Ignite Creation Date:
2025-12-26 @ 10:58 AM
Ignite Modification Date:
2025-12-31 @ 6:35 PM
Study NCT ID:
NCT02960906
Status:
COMPLETED
Last Update Posted:
2021-04-26
First Post:
2016-08-18
Is NOT Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
A BIOmarker Driven Trial With Nivolumab and Ipilimumab or VEGFR tKi in Naïve Metastatic Kidney Cancer
Sponsor:
Association Pour La Recherche des Thérapeutiques Innovantes en Cancérologie
Organization:
Study Overview
Official Title:
A Phase 2 BIOmarker Driven Trial With Nivolumab and Ipilimumab or VEGFR tKi in Naïve Metastatic Kidney Cancer
Status:
COMPLETED
Status Verified Date:
2021-04
Last Known Status:
None
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:
BIONIKK
Brief Summary:
Disease and Stage: naïve metastatic kidney cancer.
A multicenter, randomized, a Phase 2 BIOmarker driven trial with Nivolumab and Ipilimumab or VEGFR tKi in naïve metastatic Kidney cancer
A multicenter, randomized, a Phase 2 BIOmarker driven trial with Nivolumab and Ipilimumab or VEGFR tKi in naïve metastatic Kidney cancer
Detailed Description:
Research Hypothesis: Molecular groups of ccrcc will define patients who will respond to nivolumab alone, nivolumab combined with ipilimumab, or VEGFR-TKI (sunitinib or pazopanib) in subjects with previously untreated metastatic renal cell carcinoma (mRCC).
Conditions:
* Advanced or metastatic RCC: previously untreated in metastatic setting.
* Frozen tumor samples available for molecular group determination.
* Determination of molecular subgroup prior to randomization.
Product(s):
* ARM A: nivolumab alone administered IV over 60 minutes at 240 mg every 2 weeks (molecular group 1 and 4).
* ARM B : Nivolumab administered IV over 60 minutes at 3 mg/kg combined with ipilimumab administered IV over 30 minutes at 1 mg/kg every 3 weeks for 4 doses followed by nivolumab administered IV over 60 minutes at 240 mg every 2 weeks
starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference (Arm A and B),
\- ARM C: TKI (molecular group 2 and 3), pazopanib or sunitinib according to investigator's choice until disease progression, unacceptable toxicity or other reasons specified in the protocol.
Biological assessments:
Molecular groups (1 to 4) will be determined for all patients from frozen tumor tissue samples or from fresh tumor samples immediately stored in "RNA later" medium.
Further exploratory biological assessments will be performed in order to define predictive biomarkers of response to N+I, N alone or TKI (sunitinib or pazopanib) by analyzing tumor specimens and blood samples:
* To assess gene expression of immune population markers in the primary tumor as well as in the metastases before beginning treatment, and at progression if safely achievable.
* Gene expression analysis will be performed from frozen and FFPE tumor tissue in order to compare the two methods.
* To assess the density and phenotype of selected immune populations (CD8, CD3/CD20, PD-1, TIM-3, LAG3, FoxP3) as well as the phenotype of tumor cells (PD-L1, PD-L2) by immunohistochemistry (IHC) in the primary tumor and metastases, before treatment initiation and at progression if safely achievable.
* To assess the functional status of peripheral blood lymphocytes (PBL) by flow cytometry, before treatment initiation, during treatment, and at progression.
* To quantify plasmatic angiogenesis-related (i.e. VEGF-A, VEGF-C its soluble receptors VEGFR-1 and 2 and co-receptors neuropilin 1 and 2, angiopoietins, SDF-1, PDGFs…)) and endothelial cell-derived molecules (i.e. endoglin, VE-cadherin) before treatment initiation, during treatment, and at progression.
* To correlate plasmatic angiogenesis-related molecules with tumor vascularization studied by immunofluorescence (IF) and a multi-spectral analyzer (Vectra technology) on tumor tissue.
* To investigate a predictive role of the response of CXCL7 and sCD146 to TKI, nivolumab and/or nivolumab+ipilimumab.
* To determine whether the mutation and methylation analysis of circulating tumor DNA can be used as predictive biomarker of response, resistance to treatment or progression.
