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Trial registered on ANZCTR


Registration number
ACTRN12623001126606
Ethics application status
Approved
Date submitted
13/09/2023
Date registered
1/11/2023
Date last updated
1/08/2024
Date data sharing statement initially provided
1/11/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
T cells and pembrolizumab for recurrent and newly diagnosed glioblastoma
Scientific title
Phase I/II clinical trial evaluating the safety and efficacy of allogeneic cytomegalovirus-specific T cells in combination with pembrolizumab for recurrent and newly diagnosed glioblastoma multiforme
Secondary ID [1] 310587 0
Nil known
Universal Trial Number (UTN)
Trial acronym
TCaP
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Glioblastoma multiforme/astrocytoma grade 4 331446 0
Condition category
Condition code
Cancer 328186 328186 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 326991 0
Treatment: Other
Intervention code [2] 327204 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 336057 0
The incidence of dose-limiting toxicities during the intervention and serious adverse events (SAEs), abnormal laboratory parameters, vital signs and elecrocardiogram results per Common Terminology Criteria for Adverse Events, Version 5.0 (CTCAE v5.0). Vital Signs; temperature (thermometer), heart rate (pulse oximeter), respitatory rate (counting breaths per minute), blood pressure (blood pressure monitor) and oxygen saturation (pulse oximeter). The maximum tolerated dose in Phase I, will determine the dose in Phase II. This outcome will only be in Phase I.
Timepoint [1] 336057 0
Adverse events will be collected at Days 0, 3, 7, 14, 21, 28, 31, 35, 49 and 70, then every 42 days thereafter during the pembrolizumab infusions (up to 18 infusions), at study completion and 30 day safety follow-up (following last dose of study therapy) and more frequently if clinically indicated. Haematology and biochemistry blood tests will be conducted before each infusion of either intervention, and a thyroid function blood test and urine analysis will also be conducted before each pembrolizumab infusion. Vital signs observations will be recorded prior to and following each product infusion.
Primary outcome [2] 336056 0
The safety of the intervention, evaluated with the properties, incidence, nature and severity of adverse events (AEs) and serious adverse events (SAEs), abnormal laboratory parameters, vital signs including temperature (thermometer), heart rate (pulse oximeter), respiratory rate (counting breaths per minute), blood pressure (blood pressure monitor) and oxygen saturation (pulse oximeter), and electrocardiogram results. This outcome is a primary outcome in Phase I and a secondary outcome in Phase II.
Timepoint [2] 336056 0
Adverse events will be collected at Days 0, 3, 7, 14, 21, 28, 31, 35, 49 and 70, then every 42 days thereafter during the pembrolizumab infusions (up to 18 infusions), at study completion and 30 day safety follow-up (following last dose of study therapy) and more frequently if clinically indicated. Haematology and biochemistry blood tests will be conducted before each infusion of either product, and a thyroid function blood test and urine analysis will also be conducted before each pembrolizumab infusion. Vital signs observations will be recorded prior to and following each intervention.
Secondary outcome [1] 427895 0
Progression-free survival at 6 months (assessed in both Phase I and Phase II)
Timepoint [1] 427895 0
Magnetic resonance imaging (MRI) will be conducted prior to the first T cell infusion, then on days 25, 63, 119, 175, 231 and 287 after the first T cell infusion. This will be followed by standard of care MRI (approximately every 12 weeks) or as clinically indicated. Subsequent scans will therefore be approximately on days 371, 455, 539, etc. MRIs will continue until study closure or death (whichever occurs first).
Secondary outcome [2] 427893 0
Duration of response (assessed in both Phase I and Phase II).
Timepoint [2] 427893 0
Magnetic resonance imaging (MRI) will be conducted prior to the first T cell infusion, then on days 25, 63, 119, 175, 231 and 287 after the first T cell infusion. This will be followed by standard of care MRI (approximately every 12 weeks) or as clinically indicated. Subsequent scans will therefore be approximately on days 371, 455, 539, etc. MRIs will continue until study closure or death (whichever occurs first).
Secondary outcome [3] 426710 0
Disease control rate (assessed in both Phase I and Phase II).
Timepoint [3] 426710 0
Magnetic resonance imaging (MRI) will be conducted prior to the first T cell infusion, then on days 25, 63, 119, 175, 231 and 287 after the first T cell infusion. This will be followed by standard of care MRI (approximately every 12 weeks) or as clinically indicated. Subsequent scans will therefore be approximately on days 371, 455, 539, etc. MRIs will continue until study closure or death (whichever occurs first).
Secondary outcome [4] 434634 0
Objective Response Rate (assessed in both Phase I and Phase II)
Timepoint [4] 434634 0
Magnetic resonance imaging (MRI) will be conducted prior to the first T cell infusion, then on days 25, 63, 119, 175, 231 and 287 after the first T cell infusion. This will be followed by standard of care MRI (approximately every 12 weeks) or as clinically indicated. Subsequent scans will therefore be approximately on days 371, 455, 539, etc. MRIs will continue until study closure or death (whichever occurs first).
Secondary outcome [5] 427894 0
Overall survival at 6 months (assessed in both Phase I and Phase II)
Timepoint [5] 427894 0
Magnetic resonance imaging (MRI) will be conducted prior to the first T cell infusion, then on days 25, 63, 119, 175, 231 and 287 after the first T cell infusion. This will be followed by standard of care MRI (approximately every 12 weeks) or as clinically indicated. Subsequent scans will therefore be approximately on days 371, 455, 539, etc. MRIs will continue until study closure or death (whichever occurs first).

