Overview

The goal of this clinical trial is to test a combined therapy approach (allogeneic cytomegalovirus [CMV]-specific T cells and pembrolizumab) in patients with brain cancer. The type of brain cancer being studied is glioblastoma multiforme/astrocytoma grade 4.

The purpose of part 1 of this study is to determine the maximum-tolerated dose and/or recommended dose(s) for future exploration of allogeneic CMV-specific T cells as monotherapy or in combination with pembrolizumab in patients with recurrent GBM/astrocytoma grade 4. Part 2 of the study aims to investigate the anti-tumour activity of allogeneic CMV-specific T cells as monotherapy or in combination with pembrolizumab, assessed by magnetic resonance imaging and survival, in patients with recurrent or newly diagnosed GBM/grade 4 astrocytoma.

Eligibility

Inclusion Criteria:

1. At least 18 years of age on the day of signing informed consent, with histologically confirmed diagnosis of GBM or astrocytoma Grade 4^.
   1. For participants with recurrent GBM or astrocytoma grade 4, histological confirmation of primary diagnosis is available i. First occurrence of disease progression with radiological confirmation ≥12 weeks from completion of radiation therapy.

             ii. Where surgical resection of recurrent disease occurred, histological confirmation
             of GBM or astrocytoma Grade 4 is required.
             b. For participants with newly diagnosed GBM or astrocytoma Grade 4, histological
             confirmation of diagnosis is required i. Participant, in consultation with their
             treating clinicians, is willing to delay the commencement of standard of care adjuvant
             temozolomide until the completion of CMV-specific T cell therapy infusions.
             ^Note: Histological confirmation using the 2016 or 2021 World Health Organization
             (WHO) Classification of Tumours of the central nervous system (CNS) is acceptable and
             classification edition will be noted.
          2. Male participants: Must agree to use contraception during the treatment period and for
             at least 180 days after the last dose of study treatment and refrain from donating
             sperm during this period.
          3. Female participants: Must not be pregnant or undergoing in vitro fertilisation or
             breastfeeding, and at least one of the following conditions applies:
               1. Not a woman of childbearing potential (WOCBP) OR
               2. A WOCBP who agrees to follow contraceptive guidance during the treatment period
                  and for at 120 days after the last dose of study treatment.
          4. Provision of written informed consent for the trial. Approved interpreters will be
             used for patients who do not have sufficient understanding of English for informed
             consent to be obtained without an interpreter.
          5. Participants who have AEs due to previous anti-cancer therapies must have recovered to
             ≤Grade 1 or baseline. Participants with endocrine-related AEs who are adequately
             treated with hormone replacement or participants who have ≤Grade 2 neuropathy are
             eligible. Participants with >Grade 1 adverse events (AEs) due to previous anti-cancer
             therapies may be allowed to enrol on a case-by-case basis in discussion with the study
             Sponsor, if it is determined that it will not put the participant at a higher risk of
             study-related AEs or interfere with the integrity of the study outcome.
          6. For participants with disease progression, this should be the first evidence of
             measureable disease based on modified RANO criteria. Lesions situated in a previously
             irradiated area are considered measurable if progression has been demonstrated in such
             lesions.
          7. CMV-positive serology
          8. Provision of consent for the use of archival formalin-fixed, paraffin embedded or
             fresh tumour tissue obtained at the time of surgical resection or excisional biopsy.
          9. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
             Evaluation of ECOG is to be performed within 7 days prior to the first dose of study
             intervention.
         10. Have a life expectancy of at least 6 months.
         11. Have adequate organ function. Specimens must be collected within 10 days prior to the
             start of study intervention.
         12. Have availability of an human leukocyte antigen (HLA)-matched batch of allogeneic
             CMV-specific T cells.
         13. Provision of consent to access to Medicare Benefits Schedule (MBS) and Pharmaceutical
             Benefits Scheme (PBS) patient/provider health information collected by Services
             Australia (phase II participants only).
         14. Criteria for known hepatitis B and C positive participants:
        Hepatitis B and C screening tests are not required unless:
          -  Known history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
          -  As mandated by local health authority
        14.1 Hepatitis B-positive participants:
          -  Participants who are HBsAg positive are eligible if they have received HBV anti-viral
             therapy for at least 4 weeks and have undetectable HBV viral load prior to enrolment.
          -  Participants should remain on anti-viral therapy throughout study intervention and
