Phase I/II Clinical Trial of Allogeneic Cytomegalovirus-specific T Cells in Combination With Pembrolizumab for Recurrent and Newly Diagnosed Glioblastoma Multiforme
Overview
- Phase
- Phase 1
- Status
- Recruiting
- Enrollment
- 58
- Locations
- 4
- Primary Endpoint
- Duration of response
Overview
Brief Summary
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.
Detailed Description
This is a multi-centre, non-randomised, open-label, dose escalation and expansion trial of allogeneic cytomegalovirus (CMV)-specific T cells as monotherapy and in combination with pembrolizumab in participants with recurrent and newly diagnosed glioblastoma multiforme (GBM)/astrocytoma grade 4. The trial will be conducted in two parts.
Part 1 is a single-arm, sequential 3+3 dose-escalation of allogeneic CMV-specific T cells as a monotherapy and in combination with a fixed dose of pembrolizumab to determine the recommended dose(s) for future exploration. Up to 18 participants will be recruited for part 1. Part 2 will involve two arms and will examine the clinical impact of the CMV-specific T cells as monotherapy and in combination with pembrolizumab. Forty participants will be recruited for part 2 - 20 with newly diagnosed GBM/astrocytoma grade 4 and 20 with recurrent GBM/astrocytoma grade 4.
Part 2 will only be initiated if the data and safety monitoring board (DSMB) determines that the proposed dose level(s) for future exploration are safe and well tolerated. Additional groups may be explored depending on emergent safety, pharmacodynamics and/or clinical efficacy data.
Following screening and enrolment, each participant will receive four weekly infusions (Q1W) of allogeneic CMV-specific T cells, followed by up to 18 infusions of pembrolizumab. Pembrolizumab infusions will commence seven days (±3 days) after the final T-cell infusion, and be administered every 6 weeks (Q6W). The total duration of participation for each participant is approximately 26 months.
Efficacy of the combination therapy will be evaluated according to the modified Response Assessment in Neuro-Oncology (RANO) and immunotherapy (i)RANO criteria, through radiographic imaging. For group A and group B the appropriate measures for progression-free survival (PFS), overall survival (OS), disease control rate and duration of response will be assessed.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •At least 18 years of age on the day of signing informed consent, with histologically confirmed diagnosis of GBM or astrocytoma Grade 4\^.
- •a. 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.
- •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.
- •Female participants: Must not be pregnant or undergoing in vitro fertilisation or breastfeeding, and at least one of the following conditions applies:
- •Not a woman of childbearing potential (WOCBP) OR
- •A WOCBP who agrees to follow contraceptive guidance during the treatment period and for at 120 days after the last dose of study treatment.
- •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.
Exclusion Criteria
- •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.
- •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.
- •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.
- •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.
- •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.
- •Has received in an investigational agent, or has used an investigational device within 4 weeks prior to the first dose of study intervention.
- •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.
- •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.
Arms & Interventions
Part 1
Patients with recurrent disease. Interventions:
- allogeneic CMV-specific T cells (cell suspension for infusion), dose cohorts: 2 × 10^7 cells, 4 × 10^7 cells, 8 × 10^7 cells; 4 infusions; administered weekly
- pembrolizumab 400 mg (solution for injection); 18 infusions; administered every 6 weeks
Intervention: Allogeneic cytomegalovirus-specific T cells (Biological)
Part 1
Patients with recurrent disease. Interventions:
- allogeneic CMV-specific T cells (cell suspension for infusion), dose cohorts: 2 × 10^7 cells, 4 × 10^7 cells, 8 × 10^7 cells; 4 infusions; administered weekly
- pembrolizumab 400 mg (solution for injection); 18 infusions; administered every 6 weeks
Intervention: Pembrolizumab (Drug)
Part 2 Group A
Patients with recurrent disease. Interventions:
- allogeneic CMV-specific T cells (cell suspension for infusion), maximum-tolerated dose identified in phase I; 4 infusions; administered weekly
- pembrolizumab 400 mg (solution for injection); 18 infusions; administered every 6 weeks
Intervention: Allogeneic cytomegalovirus-specific T cells (Biological)
Part 2 Group A
Patients with recurrent disease. Interventions:
- allogeneic CMV-specific T cells (cell suspension for infusion), maximum-tolerated dose identified in phase I; 4 infusions; administered weekly
- pembrolizumab 400 mg (solution for injection); 18 infusions; administered every 6 weeks
Intervention: Pembrolizumab (Drug)
Part 2 Group B
Patients with newly diagnosed disease. Interventions:
- allogeneic CMV-specific T cells (cell suspension for infusion), maximum-tolerated dose identified in phase I; 4 infusions; administered weekly
- pembrolizumab 400 mg (solution for injection); 18 infusions; administered every 6 weeks
Intervention: Allogeneic cytomegalovirus-specific T cells (Biological)
Part 2 Group B
Patients with newly diagnosed disease. Interventions:
- allogeneic CMV-specific T cells (cell suspension for infusion), maximum-tolerated dose identified in phase I; 4 infusions; administered weekly
- pembrolizumab 400 mg (solution for injection); 18 infusions; administered every 6 weeks
Intervention: Pembrolizumab (Drug)
Outcomes
Primary Outcomes
Duration of response
Time Frame: Within 25 months of the first dose of study drug
Part 2 - Primary Endpoint 3
Incidence of adverse events and clinically significant changes in laboratory parameters, vital signs, and electrocardiograms (ECGs)
Time Frame: Within 49 days of the first dose of study drug
Part 1 - Primary Endpoint 2
Overall survival (percentage of participants alive)
Time Frame: 6 months
Part 2 - Primary Endpoint 4
Incidence of dose-limiting toxicities
Time Frame: Within 49 days of receiving the first dose of study drug
Part 1 - Primary Endpoint 1
Percentage of participants with confirmed complete response (CR) or partial response (PR)
Time Frame: Within 25 months of the first dose of study drug
Part 2 - Primary Endpoint 1
Percentage of participants with confirmed complete response (CR), partial response (PR), or stable disease (SD)
Time Frame: Within 25 months of the first dose of study drug
Part 2 - Primary Endpoint 2
Progression-free survival (percentage of participants with no evidence of further disease progression)
Time Frame: 6 months
Part 2 - Primary Endpoint 5
Secondary Outcomes
- Percentage of participants with confirmed CR or PR(Within 25 months of the first dose of study drug)
- Percentage of participants with confirmed CR, PR, or SD(Within 25 months of the first dose of study drug)
- Overall survival (percentage of participants alive)(6 months)
- Duration of response(Within 25 months of the first dose of study drug)
- Progression-free survival (percentage of participants with no evidence of further disease progression)(6 months)
- Incidence of adverse events and clinically significant changes in laboratory parameters, vital signs, and ECGs(Within 25 months of the first dose of study drug)