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Trial registered on ANZCTR


Registration number
ACTRN12621001596897
Ethics application status
Approved
Date submitted
27/09/2021
Date registered
22/11/2021
Date last updated
22/11/2021
Date data sharing statement initially provided
22/11/2021
Date results information initially provided
22/11/2021
Type of registration
Retrospectively registered

Titles & IDs
Public title
AUTO-CHECK: Molecular determinants of autoimmunity and immune related adverse events in advanced cancer participants treated with immune checkpoint inhibitors
Scientific title
AUTO-CHECK: Molecular determinants of autoimmunity and immune related adverse events in advanced cancer participants treated with immune checkpoint inhibitors
Secondary ID [1] 296168 0
Nil known
Universal Trial Number (UTN)
U1111-1265-2906
Trial acronym
AUTO-CHECK
Linked study record
This record is a sub-study of these studies: DREAM ACTRN12616001170415; PHAEDRA: ACTRN12617000106336; NIVORAD: ACTRN12616000352404; NUTMEG: ACTRN12617000267358; KEYPAD: ACTRN12618000132246; ILLUMNATE: ACTRN12618001742268

Health condition
Health condition(s) or problem(s) studied:
Cancer 320867 0
Condition category
Condition code
Cancer 318684 318684 0 0
Lung - Mesothelioma
Cancer 318685 318685 0 0
Womb (Uterine or endometrial cancer)
Cancer 318686 318686 0 0
Lung - Non small cell
Cancer 318687 318687 0 0
Kidney
Cancer 318688 318688 0 0
Brain
Cancer 318689 318689 0 0
Any cancer

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
This is an observational translational research substudy that will collect biospecimens and data from cancer patients participating in any of 6 investigator-initiated multi-centre clinical trials of immunotherapy (DREAM, PHAEDRA, NIVORAD, NUTMEG, KEYPAD and ILLUMINATE) and one single-site observational cohort (patients receiving any immunotherapy for any type of advanced cancer).
The general aim of this study is to determine the genetic and cellular basis for susceptibility to autoimmune adverse effects in patients receiving immune checkpoint inhibitors (ICIs).
Participation involves providing a blood sample at up to 3 timepoints: at baseline before commencing ICIs, 4-12 weeks after commencing ICIs, and at the time of any IRAE should it occur. The observational period is from the first dose of ICI, for a minimum of 12 months per patient, and involves access to medical records only.
Intervention code [1] 319818 0
Not applicable
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 326630 0
Molecular predictors of immune related adverse events (irAEs) identified from DNA extracted from blood sample.
This is a composite endpoint:
1. irAEs will be identified by physician-reported adverse events (AEs), and clinical adjudication of whether the AE was an IRAE.
2. Molecular predictors will be identified by comparing genetic sequences for patients who experienced at least one irAE (as identified above) with patients who did not have an IRAE.
Timepoint [1] 326630 0
Baseline (prior to commencing ICI treatment)
Secondary outcome [1] 392208 0
Common and rare genetic variants that are predictors of irAEs identified from DNA extracted from blood sample.
Timepoint [1] 392208 0
Baseline (prior to commencing ICI treatment)
Secondary outcome [2] 392209 0
Changes in immune cellular characteristics following commencement of ICI treatment identified from Peripheral Blood Mononuclear Cells (PBMCs) isolated from blood sample.
Timepoint [2] 392209 0
Baseline (prior to commencing ICI treatment) and 4-12 weeks after commencing ICI treatment
Secondary outcome [3] 392210 0
Changes in immune cellular characteristics following occurrence of an irAE identified from Peripheral Blood Mononuclear Cells (PBMCs) isolated from blood sample.
Timepoint [3] 392210 0
At the time of any iRAE should it occur

Eligibility
Key inclusion criteria
1. Any participant who receives at least one dose of ICI treatment in any of the following studies: DREAM, PHAEDRA, NIVORAD, NUTMEG, KEYPAD, ILLUMINATE and OCPI.
2. Written, informed consent for translational research.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
None

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
This is a hypothesis generating, exploratory study and results will be interpreted in this light.
All continuous data will be checked for normality before performing parametric tests and if required an appropriate non-parametric test will be substituted or data will be transformed (e.g. log transformation).
For values below the limit of detection (LoD), these may be imputed with LOD/sqrt(2). In the instance of large proportions of values below or above detectable limits, alternative methods such as censored linear regression may be sought.
P-values less than less than 0.05 will be considered statistically significant and no adjustments for multiple comparisons will be made.

