DNA DamageNCT06204523
Prospective Validation of a DNA Damage Repair-Hippo Pathway Signature in Patients With Advanced Gastric Cancer
An observational study of DNA Damage and Gastric Cancer, run by Regina Elena Cancer Institute at 1 site in Italy.
Trial summary
We envisioned a scenario where the interaction between the ATM-Chk2/ATR-Chk1 pathways and Hippo enables GC cells to overcome chemotherapy-induced death stimuli. First, ATM-Chk2 and ATR-Chk1 were found to be activated across all the GC molecular subtypes. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- DNA Damage, Gastric Cancer
- What is being tested?
- investigated biomarkers regarding the efficacy of first-line chemotherapy
- How many people
- 167 participants
- Where
- 1 siteItaly
- Study dates
- 26 Oct 2018to 30 Aug 2024
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Patients with inoperable locally advanced or metastatic GC who are candidates for first-line chemotherapy treatment and meet the following criteria will be included in the study
Who may be able to join
- Age >18 years;
- Histologic diagnosis of locally advanced or metastatic gastric carcinoma (GC) or gastroesophageal junction carcinoma (EJC);
- Biological material adequate for molecular analysis to be performed, taken (at surgery or by biopsy) prior to the administration of any anti-tumor treatment (chemotherapy and/or radiotherapy);
- ECOG PS 0-2;
- Adequate hematologic, hepatic, and renal function;
- Measurable disease according to RECIST criteria;
- Written informed consent.
Who cannot join
- Previous chemotherapy for metastatic disease;
- Comorbidities not controlled with appropriate medical therapy;
- Brain metastasis;
- Patient unable to give adequate consent for the study
Trial locations and contacts
1 site in 1 country.
About this study
We envisioned a scenario where the interaction between the ATM-Chk2/ATR-Chk1 pathways and Hippo enables GC cells to overcome chemotherapy-induced death stimuli. First, ATM-Chk2 and ATR-Chk1 were found to be activated across all the GC molecular subtypes. Moreover, a number of genes associated with their basal activation are recurrently mutated or amplified.
Thus, we retrospectively characterized a cohort of GC patients treated with first-line therapy for DDR- and Hippo-related markers, identifying a signature predicting inferior PFS and OS. This exploratory analysis provided the necessary information (frequency of candidate biomarkers and effect difference between groups) for a prospective study with validation purposes, which is the main goal of this trial.
Read the detailed description
This prospective, multicenter, non-interventional trial is designed for prospectively validating the DDR-Hippo signature as a predictor of inferior PFS in patients with inoperable locally advanced or metastatic GC receiving first-line therapy. Patients will be evaluated for response to chemotherapy every two cycles by current RECIST criteria. PFS will be defined as the time elapsing between the initiation of chemotherapy until objective tumor progression or death, and OS as the time elapsing between the initiation of chemotherapy until death from any cause. All molecular analyses will be centralized at the coordinating center. Investigators performing molecular analyses will be masked to clinical outcomes. Centralized radiological review is planned. The study will be conducted in accordance with the Declaration of Helsinki and adheres to the REMARK criteria.
The second task is designed for exploring genetic events functionally related to the DDR and Hippo pathways that may modify the predictive significance of the signature. These genes are schematically clustered on the basis of the expected alteration in: i) Mutated genes (cluster 1) to be evaluated by targeted DNA-Seq and amplified genes (cluster 2) to be evaluated by FISH/CISH. Cluster 1 includes TP53 (defective cell cycle progression and apoptotic response, aberrant TAZ/YAP-mediated transcription), KRAS (oncogene-induced replication stress and activation of cell cycle checkpoints to avoid apoptosis and senescence), BRCA1 and BRCA2 (defective homologous recombination repair), ARID1A, ATR and ATM (altered ATM/ATR-initiated DNA repair), RHOA (G-protein coupled receptor-mediated activation of TAZ/YAP), CTNNB1, APC and FBXW7 (Wnt-mediated control of TAZ/YAP). Cluster 2 encompasses MYC and KRAS (oncogene-induced replication stress), CCNE1, CCND1 and CDK6 (dysfunctional G1-S transition requiring compensatory activation of intra-S and G2/M checkpoints).
The present study is designed to generate prospective evidence on the ability of the investigated biomarkers to predict the efficacy of first-line chemotherapy in GC patients. The identification of patients who derive marginal benefit from chemotherapy holds the potential to expedite a wave of interventional trials with agents targeting the DDR-Hippo network (e.g. PARP inhibitors and ATR-Chk1 and ATM-Chk2 inhibitors), as well as to delineate the target population for studies with other compounds, such as immune checkpoint inhibitors. Overall, the experimental approach we propose is expected to culminate in the generation of a new tool to be used on a routine basis.
