Ignite Creation Date:
2024-05-06 @ 3:32 PM
Last Modification Date:
2024-10-26 @ 1:51 PM
Study NCT ID:
NCT04666220
Status:
UNKNOWN
Last Update Posted:
2021-02-12
First Post:
2020-11-30
Brief Title:
VETC Prognostic and Predictive Value in Renal Cell Carcinoma and Adrenal Carcinoma
Sponsor:
Humanitas Clinical and Research Center
Organization:
Humanitas Clinical and Research Center
Study Overview
Official Title:
Vessels Encapsulating Tumor Clusters VETC Prognostic and Predictive Value in Renal Cell Carcinoma and Adrenal Gland Carcinoma
Status:
UNKNOWN
Status Verified Date:
2021-02
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Metastasis is the main cause of death in cancer patients and often epithelial-to-mesenchymal transition EMT is advocated as the basic mechanism Recently Fang and colleagues described an EMT-independent process of metastasis in hepatocellular carcinoma HCC endothelium covers small cluster of tumor cells allowing tumor dissemination This process of angiogenesis named VETC vessels that encapsulate tumor clusters in HCC literature has been described under different names in other cancer types Furthermore the investigators confirmed the negative impact of VETC on patients prognosis on a large multicenter cohort of HCCs Moreover Fang et al demonstrated that patients affected by VETC-positive HCC benefit more from sorafenib therapy Interestingly this type of angiogenesis was also found in renal cell carcinoma adrenal gland pheochromocytoma thyroid follicular carcinoma and alveolar soft part sarcoma ASPS and associated to prognosis Moreover the distinction between benign and malignant neoplasms of the adrenal gland is a complex matter being the established criteria still lacking a strong reproducibility
Several tyrosine kinase inhibitors are available for different cancer types among them HCC RCC ASPS and TC may benefit from the so-called antiangiogenic tyrosine kinase inhibitors aTKI such as sunitinib sorafenib pazopanib A general histotype-independent validation of the prognostic role of VETC is missing Moreover inhibitors of tyrosine-kinase vascular endothelial growth factor receptors VEGFR-TKI represent an effective treatment for different cancer types but predictive markers are still needed In addition novel systemic immunotherapy agents are being approved in many cancer types as alternative to angiogenesis inhibitors A broader frame including metastatic mechanisms tumor microenvironment TME ie angiogenesis and immune infiltrate and treatment response could answer to several needs currently unmet Bayesian networks and causal models can be employed to effectively draw conclusions from retrospective data
The aim of the present study is to investigate in patients with RCC and adrenal carcinoma AC the VETC-expression on tumor tissue correlating the results with clinical data patients characteristics and outcome
Several tyrosine kinase inhibitors are available for different cancer types among them HCC RCC ASPS and TC may benefit from the so-called antiangiogenic tyrosine kinase inhibitors aTKI such as sunitinib sorafenib pazopanib A general histotype-independent validation of the prognostic role of VETC is missing Moreover inhibitors of tyrosine-kinase vascular endothelial growth factor receptors VEGFR-TKI represent an effective treatment for different cancer types but predictive markers are still needed In addition novel systemic immunotherapy agents are being approved in many cancer types as alternative to angiogenesis inhibitors A broader frame including metastatic mechanisms tumor microenvironment TME ie angiogenesis and immune infiltrate and treatment response could answer to several needs currently unmet Bayesian networks and causal models can be employed to effectively draw conclusions from retrospective data
The aim of the present study is to investigate in patients with RCC and adrenal carcinoma AC the VETC-expression on tumor tissue correlating the results with clinical data patients characteristics and outcome
Detailed Description:
Background and introduction
Metastasis is the main cause of death in cancer patients and often epithelial-to-mesenchymal transition EMT is advocated as the basic mechanism although some limitations have been identified 12 Recently Fang and colleagues described an EMT-independent process of metastasis in hepatocellular carcinoma HCC endothelium highlighted by CD34 immunohistochemistry covers small cluster of tumor cells allowing tumor dissemination 3 This process of angiogenesis named VETC vessels that encapsulate tumor clusters in HCC literature has been described under different names in other cancer types 4 Furthermore the investigators confirmed the negative impact of VETC on patients prognosis on a large multicenter cohort of HCCs 5 Moreover Fang et al demonstrated that patients affected by VETC-positive HCC benefit more from sorafenib therapy 6 Interestingly this type of angiogenesis was also found in renal cell carcinoma adrenal gland pheochromocytoma thyroid follicular carcinoma and alveolar soft part sarcoma ASPS and associated to prognosis 7-10 3435 Moreover the distinction between benign and malignant neoplasms of the adrenal gland is a complex matter being the established criteria still lacking a strong reproducibility 36
Several tyrosine kinase inhibitors are available for different cancer types among them HCC RCC ASPS and TC may benefit from the so-called antiangiogenic tyrosine kinase inhibitors aTKI such as sunitinib sorafenib pazopanib 11-14
Rationale of the study A general histotype-independent validation of the prognostic role of VETC is missing Moreover inhibitors of tyrosine-kinase vascular endothelial growth factor receptors VEGFR-TKI represent an effective treatment for different cancer types but predictive markers are still needed Moreover novel systemic immunotherapy agents are being approved in many cancer types as alternative to angiogenesis inhibitors A broader frame including metastatic mechanisms tumor microenvironment TME ie angiogenesis and immune infiltrate and treatment response could answer to several needs currently unmet Bayesian networks and causal models can be employed to effectively draw conclusions from retrospective data