             follow local guidelines for HBV anti-viral therapy post completion of study
             intervention
        14.2 Participants with history of HCV infection are eligible if HCV viral load is
        undetectable at screening.
        • Participants must have completed curative anti-viral therapy at least 4 weeks prior to
        enrolment.
        Exclusion Criteria:
          1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to the first
             dose of study intervention (see Appendix 3). If the urine test is positive or cannot
             be confirmed as negative, a serum pregnancy test will be required.
          2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with
             an agent directed to another stimulatory or co-inhibitory T-cell receptor.
          3. Has received prior systemic anti-cancer therapy or investigational agents within 4
             weeks prior to study intervention, with the exception of temozolomide, which is
             permitted during the trial.
          4. Recurrent disease cohorts only: Has not yet recovered from all radiation-related
             toxicities not requiring corticosteroids other than dexamethasone, or has had
             radiation pneumonitis.
             Note: A 1-week washout is permitted for palliative radiation of non-CNS disease (≤2
             weeks of radiotherapy). Participants receiving dexamethasone must be clinically stable
             and receiving a stable or weaning dose of ≤2 mg/day 1-2 weeks prior to the
             commencement of pembrolizumab.
          5. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the
             first dose of study intervention. Administration of killed vaccines is allowed.
          6. Has received in an investigational agent, or has used an investigational device within
             4 weeks prior to the first dose of study intervention.
          7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
             (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
             immunosuppressive therapy within 7 days prior to the first dose of study drug.
          8. Known additional malignancy that is progressing or has required active treatment
             within the past 5 years.
             Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of
             the skin, prostate cancer treated with radical prostatectomy, or carcinoma in situ,
             excluding carcinoma in situ of the bladder, who have undergone potentially curative
             therapy are not excluded. Participants with additional malignancy within the past 5
             years may be allowed to enrol on a case-by-case basis, in discussion with the study
             Sponsor, if the malignancy is deemed of very low recurrence potential and the
             participant has completed curative intent therapy.
          9. Has a previous known GBM/astrocytoma grade 4 recurrence previously treated with
             surgery, radiotherapy and/or chemotherapy, and evidence of further progression or
             recurrence.
         10. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
         11. Has active autoimmune disease that has required systemic treatment in the past 2 years
             except replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid).
         12. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required
             steroids or has current pneumonitis/interstitial lung disease.
         13. Has an active infection requiring systemic therapy.
         14. Has a known history of human immunodeficiency virus (HIV) infection. Note: No HIV
             testing is required unless mandated by a local health authority.
         15. Concurrent active hepatitis B (defined as HBsAg positive and/or detectable HBV DNA)
             and hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA)
             infection.
             Note: Hepatitis B and C screening tests are not required unless:
               -  Known history of HBV and HCV infection
               -  As mandated by local health authority
         16. Has not adequately recovered from major surgery or has ongoing surgical complications.
         17. Has a history or current evidence of any condition, therapy, or laboratory abnormality
             or other circumstance that might confound the results of the study, interfere with the
             participant's participation for the full duration of the study, such that it is not in
             the best interest of the participant to participate, in the opinion of the treating
             investigator.
         18. Has known psychiatric or substance-abuse disorders that would interfere with
             cooperation with the requirements of the trial.
         19. Is pregnant or breastfeeding or expecting to conceive or father children within the
             projected duration of the study, starting with the screening visit through 120 days
             after the last dose of trial treatment.
         20. Has had an allogeneic tissue/solid organ transplant or stem cell transplant.
         21. Has a baseline corrected QT interval (QTc) of >450 ms, assessed by ECG. If the
             participant's screening ECG records a QTc of >450 ms, the ECG is to be done in
             triplicate and the average of the QTc is to be recorded. If the QTc remains >450 ms,
             the participant will be excluded from enrolment.