- Conditions
- DNA Damage, Gastric Cancer
- Being tested
- investigated biomarkers regarding the efficacy of first-line chemotherapy
- Medical subject headings
- Stomach Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
investigated biomarkers regarding the efficacy of first-line chemotherapyDiagnostic test
The present study was designed to generate solid evidence on the predictivity of the investigated biomarkers regarding the efficacy of first-line chemotherapy in patients with GC
| Study group | Role | What they receive |
|---|---|---|
| Popolation | Not described Receives: Diagnostic Test: investigated biomarkers regarding the efficacy of first-line chemotherapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Identify new biomarkers that predict the activity of first-line chemotherapy, in order to achieve better patient selection.
Computational enrichment analysis will be carried out to test whether tumors of patients with shorter PFS contain a higher-than-randomly-expected representation of a specific pathway/function. Special emphasis will be placed on, but not limited to, the DDR-Hippo-Wnt pathways. For multiple hypothesis testing a Benjamini-Hochberg False Discovery Rate correction will be applied (<5%). For clinical data analysis, the Pearson's Chi-squared test of independence (2-tailed) and the Pearson's correlation coefficient will be used to assess the relationships between categorical and continuous variables, respectively.
Measured: Three years
Identify additional genetic events molecularly linked to the DDR-Hippo signature and potentially improve its predictive ability.
RNA and DNA will be extracted from 5µm FFPE tissue sections using the AllPrep DNA/RNA FFPE kit (Qiagen). Libraries for RNA-Seq will be prepared using the TruSeq Stranded Total RNA kit with an initial ribosomal depletion step (Illumina). Targeted DNA-Sequencing will be conducted by designing a custom amplicon panel with DesignStudio and employing the TruSeq Custom Amplicon Low Input Kit (Illumina). RNA will be analyzed with our cloud pipeline (RAP, available at https://bioinformatics.cineca.it/rap/) that employs the Tuxedo Suite (Tophat, Cufflinks, Cuffdiff).
For DNA analysis, applications available on Basespace (Illumina) will be used. Sequencing will be performed on our NextSeq500
Measured: Three years
Investigate pathways of interest at a deeper level, as well as identify other potential pathways/functions impacting clinical outcomes.
Clinical, pathological and molecular variables will be tested in univariate Cox analysis. A multivariate Cox proportional hazard model for PFS will be build with variables testing significant at the univariate assessment, and the related estimates reported as HR and 95%CI.
Measured: Three years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Jan 2024
- Study start26 Oct 2018
- Primary completion30 Aug 2023
- Study completion30 Aug 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for DNA DamageStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case only
- Time perspective
- Prospective
- Enrolment
- 167 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Regina Elena Cancer Institute
- Sponsor type
- University, hospital or other
- Collaborators
- Azienda Sanitaria Locale n. 2 - Lanciano Vasto Chieti, Campus Bio-Medico University, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Azienda Ospedaliera "Sant'Andrea", University of Roma La Sapienza, Azienda Ospedaliero Universitaria Policlinico Modena
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06204523
- Sponsor's protocol ID
- RS1043/18
- Status last verified
- Jan 2024
- First submitted
- 28 Mar 2023
- Last updated
- 18 Jan 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 18 Jan 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prospective Validation of a DNA Damage Repair-Hippo Pathway Signature in Patients With Advanced Gastric Cancer
- ClinicalTrials.gov ID
- NCT06204523
- Acronym / sponsor ID
- RS1043/18
- Conditions
- DNA Damage, Gastric Cancer
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 167 participants (estimated)
- Lead sponsor
- Regina Elena Cancer InstituteUniversity, hospital or other
- Collaborators
- Azienda Sanitaria Locale n. 2 - Lanciano Vasto Chieti, Campus Bio-Medico University, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Azienda Ospedaliera "Sant'Andrea", University of Roma La Sapienza, Azienda Ospedaliero Universitaria Policlinico Modena
- Study start
- 26 Oct 2018 (actual)
- Primary completion
- 30 Aug 2023 (actual)
- Study completion
- 30 Aug 2024 (estimated)
- First posted
- 12 Jan 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
We envisioned a scenario where the interaction between the ATM-Chk2/ATR-Chk1 pathways and Hippo enables GC cells to overcome chemotherapy-induced death stimuli. First, ATM-Chk2 and ATR-Chk1 were found to be activated across all the GC molecular subtypes. Moreover, a number of genes associated with their basal activation are recurrently mutated or amplified.
Thus, we retrospectively characterized a cohort of GC patients treated with first-line therapy for DDR- and Hippo-related markers, identifying a signature predicting inferior PFS and OS. This exploratory analysis provided the necessary information (frequency of candidate biomarkers and effect difference between groups) for a prospective study with validation purposes, which is the main goal of this trial.
Detailed description
This prospective, multicenter, non-interventional trial is designed for prospectively validating the DDR-Hippo signature as a predictor of inferior PFS in patients with inoperable locally advanced or metastatic GC receiving first-line therapy. Patients will be evaluated for response to chemotherapy every two cycles by current RECIST criteria. PFS will be defined as the time elapsing between the initiation of chemotherapy until objective tumor progression or death, and OS as the time elapsing between the initiation of chemotherapy until death from any cause. All molecular analyses will be centralized at the coordinating center. Investigators performing molecular analyses will be masked to clinical outcomes. Centralized radiological review is planned. The study will be conducted in accordance with the Declaration of Helsinki and adheres to the REMARK criteria.
