMV CTLs may be re-infused at a minimum of every two weeks for a maximum of five total infusions (maximum 2.5 x 104 CD3/kg) only in patients not achieving a CR and no prior dose limiting toxicity of any prior dose.
• Drug Anti-viral Therapy
  All patients will receive anti-viral therapy with one of the following: 4.2.2 Valganciclovir Dosing: 16 mg/kg/dose PO q12h OR 4.2.3 Ganciclovir Dosing: 6 mg/kg/dose IV q12h Dose adjustments: * Reduce dose by 50% for ANC less than 500 cells/mm3 * Hold the dose if ≤ 200 cells/mm3 until recovery ≥ 500 cells/mm3 * Treatment will continue for 6 months

Primary outcome measures

• To determine the safety of giving CMV CTLs combined with anti-viral therapy in neonates with CMV [Time frame: 12 weeks]
• To determine response rates to treatment with CMV CTLS and anti-viral medication [Time frame: 12 weeks]

Eligibility criteria

Inclusion criteria

• Age: ≤ 21 days of life
• Birth Weight: ≥ 2500 gms
• Gestational age: ≥ 34 weeks of age
• Diagnosis of CMV viremia, viruria, and/or infection:Either one or more:

Elevated CMV by RT-PCR in urine, saliva, CSF, or plasma; and/or Positive urine culture for CMV

\- Moderate or Severe CMV Disease

Any one or more of the following attributable to congenital CMV infection:

• Thrombocytopenia (≤ 50,000 mm3)
• Multiple petechiae
• Hepatomegaly
• Splenomegaly
• Intrauterine growth retardation
• Increased transaminases
• Increased bilirubin
• Microcephaly
• Ventriculomegaly
• Intracerebral calcifications
• Periventricular echogenicity
• Cortical or cerebral malformation
• Chorioretinitis
• Severe neonatal hearing loss
• CMV DNA by PCR in CNS
• Increased WBC for age in CNS

• Minimal Organ Criteria Hematological: ANC ≥ 750/mm3, HgB ≥ 8gm/dl, Platelets ≥ 20,000/kmm3 Renal: Serum creatinine ≤ 1.0 mg/dl Hepatic: ALT/SGOT ≤3x upper normal limits
• Donor Availability: Maternal donor available with a T-cell response CMV MACS® PepTivators. the donor is considered suitable if the percentage of IFN-gamma+ T cells is > 0.01% after stimulation with PepTivators.

Exclusion Criteria -

• Patient receiving steroids (> 0.5 mg/kg prednisone equivalent) on the same day of CMV CTL infusion. Antenatal steroids for lung maturation will have been cleared prior to CMV diagnosis.
• Concomitant enrollment in another experimental clinical trial investigating the treatment of neonatal CMV viremia and/or infection.
• Any medical condition that could compromise participation in the study according to the investigator's assessment.
• Known history of HIV infection in the mother.
• Patient's legally authorized representative unwilling or unable to comply with the protocol or unable to give informed consent.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 4 centers

• Children's Hospital Los Angeles — Los Angeles
• Washington University — St Louis
• New York Medical College — Valhalla
• Nationwide Children's Hosptial — Columbus

Identifiers

NCT: NCT05564598 · NYMC 597 · 1R01FD007837-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