Eligibility
Key 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. First occurrence of 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 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)
OR
b. A WOCBP who agrees to follow the contraceptive guidance 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 greater than 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. For participants with disease progression, this should be the first evidence of measurable disease based on modified RANO criteria. Lesions situation in a previously irradicated 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, 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 or 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 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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. A WOCBP who has a positive urine pregnancy test within 72 hours prior 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. Participants enrolled with recurrent disease must have recovered from all radiation-related toxicities not require corticosteroids (other than dexamethasone) and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (less than or equal to 2 weeks of radiotherapy) to non-CNS disease.
Note: Participants receiving dexamethasone must be clinically stable and receiving a stable or weaning dose of less than or equal to 2mg/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 (greater than or equal to 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 great than 450 ms.
If the participant’s screening electrocardiogram (ECG) records a QTc of greater than 450 ms, the ECG is to be done in triplicate and the average of the QTc is to be recorded. If the QTc remains greater than 450 ms, the participant will be excluded from enrolment.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
3+3 design with three allogeneic CMV-specific T cell dose levels in phase I, with a fixed dose of pembrolizumab. Allogeneic CMV-specific T cell dose determined in phase I to be used in phase II, in combination with pembrolizumab.
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The sample size of up to 18 participants in phase I is expected to provide sufficient evidence to determining the safety and maximum-tolerated dose (MTD) of this combination immunotherapy. MTD will be determined as the highest dose level achieved with fewer than one third of patients experiencing dose-limiting adverse events.

The safety of the combination immunotherapy will be assessed by the incidence of adverse events that are considered associated by the investigational drug. Safety evaluation of the investigational product will be determined following review of recorded vital signs, adverse events, physical examinations and recorded laboratory safety parameters.

For phase II, the sample size of 40 participant, 20 participants with recurrent disease and 20 participants with newly diagnosed disease, is expected to provide sufficient information to determine the impact on the efficacy endpoints described in the protocol. The sample size calculations are based on Weibull distribution, which assumes survival times follow a normal distribution centred around the real median overall or progression-free survival and are based on a minimum 24-month follow-up of patients and an 18-month accrual period, and assume a shape parameter equal to 5, which corresponds to an approximately normal distribution of survival time (PASS, v20.08).

The modified RANO/immunotherapy RANO (iRANO) criteria will be used to define each patient’s response to treatment as (1) complete response, (2) partial response, (3) stable disease, or (4) progression. This will be evaluated at the first MRI scan post T cell infusions, and at each MRI scan thereafter. The proportion of patients assessed in each of the modified RANO/iRANO classifications will be reported for each time point.

