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. At least 10 patients will be enrolled in the initial safety lead-in followed by the Phase II trial which will include 18 patients.
Anti-HCMV therapy, oral Valganciclovir will be given to patients at 900 mg twice a day for 2 weeks. After the induction period, the maintenance will be continued with valganciclovir at 450 mg twice daily for 4 weeks (28 days).
Male or female aged >18 years at the time of consent
Breast cancer with progressive brain metastases supra and/or infratentorial. 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.
At least one non irradiated, untreated progressive brain metastases site
Serum HCMV DNA by real time PCR > 250 copies/ml or positive CMV Ig G or Ig M.
Single resectable intracranial lesion
Last intracranial progression free survival > 12 months
All progressive brain metastases have been radiated
Brain metastases needing immediate local intervention such as mass effect, herniation, active neurological symptoms, increased intracranial pressure, those near vital structures like the motor cortex, proximity to the optic nerve/chiasm or brain stem etc (can still be included if there are any other non-radiated progressive brain metastases) Multidisciplinary discussion with neurosurgery and radiation oncology will be needed to determine which patients may be safely enrolled on the trial.
Single group
Valganciclovir
DrugValganciclovir inhibits viral DNA polymerase, effectively controlling HCMV reactivation and its associated immunosuppressive effects. Dosing for oral Valganciclovir will be based on standard of care dosing as per FDA in patients with HCMV infection. Dose adjustments will be made by the principal investigator for renal function, treatment-related AEs and disease progression according to the manufacturer's recommendations as they are present in individuals and will be assessed on a case-by-case basis.
Objective Response Rate with anti-HMCV Therapy and SOC
To estimate the CNS objective response rate (RANO-BM and RECIST V1.1) with anti-HCMV therapy and standard-of-care in metastatic breast cancer patients with progressive brain metastases and CMV viremia or positive CMV IgG or IgM.
Safety and toxicity of anti- HCMV therapy (Valganciclovir) as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTAE) v5
To assess the safety and toxicity of anti- HCMV therapy (Valganciclovir) in patients with progressive brain metastases and CMV viremia or positive CMV IgG or Ig M, as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTAE) v5.
Benefit in median overall survival from start of treatment (anti-HCMV therapy and SOC) until the end of follow up after 24 months or death
To estimate the benefit in median overall survival from start of treatment (anti-HCMV therapy and SOC) until the end of follow up after 24 months or death in patients with treated progressive brain metastases and CMV viremia or positive CMV IgG or IgM.
Prevention of memory decline with anti-HCMV therapy (Valganciclovir) as measured by the mean change in the immediate score on the Rey's Auditory Verbal Learning Test (RAVLT) from baseline to end of study
To estimate the prevention of memory decline with anti-HCMV therapy (Valganciclovir) and SOC in patients with progressive brain metastases and CMV viremia or positive CMV IgG or IgM, as measured by the mean change in the immediate score on the Rey's Auditory Verbal Learning Test (RAVLT) from baseline to end of study
Prevention of memory decline with anti-HCMV therapy (Valganciclovir) and SOC prevention of memory decline with anti-HCMV therapy (Valganciclovir) and SOC
To estimate the prevention of memory decline with anti-HCMV therapy (Valganciclovir) and SOC in patients with progressive brain metastases and CMV viremia or positive CMV IgG or IgM, as measured by the mean change in percent forgetting score on the Rey's Auditory Verbal Learning Test (RAVLT) from baseline to end of study
Exploratory Outcome
To evaluate the blood-based correlates of response to anti-HCMV therapy (Valganciclovir) in patients with progressive brain metastases and CMV viremia or positive CMV IgG or IgM. Blood-based correlates of response will include but are not limited to HCMV-DNA copies, and whole-blood based immunophenotyping
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