Trial to Study Anti- HCMV Therapy in Breast Cancer Patients With Progressive Intracranial Metastases and CMV Infection

This is a phase II trial with an initial safety lead-in evaluating the efficacy, safety, neurocognitive, and quality-of-life outcomes of anti-cytomegalovirus (CMV) therapy and standard-of-care (SOC) in patients with anti-human cytomegalovirus (HCMV)-reactivated brain metastases. Male and female patients, aged ≥18 years, who have metastatic breast cancer with progressive brain metastases and CMV viremia (\> 250 copies/ml) or positive CMV IgG or IgM will be eligible to participate in the trial. Patients can proceed with SRS as long as at least 1 lesion which is 2 cm or less in a noncritical area in the brain is spared as per the discretion of treating neurosurgeon/radiation oncologist. Multidisciplinary discussion with neurosurgery and radiation oncology will be needed to determine which patients may be safely enrolled on the trial. At least 10 patients will be enrolled in the initial safety lead-in followed by the Phase II trial which will include 18 patients. The primary endpoint will be to determine the objective response rate after the start of the treatment (anti-HCMV therapy and SOC). Anti-HCMV therapy, oral Valganciclovir will be given to patients at 900 mg twice a day for 2 weeks. Patients will be followed with weekly labs for viral clearance, hematological toxicity, and electrolyte imbalances. CMV PCR, IgG and IgM will be checked at the end of two weeks to monitor for viral clearance. After the induction period, the maintenance will be continued with valganciclovir at 450 mg twice daily for 4 weeks (28 days). Patients will be followed with every 2 weekly labs for hematological toxicity, and electrolyte imbalances. CMV PCR, IgG and IgM will be checked at the end of these four weeks. Pill counting will be done at each follow up to ensure compliance with oral valganciclovir. Patients will be followed with physical examinations and assessment of laboratory parameters as required per standard-of-care treatment. Quality-of-life, neurocognitive questionnaires, and MRI brain (if asymptomatic) every 2 months until subsequent intracranial progression or end of study, whichever comes first. MRI brain will be performed at any symptom onset regardless of study schedule. All MRIs will be evaluated for tumor response and progression using RANO-BM for intracranial and extracranial response using RECIST V1.1. Patients will be followed for 24 months. Adverse events will be recorded for up to 2 months after treatment discontinuation according to (NCI CTAE) v5. After end of study patients will be followed for survival only. Correlative studies will include HCMV-DNA copies in serum, and whole-blood based immunophenotyping from baseline to end of anti-CMV treatment. Any craniotomy brain metastatic tissue sample or lumbar puncture done as part of standard of care treatment will also be used for correlative studies. Exploratory blood samples will be transported to Dr Hong Zhao's lab at Fondren building floor 6 in \< 4 hours at Room Temperature (RT, 18-25°C) post-collection. Freeze the stabilized blood at -80 °C. The samples will be thawed and lysed using the SmartTube lysis protocol before adding to MDIPA tubes for analysis. Specimens will be stored for up to 3 years after collection. Specimen samples will be accessed by Dr. Hong Zhao's lab for analysis. Written informed consent is required before performing any trial-specific tests or procedures. Signing of the informed consent form can occur outside the 28-day screening period. All screening evaluations must be completed and reviewed to confirm that patients meet all eligibility criteria before trial entry. Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 7-28 days prior to trial entry (except where otherwise specified) may be used for screening assessments rather than repeating such tests. The investigator or qualified designer will maintain a screening log to record details of all patients screened and to confirm eligibility or record reasons for screening failure, as applicable. Neurocognitive testing will consist of the Rey Auditory Verbal Learning Test (RAVLT), Trail Making Test (TMT), and Delis-Kaplan Executive Function System (DKEFS) letter fluency test at baseline and every 8 weeks until end of study or until subsequent intracranial progression, whichever comes first These tests were selected based on the recommendation of the International Cognition and Cancer Task Force (ICCTF). Testing will require approximately 1 hour to complete and will be conducted by the research assistant.