Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000348550
Ethics application status
Approved
Date submitted
7/02/2024
Date registered
27/03/2024
Date last updated
1/08/2024
Date data sharing statement initially provided
27/03/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
A pilot study, defining the Immunophenotype of immunotherapy resistance with 89Zr- Durvalumab (MEDI4736) and CD8 T-cell PET/CT.
Scientific title
IMMUNOResist: Defining the Immunophenotype of immunotherapy resistance with 89Zr- Durvalumab (MEDI4736) and CD8 T-cell PET/CT in any stage non-small cell lung cancer.
Secondary ID [1] 311483 0
None
Universal Trial Number (UTN)
Trial acronym
IMMUNOResist
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Non-small cell lung cancer
 332713 0
Condition category
Condition code
Cancer 329426 329426 0 0
Lung - Non small cell

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Consented participants with non-small cell lung cancer, progressing on first line immunotherapy, who are receiving radiotherapy to progressive disease sites, will partake in PET/CT imaging using 89Zr- Df-Crefmirlimab (CD8) and 89Zr -durva tracers. Before radiotherapy (Day 1), a CD8 PET/CT scan will occur, and 89Zr-DF-Crefirmilab (3.0mCi/8mL) will be administered over a 5-10 minute intravenous infusion using a syringe pump (total time will be approximately 30 minutes). After 7 days post radiotherapy, participants will return for their standard of care FDG PET/CT scan and will also be asked to do the CD8 PET/CT scan again. Then after 7 days, participants will be asked to do the 89Zr -durva tracer scan, where a 10mg dose of durvalumab will also be injected through slow intravenous infusion (approximately 30 minutes).
Intervention code [1] 328205 0
Diagnosis / Prognosis
Comparator / control treatment
No control group
Control group
Active

Outcomes
Primary outcome [1] 337530 0
Quantitatively measure and describe changes in CD8 T-cell infiltration and interrogate whether radiotherapy causes changes in expression of PD-L1, a target for immunecheckpoint immunotherapy
Timepoint [1] 337530 0
At baseline and after radiotherapy.

89Zr-Df-crefmirlimab () PET/CT with blood samples before radiotherapy

CD8 PET/CT and 89Zr- durvalumab (89Zr- durva) PET/CT with blood samples after radiotherapy treatment
Secondary outcome [1] 432221 0
Concordance between 18F-FDG, 89Zr-durva, and CD8 ImmunoPET PET/CT alterations over time will be described as well as potential to alter management.
Timepoint [1] 432221 0
At baseline before and after radiotherapy.

Eligibility
Key inclusion criteria
Written and informed consent provided

18 years or above

Body weight above 30kg

Life expectancy equivalent to 12 weeks

Primary tumour characteristics: Any stage non-small cell lung cancer (AJCC v.8)

Patients are planned to receive radiotherapy to sites of progressive disease

Adequate organ and marrow function as defined below:

Absolute neutrophil count greater than 1.5 x 109/L (1500 per mm3)

Platelets greater than 100 x 109/L (100,000 per mm3)

Haemoglobin greater or equal to 9.0 g/dL (5.59 mmol/L)

Serum creatinine CL greater than 50 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976)

(eGFR) greater than 50ml/min as measured using the MDRD formula (Modification of Diet in Renal Disease).

Serum bilirubin less than or equal to 1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology), who will be allowed only in consultation with their physician

AST (SGOT)/ALT (SGPT) less than or equal to 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be less than or equal to 5x ULN

Women will be considered post-menopausal according to the following age-specific requirements:

Women under the age of 50 would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and, if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution

Women aged 50 and above would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses over a year ago, had chemotherapy-induced menopause with last menses over a year ago, or underwent surgical sterilization (bilateral oophorectomy or hysterectomy

Evidence of post-menopausal status or negative serum pregnancy test at baseline for female participants over the age of 50 or evidence that they have undergone surgical sterilization (bilateral oophorectomy or hysterectomy with oophorectomy). Subsequent pregnancy tests performed prior to PET imaging may be urinary or serum.

Eastern Cooperative Group Oncology Group (ECOG) performance score of 0-2.

Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Current or prior use of immunosuppressive medication within 28 days before the first dose of study drug, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Systemic steroid administration required to manage toxicities arising from radiation therapy delivered as part of the chemoradiation therapy for locally advanced NSCLC is allowed.



For patients who have received prior immunotherapy, including anti PD-1, PD-L1 and CTLA-4 therapy:



Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of greater than 10 mg prednisone or equivalent per day.



All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study.

Must not have experienced a greater than or equal to Grade 3 immune related AE or an immune related neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE: Patients with endocrine AE of greater than or equal to Grade 2 are permitted to enrol if they are stably maintained on appropriate replacement therapy and are asymptomatic.



Vascular access or EBUS or mediastinal biopsy) that would prevent administration of study drug.



Active or prior documented autoimmune disease within the past 2 years. NOTE: Patients with vitiligo, Grave’s disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.



Active or prior documented inflammatory bowel disease (e.g. Crohn’s disease, ulcerative colitis)



History of primary immunodeficiency.