Each of the clinical trial databases for the 7 participating studies will be collecting adverse events using CTCAE version 4.03, and using the following definition of a significant irAE:
• a grade 3-5 irAE, or
• a grade 1-2 irAE requiring initiation of corticosteroid treatment, or an increase in steroid treatment of greater than or equal to 10 mg prednisone daily (or equivalent), or
• an irAE requiring ongoing treatment, e.g. hormone replacement with thyroxine, insulin, desmopressin, etc
These adverse events may be reviewed centrally within each trial by a clinician to deem whether or not they are confirmed to meet the criteria of an irAE.

Briefly, the study outcomes will be analysed as follows:
1. Primary aim: baseline peripheral blood mononuclear cells (PBMCs) as predictors of irAE:
All patients with baseline PBMC data will be considered in this analysis. Logistic regression will be used in order to identify:
a) Individual PBMC variables, or
b) groups of PBMC variables,
that are predictive of irAEs.

2. Genetic variants as predictors of irAE
A nested case control study (where patients with an irAE are determined to be cases, and those who have not are controls ) will be performed in order to identify common and rare genetic variants that are different between cases and controls. Case controls will be matched where possible based on: trial, ICI treatment, gender, time since commencing ICI, ethnicity and number of lines of previous chemotherapy,

3. Changes in PBMCs with ICI treatment
Firstly, all patients with PBMC data will be used to summarise PBMCs at baseline and on treatment. Next, patients with matched timepoints will be used to explore the changes between these two timepoints (treatment – baseline). This change will be explored with linear regression, adjusting for the study and the baseline PBMC measurement. A suitable alternative test will be used in the presence of a large amount of censored data (such as a censored regression) or if the normality assumption is violated.

4. Changes in PBMCs with irAE
Firstly, changes over time will be looked at graphically, by whether the participant experienced an irAE or not, over time (baseline and on treatment).
Next, for participants with the three matched timepoints (baseline, on treatment and irAE) the PBMC data will be modelled over these three timepoints.
If required, explorations may be performed with linear regression, adjusting for the study.

5. IRAE and tumour response
An AE will be determined to be an irAE as described above.. Tumour response will be assessed by RECIST v1.1, and response is a complete response or a partial response. Only participants who are evaluable for response will be included in this analysis.
A crosstab of irAE (Y/N) and response (Y/N) will be given. Each study will be given, as well as a pooled estimate over all of the studies.
The timing of the irAE and the response is not of importance as no statistical test/model is to be performed. This analysis will be performed when the response data is available for all trials.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 18810 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment postcode(s) [1] 33259 0
2050 - Camperdown
Recruitment outside Australia
Country [1] 24152 0
New Zealand
State/province [1] 24152 0