Disease control rate and objective response rate will be summarised using the number and proportion of participants in each response category.

Descriptive summary statistics will be presented as appropriate. Continuous data will be summarised by sample size, mean, standard deviation, median, minimum, maximum and where appropriate 95% confidence intervals.

Categorical data will be summarised using the number and percentage of participants who respond to each specific category.

The time-to-event endpoints, overall survival, progression-free survival, the proportion progression-free at 6 and 12 months, and the proportion alive at 6 and 12 months, and duration of response, will be analysed using Kaplan–Meier analyses and Cox proportional hazards models to calculate and compare survival times. The time-to-event will be as defined as the time of enrolment until first occurrence of the event as defined in the endpoints section, or until the time of the last follow-up for censored cases.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
14/05/2024
Actual
14/05/2024
Date of last participant enrolment
Anticipated
1/04/2026
Actual
Date of last data collection
Anticipated
11/01/2028
Actual
Sample size
Target
58
Accrual to date
1
Final
Recruitment in Australia
Recruitment state(s)
QLD,VIC
Recruitment postcode(s) [1] 41329 0
4102 - Woolloongabba
Recruitment postcode(s) [2] 41327 0
4006 - Bowen Hills
Recruitment postcode(s) [3] 41330 0
3084 - Heidelberg
Recruitment postcode(s) [4] 41328 0
4029 - Royal Brisbane Hospital

Funding & Sponsors
Funding source category [1] 314796 0
Commercial sector/Industry
Name [1] 314796 0
CUREator program (Brandon BioCatalyst)
Country [1] 314796 0
Australia
Primary sponsor type
Other Collaborative groups
Name
QIMR Berghofer Medical Research Institute
Address
300 Herston Road, Herston QLD 4066
Country
Australia
Secondary sponsor category [1] 316784 0
None
Name [1] 316784 0
Address [1] 316784 0
Country [1] 316784 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313813 0
Uniting Care Health HREC
Ethics committee address [1] 313813 0
Ethics committee country [1] 313813 0
Australia
Date submitted for ethics approval [1] 313813 0
05/09/2023
Approval date [1] 313813 0
Ethics approval number [1] 313813 0
13/01/2024
Ethics committee name [2] 313808 0
Metro North Health HREC B (EC00168)
Ethics committee address [2] 313808 0
Ethics committee country [2] 313808 0
Australia
Date submitted for ethics approval [2] 313808 0
01/08/2023
Approval date [2] 313808 0
20/09/2023
Ethics approval number [2] 313808 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 129410 0
Prof Rajiv Khanna
Address 129410 0
QIMR Berghofer Centre for Immunotherapy and Vaccine Development, Tumour Immunology Laboratory, Level 10, CBCRC, QIMR Berghofer, 300 Herston Rd, Herston QLD 4006
Country 129410 0
Australia
Phone 129410 0
+61 7 3845 3510
Fax 129410 0
Email 129410 0
Rajiv.Khanna@qimrberghofer.edu.au
Contact person for public queries
Name 129411 0
Michelle Neller
Address 129411 0
QIMR Berghofer Medical Research Institute' 300 Herston Rd' Herston, QLD 4006
Country 129411 0
Australia
Phone 129411 0
+61 7 33620412
Fax 129411 0
Email 129411 0
immunotherapy@qimrberghofer.edu.au
Contact person for scientific queries
Name 129412 0
Rajiv Khanna
Address 129412 0
QIMR Berghofer Centre for Immunotherapy and Vaccine Development, Tumour Immunology Laboratory, Level 10, CBCRC, QIMR Berghofer, 300 Herston Rd, Herston QLD 4006
Country 129412 0
Australia
Phone 129412 0
+61 7 33620412
Fax 129412 0
Email 129412 0
immunotherapy@qimrberghofer.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Sponsor discretion to not share, however de-identified data will be shared through publication in peer-reviewed journal articles and in relevant seminar presentations and may be presented as individual or aggregate data.


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.