Objectives of the study General objectives
1 The systematic investigation of VETC in RCC and AC in order to depict the impact of this phenomenon
2 To explore the possible role of TME and in particular of VETC in predicting a more beneficial response to VEGFR-TKIs providing a new tool in guiding the therapeutic choice
Study Design The study is monocentric observational and it will be performed on clinical and histological data collected in the course of study
For all series clinical and epidemiological features will be recorded all available histological slides will be reviewed and on the primary tumor slides histological characteristics will be re-assessed
Whenever multiple samples of tumors would be present those having the tumor-surrounding tissue interface will be selected and stained with CD34 antibody
VETC will be evaluated independently by at least two pathologists blinded to clinical data VETC will be recorded as positive or negative being VETC defined as CD34 unequivocal immunoreactivity of a continuous lining of endothelial cells around tumor clusters VETC will be considered alternative to the common capillary pattern consisting in small circular or linear blood vessels
Statistical considerations The project plans to collect data of 100 of patients who underwent surgery for RCC at our institution between 2005 and 2007 for the evaluation of VETC impact on prognosis and data of 60 patients who received sunitinib or pazopanib as first-line treatment for RCC at our center to explore if patients with VETC vascular phenotype would benefit more from the treatment with TKIs Furthermore the investigators will collect data of 20 patients who underwent surgery for AC at our Institution between 2000 and 2018
Bayesian Analysis Directed acyclic graphs will be constructed with available scientific information adjustment sets and conditional independencies will be calculated 15-17 Prior predictive simulations when relevant will be deployed to regularize the prior and reduce overfitting Continuous variables will be standardized to facilitate sampling Models will be fit using Stan a probabilistic programming language and R 1819 Stan runs a No U-Turn sampler an extension to Hamiltonian Monte Carlo HMC sampling which is itself a form of Markov Chain Monte Carlo 20-22 Four chains for 4000 iterations or 8000 whenever the bulk effective sample size will be low will be generated The final 2000 or 4000 iterations of each chain converge as indicated by post-modeling diagnostics such as the number of effective Gelman-Rubin R 23 A satisfactory posterior predictive model performance will be ensured before using sample means for estimates and sample quantiles for compatibility intervals CI 2324 CI will be calculated as 89 of the highest posterior density interval HDPI 23 Whenever more clusters of data would be present the investigators will use varying effects multilevel hierarchical models 25 To limit divergent transitions the investigators will reparameterize the models with a non-centered equivalent form 26 Predictive accuracy will be measured trough widely applicable information criteria WAIC 27
Withdrawal of subjects Missing data will be treated modeling the missingness process 28-29
Forms and procedures for collecting data and data managing To each subject will be assigned a sequential identification number For each subject data will be collected in a case report form CRF CRF will include SIN name sex date of birth date of primary surgery side size histotype relevant grading necrosis lymphovascular invasion R stage date of TKI therapy date of disease progression prognostic scores IMDC score 30 MSKCC score 31 Karnofsky score 32 first-last line data type dates of beginning and end best response progression date last follow-up status last contact death VETC All data will be registered in Microsoft Excel spreadsheet format Data are collected by the data manager and database base will be locked with a password Spaces will be filled with NA whenever a characteristic was not explored or an item is not applicable to the individual case
For AC CRF will include SIN name sex date of birth date of primary surgery side size and prognostic criteria for malignancy based on Weiss Classification mod 33
Ethical considerations Patient protection The responsible investigator will ensure that this study will be conducted in agreement with either the Declaration of Helsinki Tokyo Venice Hong Kong and Somerset West amendments or the laws and regulations of the country
The protocol has been written and the study will be conducted according to the institutional ICH Guideline for Good Clinical Practice The protocol and its annexes were subject to review and approval by the competent Independent Ethics Committees IEC
Subject identification - Personal Data protection All records identifying the subject must be kept confidential and to the extent permitted by the applicable laws andor regulations not be made publicly available The name of the patient will not be asked for nor recorded at the Data Center A sequential identification number will be automatically attributed to each patient registered in the study This number will identify the patient and must be included on all case report forms In order to avoid identification errors patient initials and date of birth will also be reported on the case report forms
Any and all patient information or documentation pertaining to a clinical trial to the extent permitting through a key kept anywhere regardless of whether such key is supplied along with the information or documentation or not must be considered as containing sensitive personal data of the patient and is therefore subjected to the provisions of applicable data protection privacy regulations Breach of such regulations may result in administrative or even criminal sanctions
