Ignite Creation Date:
2024-05-06 @ 12:44 PM
Last Modification Date:
2024-10-26 @ 1:03 PM
Study NCT ID:
NCT03832621
Status:
COMPLETED
Last Update Posted:
2022-04-04
First Post:
2019-01-31
Brief Title:
NIVOLUMAB Plus IPILIMUMAB and TEMOZOLOMIDE in Microsatellite Stable MGMT Silenced Metastatic Colorectal Cancer
Sponsor:
Fondazione IRCCS Istituto Nazionale dei Tumori Milano
Organization:
Fondazione IRCCS Istituto Nazionale dei Tumori Milano
Study Overview
Official Title:
NIVOLUMAB Plus IPILIMUMAB and TEMOZOLOMIDE in Combination in Microsatellite Stable MSS MGMT Silenced Metastatic Colorectal Cancer mCRC the MAYA Study
Status:
COMPLETED
Status Verified Date:
2021-09
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:
MAYA
Brief Summary:
This is a Phase II multicenter single-arm trial designed to evaluate the efficacy and safety of nivolumab NIVO ipilimumab IPI and temozolomide TMZ combination in 27 patients with MSS MGMT-silenced mCRC with initial clinical benefit following lead-in treatment with single-agent TMZ
Immune checkpoint inhibitors have been shown to trigger durable antitumor effects in a subset of patients A high number of tumor mutations so called tumor mutational burden has recently been found associated with increased immunogenicity due to a high number of neoantigens and improved treatment efficacy across several different solid tumors In mCRCs only a small fraction of tumors 5 display a high mutational load and are usually associated with inactivation of mismatch repair genes such as MLH1 MSH2 and MSH6 Checkpoint inhibitors may have increased activity in dMMRmicrosatellite instability-high MSI-H tumors a hypothesis which was tested in various Phase II trials with positive results On the opposite mismatch repair proficient colorectal cancer is unresponsive to immune checkpoint inhibitors
Previous reports indicate that acquired resistance to TMZ may emerge through the induction of a microsatellite-instability-positive phenotype and recent data showed that inactivation of MMR driven by acquired resistance to the clinical agent temozolomide increased mutational load promoted continuous renewal of neoantigens in human colorectal cancers and triggered immune surveillance in mouse models
On all of the above grounds the investigators hypothesize that treatment of microsatellite stable MGMT hypermethylated CRCs with alkylating agents could reshape the tumor genetic landscape by increasing the tumor mutational burden leading to achieve potential sensitization to immunotherapy
Immune checkpoint inhibitors have been shown to trigger durable antitumor effects in a subset of patients A high number of tumor mutations so called tumor mutational burden has recently been found associated with increased immunogenicity due to a high number of neoantigens and improved treatment efficacy across several different solid tumors In mCRCs only a small fraction of tumors 5 display a high mutational load and are usually associated with inactivation of mismatch repair genes such as MLH1 MSH2 and MSH6 Checkpoint inhibitors may have increased activity in dMMRmicrosatellite instability-high MSI-H tumors a hypothesis which was tested in various Phase II trials with positive results On the opposite mismatch repair proficient colorectal cancer is unresponsive to immune checkpoint inhibitors
Previous reports indicate that acquired resistance to TMZ may emerge through the induction of a microsatellite-instability-positive phenotype and recent data showed that inactivation of MMR driven by acquired resistance to the clinical agent temozolomide increased mutational load promoted continuous renewal of neoantigens in human colorectal cancers and triggered immune surveillance in mouse models
On all of the above grounds the investigators hypothesize that treatment of microsatellite stable MGMT hypermethylated CRCs with alkylating agents could reshape the tumor genetic landscape by increasing the tumor mutational burden leading to achieve potential sensitization to immunotherapy
Detailed Description:
In advanced CRC the occurrence of chemorefractory disease poses a major therapeutic challenge for presence of an adequate performance status to potentially receive further treatments Patients who progress after all approved treatments may be generally considered suitable for new investigational drugs or strategies Thus in the era of personalized medicine tumor molecular profiling may lead to the identification of therapeutic targets or predictive biomarkers for pharmacological intervention The DNA repair gene O6-methylguanine-DNA methyltransferase MGMT is responsible of the elimination of alkyl groups from the O6-position of guanine If inactive it may be involved in early steps of colorectal tumor genesis leading to an increase of G-to-A point mutations Epigenetic silencing of MGMT during colorectal tumor genesis is associated with hypermethylation of the CpG island in its promoter This transcriptional gene silencing is responsible for diminished DNA-repair of O6-alkylguanine adducts with the consequence of enhancing chemosensitivity to alkylating agents including dacarbazine and its oral prodrug temozolomide TMZ Previous phase II studies showed that TMZ induced an average objective response rate by RECIST criteria in 10 of heavily pre-treated patients with advanced CRC carrying MGMT promoter methylated tumors Thus MGMT methylation by methylation-specific PCR MSP used for patients screening seemed to be a necessary but not sufficient condition to identify response to TMZ Digital PCR quantification of MGMT methylation refined patients selection with benefit restricted to those with highly hyper-methylated tumors Further analysis showed that MGMT negativelow expression by immunohistochemistry IHC is found in about one third of MSP-methylated samples and is associated with increased response rate However even in responding mCRC patients acquired resistance to single agent TMZ emerges rapidly and almost invariably within 6 months from treatment initiation