The second task is designed for exploring genetic events functionally related to the DDR and Hippo pathways that may modify the predictive significance of the signature. These genes are schematically clustered on the basis of the expected alteration in: i) Mutated genes (cluster 1) to be evaluated by targeted DNA-Seq and amplified genes (cluster 2) to be evaluated by FISH/CISH. Cluster 1 includes TP53 (defective cell cycle progression and apoptotic response, aberrant TAZ/YAP-mediated transcription), KRAS (oncogene-induced replication stress and activation of cell cycle checkpoints to avoid apoptosis and senescence), BRCA1 and BRCA2 (defective homologous recombination repair), ARID1A, ATR and ATM (altered ATM/ATR-initiated DNA repair), RHOA (G-protein coupled receptor-mediated activation of TAZ/YAP), CTNNB1, APC and FBXW7 (Wnt-mediated control of TAZ/YAP). Cluster 2 encompasses MYC and KRAS (oncogene-induced replication stress), CCNE1, CCND1 and CDK6 (dysfunctional G1-S transition requiring compensatory activation of intra-S and G2/M checkpoints).
The present study is designed to generate prospective evidence on the ability of the investigated biomarkers to predict the efficacy of first-line chemotherapy in GC patients. The identification of patients who derive marginal benefit from chemotherapy holds the potential to expedite a wave of interventional trials with agents targeting the DDR-Hippo network (e.g. PARP inhibitors and ATR-Chk1 and ATM-Chk2 inhibitors), as well as to delineate the target population for studies with other compounds, such as immune checkpoint inhibitors. Overall, the experimental approach we propose is expected to culminate in the generation of a new tool to be used on a routine basis.
Study design
- Observational model
- Case only
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Popolation | – | Diagnostic Test: investigated biomarkers regarding the efficacy of first-line chemotherapy |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Patients with inoperable locally advanced or metastatic GC who are candidates for first-line chemotherapy treatment and meet the following criteria will be included in the study
Key inclusion criteria (7 listed)
- Age >18 years;
- Histologic diagnosis of locally advanced or metastatic gastric carcinoma (GC) or gastroesophageal junction carcinoma (EJC);
- Biological material adequate for molecular analysis to be performed, taken (at surgery or by biopsy) prior to the administration of any anti-tumor treatment (chemotherapy and/or radiotherapy);
- ECOG PS 0-2;
- Adequate hematologic, hepatic, and renal function;
Key exclusion criteria (4 listed)
- Previous chemotherapy for metastatic disease;
- Comorbidities not controlled with appropriate medical therapy;
- Brain metastasis;
- Patient unable to give adequate consent for the study
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| investigated biomarkers regarding the efficacy of first-line chemotherapyThe present study was designed to generate solid evidence on the predictivity of the investigated biomarkers regarding the efficacy of first-line chemotherapy in patients with GC | Diagnostic test | Popolation |
Primary outcome
Identify new biomarkers that predict the activity of first-line chemotherapy, in order to achieve better patient selection.
Time frame: Three years
Computational enrichment analysis will be carried out to test whether tumors of patients with shorter PFS contain a higher-than-randomly-expected representation of a specific pathway/function. Special emphasis will be placed on, but not limited to, the DDR-Hippo-Wnt pathways. For multiple hypothesis testing a Benjamini-Hochberg False Discovery Rate correction will be applied (<5%). For clinical data analysis, the Pearson's Chi-squared test of independence (2-tailed) and the Pearson's correlation coefficient will be used to assess the relationships between categorical and continuous variables, respectively.
Identify additional genetic events molecularly linked to the DDR-Hippo signature and potentially improve its predictive ability.
Time frame: Three years
RNA and DNA will be extracted from 5µm FFPE tissue sections using the AllPrep DNA/RNA FFPE kit (Qiagen). Libraries for RNA-Seq will be prepared using the TruSeq Stranded Total RNA kit with an initial ribosomal depletion step (Illumina). Targeted DNA-Sequencing will be conducted by designing a custom amplicon panel with DesignStudio and employing the TruSeq Custom Amplicon Low Input Kit (Illumina). RNA will be analyzed with our cloud pipeline (RAP, available at https://bioinformatics.cineca.it/rap/) that employs the Tuxedo Suite (Tophat, Cufflinks, Cuffdiff). For DNA analysis, applications available on Basespace (Illumina) will be used. Sequencing will be performed on our NextSeq500
Investigate pathways of interest at a deeper level, as well as identify other potential pathways/functions impacting clinical outcomes.
Time frame: Three years
Clinical, pathological and molecular variables will be tested in univariate Cox analysis. A multivariate Cox proportional hazard model for PFS will be build with variables testing significant at the univariate assessment, and the related estimates reported as HR and 95%CI.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jan 2024.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of DNA Damage and Gastric Cancer, run by Regina Elena Cancer Institute at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 18 Jan 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Identify new biomarkers that predict the activity of first-line chemotherapy, in order to achieve better patient selection. (time frame: Three years). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jan 2024.