Patient information or documentation may be considered anonymous and as such not subject to privacy regulations only when no key whatsoever permitting the identification of the patient is any longer available
Informed consent All patients will be informed of the aims of the study They will be informed as to the strict confidentiality of their patient data but that their medical records may be reviewed for study purposes by authorized individuals other than their treating physicianIt will be emphasized that the participation is voluntary and that the patient is allowed to refuse further participation in the protocol whenever heshe wants This will not prejudice the patients subsequent care Documented informed consent must be obtained for all patients included in the study before they are registered at the Data Center This must be done in accordance with the national and local regulatory requirements For European Union member states the informed consent procedure must conform to the ICH guidelines on Good Clinical Practice This implies that the written informed consent form should be signed and personally dated by the patient or by the patients legally acceptable representative
Conflict of Interest Any investigator andor research staff member who has a conflict of interest with this study such as patent ownership royalties or financial gain greater than the minimum allowable by their institution must fully disclose the nature of the conflict of interest
Data ownership According to the ICH Guidelines on Good Clinical Practice the sponsor of a study the Institution should the investigator or study coordinators act as sponsor in the performance of herhis institutional duties under the employment or collaboration agreement with Humanitas is the owner of the data resulting therefrom All centers and investigators participating in the study should be made aware of such circumstance and invited not to disseminate information or data without the Institutions prior express consent
Metastasis is the main cause of death in cancer patients and often epithelial-to-mesenchymal transition EMT is advocated as the basic mechanism although some limitations have been identified 12 Recently Fang and colleagues described an EMT-independent process of metastasis in hepatocellular carcinoma HCC endothelium highlighted by CD34 immunohistochemistry covers small cluster of tumor cells allowing tumor dissemination 3 This process of angiogenesis named VETC vessels that encapsulate tumor clusters in HCC literature has been described under different names in other cancer types 4 Furthermore the investigators confirmed the negative impact of VETC on patients prognosis on a large multicenter cohort of HCCs 5 Moreover Fang et al demonstrated that patients affected by VETC-positive HCC benefit more from sorafenib therapy 6 Interestingly this type of angiogenesis was also found in renal cell carcinoma adrenal gland pheochromocytoma thyroid follicular carcinoma and alveolar soft part sarcoma ASPS and associated to prognosis 7-10 3435 Moreover the distinction between benign and malignant neoplasms of the adrenal gland is a complex matter being the established criteria still lacking a strong reproducibility 36
Several tyrosine kinase inhibitors are available for different cancer types among them HCC RCC ASPS and TC may benefit from the so-called antiangiogenic tyrosine kinase inhibitors aTKI such as sunitinib sorafenib pazopanib 11-14
Rationale of the study A general histotype-independent validation of the prognostic role of VETC is missing Moreover inhibitors of tyrosine-kinase vascular endothelial growth factor receptors VEGFR-TKI represent an effective treatment for different cancer types but predictive markers are still needed Moreover novel systemic immunotherapy agents are being approved in many cancer types as alternative to angiogenesis inhibitors A broader frame including metastatic mechanisms tumor microenvironment TME ie angiogenesis and immune infiltrate and treatment response could answer to several needs currently unmet Bayesian networks and causal models can be employed to effectively draw conclusions from retrospective data
Objectives of the study General objectives
1 The systematic investigation of VETC in RCC and AC in order to depict the impact of this phenomenon
2 To explore the possible role of TME and in particular of VETC in predicting a more beneficial response to VEGFR-TKIs providing a new tool in guiding the therapeutic choice
Study Design The study is monocentric observational and it will be performed on clinical and histological data collected in the course of study
For all series clinical and epidemiological features will be recorded all available histological slides will be reviewed and on the primary tumor slides histological characteristics will be re-assessed
Whenever multiple samples of tumors would be present those having the tumor-surrounding tissue interface will be selected and stained with CD34 antibody
VETC will be evaluated independently by at least two pathologists blinded to clinical data VETC will be recorded as positive or negative being VETC defined as CD34 unequivocal immunoreactivity of a continuous lining of endothelial cells around tumor clusters VETC will be considered alternative to the common capillary pattern consisting in small circular or linear blood vessels
Statistical considerations The project plans to collect data of 100 of patients who underwent surgery for RCC at our institution between 2005 and 2007 for the evaluation of VETC impact on prognosis and data of 60 patients who received sunitinib or pazopanib as first-line treatment for RCC at our center to explore if patients with VETC vascular phenotype would benefit more from the treatment with TKIs Furthermore the investigators will collect data of 20 patients who underwent surgery for AC at our Institution between 2000 and 2018