Immune checkpoint inhibitors have been shown to trigger durable antitumor effects in a subset of patients A high number of tumor mutations so called tumor mutational burden has recently been found associated with increased immunogenicity due to a high number of neoantigens and improved treatment efficacy across several different solid tumors Early clinical testing indicated that only 1 of 33 CRC patients had a response to anti PD-1 treatment in contrast to substantial fractions of patients with melanomas renal-cell cancers and lung tumors who showed benefit from PD-1 blockade Similarly anti CTLA-4 treatment up today brought to unsatisfactory results in unselected mCRC patients The probability of response has been ascribed to a high mutational burden that is an elevated number of somatic mutations which translates in increased number of neo-antigens In mCRCs only a small fraction of tumors 5 display a high mutational load and are usually associated with inactivation of mismatch repair genes such as MLH1 MSH2 and MSH6 Molecular alterations in these genes occur as an initial step in colon tumor genesis leading to the microsatellite instability MSI phenotype Indeed mismatch repair-deficient dMMR colorectal cancers have 10 to 100 times as many somatic mutations as mismatch repair-proficient colorectal cancers Moreover mismatch repair-deficient cancers contain prominent lymphocyte infiltrates a finding consistent with an immune response Thus checkpoint inhibitors may have increased activity in dMMRmicrosatellite instability-high MSI-H tumors a hypothesis which was tested in various Phase II trials with positive results On the opposite mismatch repair proficient colorectal cancer is unresponsive to immune checkpoint inhibitors
Previous reports indicate that acquired resistance to TMZ may emerge through the induction of a microsatellite-instability-positive phenotype On the other hand TMZ by itself has been shown to induce an increase of mutational load in other MGMT deficient solid tumors such as melanoma or glioblastoma In parallel other studies have demonstrated that alkylating agents side effects can influence the immune cell compartment by selectively depleting the immuno-suppressive T regulator lymphocytes Tregs and activating the immuno-active T cytotoxic lymphocytes Tc and natural killers NK The investigators recently showed that inactivation of MMR driven by acquired resistance to the clinical agent temozolomide increased mutational load promoted continuous renewal of neoantigens in human colorectal cancers and triggered immune surveillance in mouse models
On all of the above grounds the investigators hypothesize that treatment of microsatellite stable MGMT hypermethylated CRCs with alkylating agents could reshape the tumor genetic landscape by increasing the tumor mutational burden either directly by inducing GA mutations orand indirectly by inactivating DNA repair genes such as MLH1 MSH2 or MSH6 which in turn could lead to hypermutated phenotype therefore enhancing formation of cancer neoantigens and immunogenicity TMZ treatment can also modulate the repertoire of immune cells Tregs Tc NK favoring T cell activation To achieve potential sensitization to immunotherapy by means of TMZ-induced MSI-like status treatment with TMZ should be active ie inducing a SDPRCR
Immune checkpoint inhibitors have been shown to trigger durable antitumor effects in a subset of patients A high number of tumor mutations so called tumor mutational burden has recently been found associated with increased immunogenicity due to a high number of neoantigens and improved treatment efficacy across several different solid tumors Early clinical testing indicated that only 1 of 33 CRC patients had a response to anti PD-1 treatment in contrast to substantial fractions of patients with melanomas renal-cell cancers and lung tumors who showed benefit from PD-1 blockade Similarly anti CTLA-4 treatment up today brought to unsatisfactory results in unselected mCRC patients The probability of response has been ascribed to a high mutational burden that is an elevated number of somatic mutations which translates in increased number of neo-antigens In mCRCs only a small fraction of tumors 5 display a high mutational load and are usually associated with inactivation of mismatch repair genes such as MLH1 MSH2 and MSH6 Molecular alterations in these genes occur as an initial step in colon tumor genesis leading to the microsatellite instability MSI phenotype Indeed mismatch repair-deficient dMMR colorectal cancers have 10 to 100 times as many somatic mutations as mismatch repair-proficient colorectal cancers Moreover mismatch repair-deficient cancers contain prominent lymphocyte infiltrates a finding consistent with an immune response Thus checkpoint inhibitors may have increased activity in dMMRmicrosatellite instability-high MSI-H tumors a hypothesis which was tested in various Phase II trials with positive results On the opposite mismatch repair proficient colorectal cancer is unresponsive to immune checkpoint inhibitors
Previous reports indicate that acquired resistance to TMZ may emerge through the induction of a microsatellite-instability-positive phenotype On the other hand TMZ by itself has been shown to induce an increase of mutational load in other MGMT deficient solid tumors such as melanoma or glioblastoma In parallel other studies have demonstrated that alkylating agents side effects can influence the immune cell compartment by selectively depleting the immuno-suppressive T regulator lymphocytes Tregs and activating the immuno-active T cytotoxic lymphocytes Tc and natural killers NK The investigators recently showed that inactivation of MMR driven by acquired resistance to the clinical agent temozolomide increased mutational load promoted continuous renewal of neoantigens in human colorectal cancers and triggered immune surveillance in mouse models
On all of the above grounds the investigators hypothesize that treatment of microsatellite stable MGMT hypermethylated CRCs with alkylating agents could reshape the tumor genetic landscape by increasing the tumor mutational burden either directly by inducing GA mutations orand indirectly by inactivating DNA repair genes such as MLH1 MSH2 or MSH6 which in turn could lead to hypermutated phenotype therefore enhancing formation of cancer neoantigens and immunogenicity TMZ treatment can also modulate the repertoire of immune cells Tregs Tc NK favoring T cell activation To achieve potential sensitization to immunotherapy by means of TMZ-induced MSI-like status treatment with TMZ should be active ie inducing a SDPRCR
Study Oversight
Has Oversight DMC:
None
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?:
None