Funding & Sponsors
Funding source category [1] 300758 0
Government body
Name [1] 300758 0
Cancer Australia
Country [1] 300758 0
Australia
Primary sponsor type
University
Name
Australian National University
Address
The John Curtin School of Medical Research
131 Garran Road, Acton ACT 2601
Country
Australia
Secondary sponsor category [1] 300294 0
University
Name [1] 300294 0
The University of Sydney
Address [1] 300294 0
Locked Bag 77
Camperdown NSW 1450
Country [1] 300294 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301538 0
Sydney Local Health District HREC (RPAH zone)
Ethics committee address [1] 301538 0
Royal Prince Alfred Hospital
Missenden Rd
Camperdown NSW 2050
Ethics committee country [1] 301538 0
Australia
Date submitted for ethics approval [1] 301538 0
24/03/2017
Approval date [1] 301538 0
18/05/2017
Ethics approval number [1] 301538 0
X16-0234 & HREC/16/RPAH/287 6.0/9.11/MAY17
Ethics committee name [2] 307948 0
Sydney Local Health District HREC (RPAH zone)
Ethics committee address [2] 307948 0
Royal Prince Alfred Hospital
Missenden Rd
Camperdown NSW 2050
Ethics committee country [2] 307948 0
Australia
Date submitted for ethics approval [2] 307948 0
31/05/2017
Approval date [2] 307948 0
11/07/2017
Ethics approval number [2] 307948 0
X16-0346 & HREC/16/RPAH/472 9.6/JUN17
Ethics committee name [3] 307949 0
Northern Sydney Local Health District HREC
Ethics committee address [3] 307949 0
Kolling Building Level 13
Royal North Shore Hospital
Pacific Hwy
St Leonards NSW 2065
Ethics committee country [3] 307949 0
Australia
Date submitted for ethics approval [3] 307949 0
Approval date [3] 307949 0
20/11/2017
Ethics approval number [3] 307949 0
RESP/15/311 & HREC/15/HAWKE/430
Ethics committee name [4] 307950 0
Sydney Local Health District HREC (RPAH zone)
Ethics committee address [4] 307950 0
Royal Prince Alfred Hospital
Missenden Rd
Camperdown NSW 2050
Ethics committee country [4] 307950 0
Australia
Date submitted for ethics approval [4] 307950 0
Approval date [4] 307950 0
10/08/2017
Ethics approval number [4] 307950 0
X17-0109 & HREC/17/RPAH/159
Ethics committee name [5] 307951 0
Northern Sydney Local Health District HREC
Ethics committee address [5] 307951 0
Kolling Building Level 13
Royal North Shore Hospital
Pacific Hwy
St Leonards NSW 2065
Ethics committee country [5] 307951 0
Australia
Date submitted for ethics approval [5] 307951 0
Approval date [5] 307951 0
27/09/2017
Ethics approval number [5] 307951 0
RESP/17/71 & HREC/17/HAWKE/94
Ethics committee name [6] 307952 0
Sydney Local Health District HREC (RPAH zone)
Ethics committee address [6] 307952 0
Royal Prince Alfred Hospital
Missenden Rd
Camperdown NSW 2050
Ethics committee country [6] 307952 0
Australia
Date submitted for ethics approval [6] 307952 0
Approval date [6] 307952 0
04/09/2018
Ethics approval number [6] 307952 0
X18-0284 & HREC/18/RPAH/402
Ethics committee name [7] 307953 0
ACT Health human research ethics committee
Ethics committee address [7] 307953 0
Canberra Hospital, Level 6 Building 10, Gilmore Cres, Garran ACT 2605
Ethics committee country [7] 307953 0
Australia
Date submitted for ethics approval [7] 307953 0
Approval date [7] 307953 0
11/02/2015
Ethics approval number [7] 307953 0
ETH.1.15.015

Summary
Brief summary
Checkpoint inhibitors are a new and effective class of cancer treatment. Sometimes these drugs result in unpredictable and severe inflammatory side effects. We will apply techniques that have helped us understand autoimmune disease to investigate patients treated with checkpoint inhibitors, aiming to elucidate how individual genetic variation predisposes patients to side effects. If successful, this project will improve how these powerful drugs are prescribed and reduce the risk of toxicity.
Trial website
Trial related presentations / publications
Public notes
This record is a sub-study of six studies and one cohort. Each study/cohort has obtained ethics approval for the sub-study separately. Therefore, there are seven ethics approvals listed here.

Contacts
Principal investigator
Name 87326 0
Prof Matthew Cook
Address 87326 0
Immunology and Translational Research
Level 6, Building 10,
Gilmore Crescent
Garran ACT 2605
Country 87326 0
Australia
Phone 87326 0
+61262443272
Fax 87326 0
Email 87326 0
matthew.cook@anu.edu.au
Contact person for public queries
Name 87327 0
Dr Michelle Cummins
Address 87327 0
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country 87327 0
Australia
Phone 87327 0
+61 2 9562 5016
Fax 87327 0
Email 87327 0
autocheck.study@sydney.edu.au
Contact person for scientific queries
Name 87328 0
Dr Michelle Cummins
Address 87328 0
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country 87328 0
Australia
Phone 87328 0
+61 2 9562 5016
Fax 87328 0
Email 87328 0
autocheck.study@sydney.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
Exploratory analyses only


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Plain language summaryNo Analysis not yet commenced - no results available

Documents added automatically
No additional documents have been identified.