None listed
Conditions
Brief summary
This study aims to assess the safety and potential effectiveness of a new treatment combining two different cancer treatments, a T cell-based immunotherapy and pembrolizumab (a drug that is used to prevent cancer cells from hiding from T cells), for glioblastoma multiforme (GBM) or astrocytoma grade 4. Who is it for? You may be eligible for this study if you are aged 18 years or older, you have been diagnosed with GBM or astrocytoma Grade 4 brain cancer and you have been exposed to a common virus called cytomegalovirus (CMV) at some point in your life, this exposure will be determined by a blood test. Study details In this trial, based on the patient tissue type, the best-matching T cell therapy available will be selected and given to patients over four infusions, followed by 18 doses of pembrolizumab (at an interval 6 weeks between each treatment). The main aims of this clinical trial are to see whether this CMV-specific T cell therapy combined with pembrolizumab is safe for people with GBM/astrocytoma grade 4, and it if can show effectiveness against this type of tumour. The trial is being conducted in two parts. Phase I of this trial aims to work out the highest dose of T cells that does not have serious side effects. Participants will be enrolled firstly into the lowest T-cell dose group, if there are no serious side effects noted then enrolment into the higher T-cell dosing groups will occur. Once the maximum tolerated dose is determined, the second part (Phase II) will begin enrolling participants. Phase II of the trial is used to gather additional safety data and determine the efficacy of four infusions of the maximum tolerated dose (determined in phase I) of allogeneic CMV-specific T cells in combination with pembrolizumab. Participants enrolled in either Phase I or Phase II will be asked to undergo routine blood tests and MRI scans to determine any impact the combined treatments may be having on their cancer. Overall participation is not expected to exceed approximately 26 months. It is hoped this research will determine the maximum safest dose of T-cell therapy that can be administered to brain cancer patients together with pembrolizumab. Once a safe dose has been determined, a larger trial enrolling more cancer patients may be undertaken to further assess the efficacy of the combined treatments.
Interventions
Two investigational products are being tested in this study as a combination immunotherapy strategy. The first product is allogeneic cytomegalovirus (CMV)-specific T cells. This product has previously been generated in a cell therapy manufacturing facility from the peripheral blood of healthy donors recruited via the Australian Bone Marrow Donor Registry or Australian Red Cross Lifeblood. Batches of product will be selected for participants based on human leukocyte antigen matching. The second p
Two investigational products are being tested in this study as a combination immunotherapy strategy. The first product is allogeneic cytomegalovirus (CMV)-specific T cells. This product has previously been generated in a cell therapy manufacturing facility from the peripheral blood of healthy donors recruited via the Australian Bone Marrow Donor Registry or Australian Red Cross Lifeblood. Batches of product will be selected for participants based on human leukocyte antigen matching. The second product is pembrolizumab (Keytruda ®), supplied by MSD Australia. In phase I of the trial, the safety of escalating doses of the allogeneic CMV-specific T cells in combination with a fixed dose of pembrolizumab will be tested in 9–18 participants with recurrent glioblastoma multiforme/astrocytoma grade 4. Participants will be recruited from the Newro Foundation/Briz Brain & Spine. Each participant will receive four intravenous infusions of allogeneic CMV-specific T cells (at a dose of either 2 × 10^7 , 4 × 10^7 or 8 × 10^7 cells) suspended in normal saline. One infusion will be given per week. The Investigational Product will be administered intravenously over 5–10 min by a qualified person (e.g. nurse or clinician). This will be followed by a saline flush, which will take an additional 5–10 min. One week after the final infusion, participants will start receiving intravenous infusions of pembrolizumab (400 mg), which will continue every 6 weeks for up to 18 infusions. These infusions will be administered by a qualified person and will take 30 minutes, followed by a 5–10 min saline flush. The dose of allogeneic CMV-specific T cells for further exploration, in combination with pembrolizumab, will be determined in this phase, based on safety data. In phase II of the trial, the efficacy of allogeneic CMV-specific T cells in combination with pembrolizumab will be tested in 20 participants with recurrent glioblastoma multiforme/astrocytoma grade 4 and 20 participants with newly diagnosed glioblastoma multiforme/astrocytoma grade 4. These participants will be recruited from the Newro Foundation/Briz Brain & Spine, Royal Brisbane and Women’s Hospital, Princess Alexandra Hospital and The Austin Hospital. The infusion procedures from phase I, described above, will be followed for phase II, with the dose of T cells will be based on phase I data. Participants will attend clinic visits to receive the interventional treatment. All procedures will be recorded in the electronic database and monitored according to requirements. Participants from Phase I will not be eligible to participate in Phase II. It is anticipated that safety data from phase I will be reviewed within 3 months of the last participant completing their treatment on study, enrolment for Phase II will then begin after this review takes place. The dosing schedule for both Phase I and Phase II of Pembrolizumab (400mg), is every 6 weeks for up to 18 infusions.' - Participant duration is approximately 26 months.
Sponsors
QIMR Berghofer Medical Research Institute
Study design
Allocation
Non-randomised trial
Intervention model
Other
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Participants who are 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. Disease progression with radiological confirmation greater than or equal to 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: Participant eligibility will not be dependent on IDH status. Histological confirmation using the 2016 or 2021 WHO Classification of Tumours of the CNS is acceptable and classification edition will be noted. 2. Male participants: A male participant must agree to use a contraception as detailed in the trial protocol 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: A female participant is eligible to participate if she is not pregnant, not undergoing in vitro fertilisation and not breastfeeding, and at least one of the following conditions applies: a. Not a woman of childbearing potential (WOCBP) as defined in the trial protocol OR b. A WOCBP who agrees to follow the contraceptive guidance in the trial protocol during the treatment period and for at 120 days after the last dose of study treatment. 4. The participant (or legally acceptable representative if applicable) provides 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 less than or equal to Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement or participants who have less than or equal to Grade 2 neuropathy are eligible. Participants with >Grade 1 AE(s) 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. In phase II of the trial, participants with disease progression must have 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 (FFPE) or fresh tumour tissue obtained at the time of surgical resection or excisional biopsy. Note: Clinical outcome predictors IDH1/2, MGMT status, ATRX, p53, 1p19q, EGFR amplification and Ki-67 not available at screening will be analysed following the completion of recruitment. 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 as defined in the trial protocol. Specimens must be collected within 10 days prior to the start of study intervention. 12. Have availability of an 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 HBV or 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. 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 (e.g., CTLA-4, OX-40, CD137). 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 (less than or equal to 2 weeks of radiotherapy). Participants receiving dexamethasone must be clinically stable and receiving a stable or weaning dose of less than or equal to 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 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 severe hypersensitivity (greater than or equal to Grade 3) to pembrolizumab and/or any of its excipients. 10. Has active autoimmune disease that has required systemic treatment in the past 2 years except replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid). 11. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. 12. Has an active infection requiring systemic therapy. 13. Has a known history of human immunodeficiency virus (HIV) infection. Note: No HIV testing is required unless mandated by a local health authority. 14. 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 15. Has not adequately recovered from major surgery or has ongoing surgical complications. 16. 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. 17. Has known psychiatric or substance-abuse disorders that would interfere with cooperation with the requirements of the trial. 18. 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. 19. Has had an allogeneic tissue/solid organ transplant or stem cell transplant. 20. Has a baseline corrected QT interval (QTc) of >450 ms. If the participant’s screening electrocardiogram (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.
Outcome results
None listed