* Identify genetic and epigenetic alterations associated with either response or resistance to immune checkpoint inhibitors and tyrosine kinase inhibitors
* Evaluate association between immune cells composing tumor microenvironment and response and/or resistance to immune checkpoint inhibitors or tyrosine kinase inhibitors
* Evaluate additional genetic and epigenetic tumor alterations at resistance/progression or after resection of residual mass.
Statistical Considerations:
An adaptative design will be used to ensure that conclusions can be made with a limited number of patients in each molecular group, which is the major constraint of the study.
Sample Size: Approximately 150 patients are planned to be treated. Given an expected failure rate of molecular grouping of less than 20%, 150-200 patients must be included.
Conditions:
* Advanced or metastatic RCC: previously untreated in metastatic setting.
* Frozen tumor samples available for molecular group determination.
* Determination of molecular subgroup prior to randomization.
Product(s):
* ARM A: nivolumab alone administered IV over 60 minutes at 240 mg every 2 weeks (molecular group 1 and 4).
* ARM B : Nivolumab administered IV over 60 minutes at 3 mg/kg combined with ipilimumab administered IV over 30 minutes at 1 mg/kg every 3 weeks for 4 doses followed by nivolumab administered IV over 60 minutes at 240 mg every 2 weeks
starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference (Arm A and B),
\- ARM C: TKI (molecular group 2 and 3), pazopanib or sunitinib according to investigator's choice until disease progression, unacceptable toxicity or other reasons specified in the protocol.
Biological assessments:
Molecular groups (1 to 4) will be determined for all patients from frozen tumor tissue samples or from fresh tumor samples immediately stored in "RNA later" medium.
Further exploratory biological assessments will be performed in order to define predictive biomarkers of response to N+I, N alone or TKI (sunitinib or pazopanib) by analyzing tumor specimens and blood samples:
* To assess gene expression of immune population markers in the primary tumor as well as in the metastases before beginning treatment, and at progression if safely achievable.
* Gene expression analysis will be performed from frozen and FFPE tumor tissue in order to compare the two methods.
* To assess the density and phenotype of selected immune populations (CD8, CD3/CD20, PD-1, TIM-3, LAG3, FoxP3) as well as the phenotype of tumor cells (PD-L1, PD-L2) by immunohistochemistry (IHC) in the primary tumor and metastases, before treatment initiation and at progression if safely achievable.
* To assess the functional status of peripheral blood lymphocytes (PBL) by flow cytometry, before treatment initiation, during treatment, and at progression.
* To quantify plasmatic angiogenesis-related (i.e. VEGF-A, VEGF-C its soluble receptors VEGFR-1 and 2 and co-receptors neuropilin 1 and 2, angiopoietins, SDF-1, PDGFs…)) and endothelial cell-derived molecules (i.e. endoglin, VE-cadherin) before treatment initiation, during treatment, and at progression.
* To correlate plasmatic angiogenesis-related molecules with tumor vascularization studied by immunofluorescence (IF) and a multi-spectral analyzer (Vectra technology) on tumor tissue.
* To investigate a predictive role of the response of CXCL7 and sCD146 to TKI, nivolumab and/or nivolumab+ipilimumab.
* To determine whether the mutation and methylation analysis of circulating tumor DNA can be used as predictive biomarker of response, resistance to treatment or progression.
* Identify genetic and epigenetic alterations associated with either response or resistance to immune checkpoint inhibitors and tyrosine kinase inhibitors
* Evaluate association between immune cells composing tumor microenvironment and response and/or resistance to immune checkpoint inhibitors or tyrosine kinase inhibitors
* Evaluate additional genetic and epigenetic tumor alterations at resistance/progression or after resection of residual mass.
Statistical Considerations:
An adaptative design will be used to ensure that conclusions can be made with a limited number of patients in each molecular group, which is the major constraint of the study.
Sample Size: Approximately 150 patients are planned to be treated. Given an expected failure rate of molecular grouping of less than 20%, 150-200 patients must be included.
Study Oversight
Has Oversight DMC:
True
Is a FDA Regulated Drug?:
False
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?: