Ignite Creation Date:
2024-05-06 @ 4:56 PM
Last Modification Date:
2024-10-26 @ 2:18 PM
Study NCT ID:
NCT05136326
Status:
RECRUITING
Last Update Posted:
2023-03-01
First Post:
2021-11-17
Brief Title:
Preoperative Chemoradiotherapy With CApecitabine and Temozolomide in MGMT Silenced MSS Locally Advanced RecTal Cancer
Sponsor:
Fondazione IRCCS Istituto Nazionale dei Tumori Milano
Organization:
Fondazione IRCCS Istituto Nazionale dei Tumori Milano
Study Overview
Official Title:
Multicenter Phase II Study of Preoperative Chemoradiotherapy With CApecitabine Plus Temozolomide in Patients With MGMT Silenced and Microsatellite Stable Locally Advanced RecTal Cancer the CATARTIC Trial
Status:
RECRUITING
Status Verified Date:
2023-02
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:
CATARTIC
Brief Summary:
In patients with locally advanced rectal cancer LARC preoperative chemo-radiotherapy CTRT is considered the standard of care Preoperative CTRT approach often results in a significant tumor downstaging and local control with evidence of complete pathological response pCR rate of about 15 in high volume institutions In high-risk LARC a new strategy called total neoadjuvant therapy TNT has emerged in which systemic chemotherapy with fluorouracil and oxaliplatin RAPIDO trial or with the triplet FOLFIRINOX as was used in the PRODIGE 23 study is incorporated before or after the administration of short-course RT or neoadjuvant CTRT and prior to surgery However given the fact that TNT may represent an overtreatment for a subset of patients additional therapeutic strategies are warranted to improve the outcomes also in patients with lower risk that are not good candidate for a TNT
In the era of personalized medicine tumor molecular profiling may lead to the identification of therapeutic targets for pharmacological intervention potentially useful to enhance treatment outcomes
O6-methylguanine-DNA-methyltransferase MGMT repairs DNA damage induced by alkylating agents and MGMT inactivation due to promoter methylation confers enhanced sensitivity to alkylating agents such as temozolomide TMZ
TMZ has modest activity in patients with MGMT-methylated pretreated metastatic colorectal cancer and responses are restricted to tumors with complete MGMT loss by immunohistochemistry IHC and microsatellite stable MSS status
Both capecitabine and temozolomide induces deoxythymidine triphosphate thymidine pool depletion might induce deoxyribonucleic acid DNA-double strand breaks and eventually apoptosis in rapidly dividing cells On the basis of such evidences there is a strong biological and clinical rationale for testing the addition of TMZ to capecitabine-based CTRT in patients with MGMT silenced and MSS technically resectable LARC
The aim of this trial is investigating whether the addition of TMZ to standard concurrent capecitabine-based long-course chemoradiation may increase pCR rate as compared to historical control in patients with locally advanced rectal cancer not candidate to TNT and molecularly selected for the presence of MGMT silencing and microsatellite stable status
In the era of personalized medicine tumor molecular profiling may lead to the identification of therapeutic targets for pharmacological intervention potentially useful to enhance treatment outcomes
O6-methylguanine-DNA-methyltransferase MGMT repairs DNA damage induced by alkylating agents and MGMT inactivation due to promoter methylation confers enhanced sensitivity to alkylating agents such as temozolomide TMZ
TMZ has modest activity in patients with MGMT-methylated pretreated metastatic colorectal cancer and responses are restricted to tumors with complete MGMT loss by immunohistochemistry IHC and microsatellite stable MSS status
Both capecitabine and temozolomide induces deoxythymidine triphosphate thymidine pool depletion might induce deoxyribonucleic acid DNA-double strand breaks and eventually apoptosis in rapidly dividing cells On the basis of such evidences there is a strong biological and clinical rationale for testing the addition of TMZ to capecitabine-based CTRT in patients with MGMT silenced and MSS technically resectable LARC
The aim of this trial is investigating whether the addition of TMZ to standard concurrent capecitabine-based long-course chemoradiation may increase pCR rate as compared to historical control in patients with locally advanced rectal cancer not candidate to TNT and molecularly selected for the presence of MGMT silencing and microsatellite stable status
Detailed Description:
Preoperative CTRT long-course radiotherapy with a recommended dose of 45-50 Gy in 25-28 fractions plus a boost with a further 54 Gy in 3 fractions and concomitant administration of oral capecitabine or continuous intravenous infusions of 5-fluorouracil is considered the standard of care in the management of LARC based on the significantly better down-staging and local control obtained by preoperative CTRT compared with radiotherapy RT alone with a consequent reduction of local recurrence rate and given its superior tolerability profile compared with postoperative treatment Preoperative CTRT approach often results in a significant tumor downstaging and local control with evidence of complete pathological response pCR rate of about 15 in high volume institutions In high-risk LARC a new strategy called total neoadjuvant therapy TNT has emerged in which systemic chemotherapy with fluorouracil and oxaliplatin RAPIDO trial or with the triplet FOLFIRINOX as was used in the PRODIGE 23 study is incorporated before or after the administration of short-course RT or neoadjuvant CTRT and prior to surgery However given the fact that TNT may represent an overtreatment for a subset of patients additional therapeutic strategies are warranted to improve the outcomes also in patients with lower risk that are not good candidate for a TNT
In the era of personalized medicine tumor molecular profiling may lead to the identification of therapeutic targets for pharmacological intervention potentially useful to enhance treatment outcomes About 30-40 of colorectal carcinomas CRCs are characterized by the promoter methylation of the O6-methylguanine-DNA-methyltransferase MGMT gene encoding a repair enzyme involved in the elimination of alkyl groups from the O6-position of guanine usually caused by alkylating agents MGMT defect due to epigenetic silencing of the MGMT gene may be involved in early steps of colorectal tumor genesis leading to an increase of G-to-A transitions and may be associated with enhanced chemosensitivity to alkylating agents including dacarbazine and its oral analogue temozolomide TMZ - as shown for melanoma and glioblastoma Previous phase II studies showed that TMZ can induce an objective response by RECIST criteria in about 10 of heavily pre-treated patients with advanced CRC carrying MGMT promoter methylated as determined by the qualitative assay methylation-specific polymerase chain reaction MSP To refine patient selection for TMZ therapy we recently showed how digital PCR quantification of MGMT methylation may further refine patient selection with benefit restricted to those with highly hyper-methylated tumors Moreover we 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 since patients with retained MGMT expression in their tumors do not benefit from TMZ therapy Therefore ongoing trials MAYA NCT03832621 ARETHUSA NCT03519412 FLIRT-bev NCT04689347 ERASE-TMZ EUDRACT2020-005437-32 select patients based on lack of MGMT expression assessed by means of IHC and presence of MGMT methylation by pyrosequencing or methylBEAMing Finally patients with microsatellite instability-high MSI-high metastatic colorectal cancer mCRC are intrinsically resistant to TMZ and therefore should be excluded by clinical trials on TMZ-based therapies Based on these data an assessment of MGMT promoter methylation coupled with absent protein expression and of the microsatellite instability status could optimize the prediction of response
Finally previous reports indicate that acquired resistance to TMZ may emerge through the induction of a MSI-like phenotype with emergence of MMR gene mutations and elevated tumor mutational burden characterized by GA transitions signature 8 according to Alexandrov et al Nature 2013 The recently completed MAYA trial NCT03832621 investigated the combination of TMZ with nivolumab and ipilimumab in patients with metastatic and chemorefractory disease however no data are available on potential synergy between RT and TMZ in inducing potential sensitization to immunotherapy of cold tumors and translational data are required
Both capecitabine and temozolomide induces deoxythymidine triphosphate Thymidine pool depletion might induce deoxyribonucleic acid DNA-double strand breaks and eventually apoptosis in rapidly dividing cells On the basis of such evidences there is a strong biological and clinical rationale for testing the addition of TMZ to capecitabine-based CTRT in patients with MGMT silenced and MSS technically resectable LARC Concurrent treatment with TMZ during RT followed by adjuvant TMZ is the standard of care for the treatment of malignant glioblastomas showing a survival benefit compared to radiation alone at the cost of a limited additional toxicity When used together to radiotherapy TMZ stabilize RT-induced double-strand breaks by producing 12-base adducts in DNA including the cytotoxic lesions O6-methylguanine and 3-methyladenine Therefore the synergy between RT and TMZ could be of particular value in patients with MGMT silenced MSS rectal cancers candidates for preoperative CTRT Therefore there is a strong rationale to investigate capecitabine plus temozolomide CAPTEM-based CTRT in this molecular subgroup
In a phase 1 study Jeong and colleagues evaluated the dose limiting toxicity DLT and the recommended dose RD of temozolomide when combined with capecitabine as preoperative CTRT in patients with molecularly unselected LARC showing that this treatment strategy is feasible and safe No dose limiting toxicities were observed in patients treated with the highest temozolomide dose level tested in the study of 75 mgm2day nor National Cancer Institute Common Terminology Criteria for Adverse Event NCI-CTCAE grade IV adverse events AEs were observed Overall the most frequent AE reported was nausea occurring in 772 of the 22 patients treated The MGMT promoter hypermethylation was detected in the 727 of patient enrolled Tumor downstaging of the primary tumor and lymph nodes was observed in 818 and 727 of patients respectively the R0 resection rate was 909 and a pCR of the primary tumor ypT0 was achieved in 318 of patients As expected the pCR rates were higher in the hypermethylated than in the unmethylated MGMT group 375 vs 167 although this difference did not reach the statistical significance odds ratio 033 95 Confidence Interval CI 003-358 p0616
The aim of this trial is investigating whether the addition of TMZ to standard concurrent capecitabine-based long-course chemoradiation may increase pCR rate as compared to historical control in patients with locally advanced rectal cancer not candidate to TNT and molecularly selected for the presence of MGMT silencing and microsatellite stable status
In the era of personalized medicine tumor molecular profiling may lead to the identification of therapeutic targets for pharmacological intervention potentially useful to enhance treatment outcomes About 30-40 of colorectal carcinomas CRCs are characterized by the promoter methylation of the O6-methylguanine-DNA-methyltransferase MGMT gene encoding a repair enzyme involved in the elimination of alkyl groups from the O6-position of guanine usually caused by alkylating agents MGMT defect due to epigenetic silencing of the MGMT gene may be involved in early steps of colorectal tumor genesis leading to an increase of G-to-A transitions and may be associated with enhanced chemosensitivity to alkylating agents including dacarbazine and its oral analogue temozolomide TMZ - as shown for melanoma and glioblastoma Previous phase II studies showed that TMZ can induce an objective response by RECIST criteria in about 10 of heavily pre-treated patients with advanced CRC carrying MGMT promoter methylated as determined by the qualitative assay methylation-specific polymerase chain reaction MSP To refine patient selection for TMZ therapy we recently showed how digital PCR quantification of MGMT methylation may further refine patient selection with benefit restricted to those with highly hyper-methylated tumors Moreover we 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 since patients with retained MGMT expression in their tumors do not benefit from TMZ therapy Therefore ongoing trials MAYA NCT03832621 ARETHUSA NCT03519412 FLIRT-bev NCT04689347 ERASE-TMZ EUDRACT2020-005437-32 select patients based on lack of MGMT expression assessed by means of IHC and presence of MGMT methylation by pyrosequencing or methylBEAMing Finally patients with microsatellite instability-high MSI-high metastatic colorectal cancer mCRC are intrinsically resistant to TMZ and therefore should be excluded by clinical trials on TMZ-based therapies Based on these data an assessment of MGMT promoter methylation coupled with absent protein expression and of the microsatellite instability status could optimize the prediction of response
Finally previous reports indicate that acquired resistance to TMZ may emerge through the induction of a MSI-like phenotype with emergence of MMR gene mutations and elevated tumor mutational burden characterized by GA transitions signature 8 according to Alexandrov et al Nature 2013 The recently completed MAYA trial NCT03832621 investigated the combination of TMZ with nivolumab and ipilimumab in patients with metastatic and chemorefractory disease however no data are available on potential synergy between RT and TMZ in inducing potential sensitization to immunotherapy of cold tumors and translational data are required
Both capecitabine and temozolomide induces deoxythymidine triphosphate Thymidine pool depletion might induce deoxyribonucleic acid DNA-double strand breaks and eventually apoptosis in rapidly dividing cells On the basis of such evidences there is a strong biological and clinical rationale for testing the addition of TMZ to capecitabine-based CTRT in patients with MGMT silenced and MSS technically resectable LARC Concurrent treatment with TMZ during RT followed by adjuvant TMZ is the standard of care for the treatment of malignant glioblastomas showing a survival benefit compared to radiation alone at the cost of a limited additional toxicity When used together to radiotherapy TMZ stabilize RT-induced double-strand breaks by producing 12-base adducts in DNA including the cytotoxic lesions O6-methylguanine and 3-methyladenine Therefore the synergy between RT and TMZ could be of particular value in patients with MGMT silenced MSS rectal cancers candidates for preoperative CTRT Therefore there is a strong rationale to investigate capecitabine plus temozolomide CAPTEM-based CTRT in this molecular subgroup
In a phase 1 study Jeong and colleagues evaluated the dose limiting toxicity DLT and the recommended dose RD of temozolomide when combined with capecitabine as preoperative CTRT in patients with molecularly unselected LARC showing that this treatment strategy is feasible and safe No dose limiting toxicities were observed in patients treated with the highest temozolomide dose level tested in the study of 75 mgm2day nor National Cancer Institute Common Terminology Criteria for Adverse Event NCI-CTCAE grade IV adverse events AEs were observed Overall the most frequent AE reported was nausea occurring in 772 of the 22 patients treated The MGMT promoter hypermethylation was detected in the 727 of patient enrolled Tumor downstaging of the primary tumor and lymph nodes was observed in 818 and 727 of patients respectively the R0 resection rate was 909 and a pCR of the primary tumor ypT0 was achieved in 318 of patients As expected the pCR rates were higher in the hypermethylated than in the unmethylated MGMT group 375 vs 167 although this difference did not reach the statistical significance odds ratio 033 95 Confidence Interval CI 003-358 p0616
The aim of this trial is investigating whether the addition of TMZ to standard concurrent capecitabine-based long-course chemoradiation may increase pCR rate as compared to historical control in patients with locally advanced rectal cancer not candidate to TNT and molecularly selected for the presence of MGMT silencing and microsatellite stable status
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
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| INT 18821 | OTHER | Fondazione IRCCS Istutituo Nazionale dei Tumori | None |