History of organ transplant that requires therapeutic immunosuppression.



Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any patient known to have hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the patient to give written informed consent.



Known active hepatitis infection, positive hepatitis C virus (HCV) antibody, hepatitis B virus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc), at screening. Participants with a past or resolved HBV infection (defined as the presence of antiHBc and absence of HBsAg) are eligible. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.



Participants co-infected with HBV and HCV, or co-infected with HBV and HDV, namely: HBV positive (presence of HBsAg and/or anti HBcAb with detectable HBV DNA); AND



HCV positive (presence of anti-HCV antibodies); OR



HDV positive (presence of anti-HDV antibodies).



Known to have tested positive for human immunodeficiency virus (HIV) (positive HIV?1/2 antibodies) or active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice).



Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving study drug.



History of another primary malignancy within 5 years prior to starting study drug, except for adequately treated basal or squamous cell carcinoma of the skin or cancer of the cervix in situ and the disease under study.



Female patients who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control



PET contraindications, e.g. Total serum bilirubin greater than 1.5 times upper limit of normal (abnormal hepatic metabolism may interfere with hepatic excretion)



Any condition that, in the opinion of the investigator, would interfere with evaluation or interpretation of patient safety or study results

Study design
Purpose of the study
Diagnosis
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
Single group
Other design features
Phase
Phase 0
Type of endpoint/s
Efficacy
Statistical methods / analysis
Primary Analysis

The primary objective is to describe the distribution of CD8 ImmunoPEt within tumours at baseline, and after radiotherapy, and 89Zr-durva after radiotherapy.

Quantitative measures on 89Zr-durva PET/CT, FDG PET/CT and 89Zr-durva immunohistochemistry will be summarized.

Correlations between quantitative measures will be expressed as a Pearson/Spearman correlation coefficient depending on distribution of data.

CD8 ImmunoPET and FDG PET/CT pre, and 89Zr-durva PET/CT, CD8 ImmunoPET and FDG PET/CT post- radiotherapy in the following absolute measures of MTV, SUVmax, SUVmean, SUVpeak, and %ID will be summarised. Results will be displayed in graphs.



Secondary analysis

Concordance between FDG, 89Zr-durva, and CD8 ImmunoPET PET/CT alterations over time will be assessed using a weighted kappa coefficient with weights based on quadratic differences.

Associations between intra-treatment response and overall survival (OS) / disease progression free survival (DFS) will be described graphically using Kaplan-Meier product limit curves.

Proportion of patients in which 89Zr-durva and CD8 ImmunoPET PET/CT provides information not seen on FDG-PET or PD-L1 immunohistochemistry performed at baseline and proportion of patients in which additional information from 89Zr-durva PET/CT with the potential to alter management will be described.

Exploratory Analysis

The relationship between changes seen on imaging with 89Zr-durva PET/CT, CD8 ImmunoPET will be qualitatively compared with data from mass cytometry of PBMC, TCR characterization and cytokine profiling

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
27/05/2024
Actual
20/06/2024
Date of last participant enrolment
Anticipated
1/04/2025
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
5
Accrual to date
1
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 26124 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [2] 26125 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 41982 0
3000 - Melbourne
Recruitment postcode(s) [2] 41983 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 315696 0
Government body
Name [1] 315696 0
Victorian Cancer Agency
Country [1] 315696 0
Australia
Funding source category [2] 315697 0
Hospital
Name [2] 315697 0
Peter MacCallum Cancer Centre
Country [2] 315697 0
Australia
Funding source category [3] 315721 0
Commercial sector/Industry
Name [3] 315721 0
AstraZeneca
Country [3] 315721 0
Australia
Primary sponsor type
Hospital
Name
Peter MacCallum Cancer Centre
Address
Country
Australia
Secondary sponsor category [1] 317894 0
None
Name [1] 317894 0
Address [1] 317894 0
Country [1] 317894 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 314565 0
Peter MacCallum Cancer Centre Human Research Ethics Committee
Ethics committee address [1] 314565 0
Ethics committee country [1] 314565 0
Australia
Date submitted for ethics approval [1] 314565 0
05/12/2023
Approval date [1] 314565 0
04/04/2024
Ethics approval number [1] 314565 0
HREC/104672/PMCC

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

Contacts
Principal investigator
Name 132030 0
Dr Fiona Hegi-Johnson
Address 132030 0
Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne Victoria 3000
Country 132030 0
Australia
Phone 132030 0
+61 03 8559 5000
Fax 132030 0
Email 132030 0
[email protected]
Contact person for public queries
Name 132031 0
Angie Tran
Address 132031 0
Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne Victoria 3000 ·
Country 132031 0
Australia
Phone 132031 0
+61 03 8559 7125
Fax 132031 0
Email 132031 0
[email protected]
Contact person for scientific queries
Name 132032 0
Fiona Hegi-Johnson
Address 132032 0
Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne Victoria 3000
Country 132032 0
Australia
Phone 132032 0
+61 03 8559 5000
Fax 132032 0
Email 132032 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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.