Bayesian Analysis Directed acyclic graphs will be constructed with available scientific information adjustment sets and conditional independencies will be calculated 15-17 Prior predictive simulations when relevant will be deployed to regularize the prior and reduce overfitting Continuous variables will be standardized to facilitate sampling Models will be fit using Stan a probabilistic programming language and R 1819 Stan runs a No U-Turn sampler an extension to Hamiltonian Monte Carlo HMC sampling which is itself a form of Markov Chain Monte Carlo 20-22 Four chains for 4000 iterations or 8000 whenever the bulk effective sample size will be low will be generated The final 2000 or 4000 iterations of each chain converge as indicated by post-modeling diagnostics such as the number of effective Gelman-Rubin R 23 A satisfactory posterior predictive model performance will be ensured before using sample means for estimates and sample quantiles for compatibility intervals CI 2324 CI will be calculated as 89 of the highest posterior density interval HDPI 23 Whenever more clusters of data would be present the investigators will use varying effects multilevel hierarchical models 25 To limit divergent transitions the investigators will reparameterize the models with a non-centered equivalent form 26 Predictive accuracy will be measured trough widely applicable information criteria WAIC 27
Withdrawal of subjects Missing data will be treated modeling the missingness process 28-29
Forms and procedures for collecting data and data managing To each subject will be assigned a sequential identification number For each subject data will be collected in a case report form CRF CRF will include SIN name sex date of birth date of primary surgery side size histotype relevant grading necrosis lymphovascular invasion R stage date of TKI therapy date of disease progression prognostic scores IMDC score 30 MSKCC score 31 Karnofsky score 32 first-last line data type dates of beginning and end best response progression date last follow-up status last contact death VETC All data will be registered in Microsoft Excel spreadsheet format Data are collected by the data manager and database base will be locked with a password Spaces will be filled with NA whenever a characteristic was not explored or an item is not applicable to the individual case
For AC CRF will include SIN name sex date of birth date of primary surgery side size and prognostic criteria for malignancy based on Weiss Classification mod 33
Ethical considerations Patient protection The responsible investigator will ensure that this study will be conducted in agreement with either the Declaration of Helsinki Tokyo Venice Hong Kong and Somerset West amendments or the laws and regulations of the country
The protocol has been written and the study will be conducted according to the institutional ICH Guideline for Good Clinical Practice The protocol and its annexes were subject to review and approval by the competent Independent Ethics Committees IEC
Subject identification - Personal Data protection All records identifying the subject must be kept confidential and to the extent permitted by the applicable laws andor regulations not be made publicly available The name of the patient will not be asked for nor recorded at the Data Center A sequential identification number will be automatically attributed to each patient registered in the study This number will identify the patient and must be included on all case report forms In order to avoid identification errors patient initials and date of birth will also be reported on the case report forms
Any and all patient information or documentation pertaining to a clinical trial to the extent permitting through a key kept anywhere regardless of whether such key is supplied along with the information or documentation or not must be considered as containing sensitive personal data of the patient and is therefore subjected to the provisions of applicable data protection privacy regulations Breach of such regulations may result in administrative or even criminal sanctions
Patient information or documentation may be considered anonymous and as such not subject to privacy regulations only when no key whatsoever permitting the identification of the patient is any longer available
Informed consent All patients will be informed of the aims of the study They will be informed as to the strict confidentiality of their patient data but that their medical records may be reviewed for study purposes by authorized individuals other than their treating physicianIt will be emphasized that the participation is voluntary and that the patient is allowed to refuse further participation in the protocol whenever heshe wants This will not prejudice the patients subsequent care Documented informed consent must be obtained for all patients included in the study before they are registered at the Data Center This must be done in accordance with the national and local regulatory requirements For European Union member states the informed consent procedure must conform to the ICH guidelines on Good Clinical Practice This implies that the written informed consent form should be signed and personally dated by the patient or by the patients legally acceptable representative
Conflict of Interest Any investigator andor research staff member who has a conflict of interest with this study such as patent ownership royalties or financial gain greater than the minimum allowable by their institution must fully disclose the nature of the conflict of interest
Data ownership According to the ICH Guidelines on Good Clinical Practice the sponsor of a study the Institution should the investigator or study coordinators act as sponsor in the performance of herhis institutional duties under the employment or collaboration agreement with Humanitas is the owner of the data resulting therefrom All centers and investigators participating in the study should be made aware of such circumstance and invited not to disseminate information or data without the Institutions prior express consent
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None