Ignite Creation Date:
2024-05-06 @ 4:36 PM
Last Modification Date:
2024-10-26 @ 2:12 PM
Study NCT ID:
NCT05031975
Status:
UNKNOWN
Last Update Posted:
2022-09-02
First Post:
2021-08-24
Brief Title:
Temozolomide and Irinotecan in Patients With MGMT Silenced Colorectal Cancer After Adjuvant Chemotherapy
Sponsor:
Fondazione IRCCS Istituto Nazionale dei Tumori Milano
Organization:
Fondazione IRCCS Istituto Nazionale dei Tumori Milano
Study Overview
Official Title:
Temozolomide and Irinotecan Consolidation in Patients With MGMT Silenced Microsatellite Stable Colorectal Cancer With Persistence of Minimal Residual Disease in Liquid Biopsy After Standard Adjuvant Chemotherapy the ERASE-TMZ Study
Status:
UNKNOWN
Status Verified Date:
2022-08
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:
ERASE-TMZ
Brief Summary:
Surgical resection is curative for 75 of stage II and 50 of stage III colon cancer patients The magnitude of benefit of adjuvant chemotherapy in terms of disease-free DFS and overall survival OS varies according to TNM stage and microsatellite status Standard adjuvant chemotherapy includes fluoropyrimidine and oxaliplatin regimens for up to six months
Circulating tumor DNA ctDNA detected after surgical resection reflects the presence of micrometastatic disease and pivotal observational studies addressed the prognostic value of ctDNA in the post-surgical setting Adjuvant chemotherapy can promote the clearance of ctDNA and ctDNA clearance after adjuvant chemotherapy is prognostic for better DFS in patients with stage III resected cancers and post-operative positive ctDNA
ctDNA may be investigated as a potential real-time surrogate biomarker of the efficacy of adjuvant therapy but suggest that patients with ctDNA persistence after standard chemotherapy might be molecularly metastatic and may benefit from additional consolidation non-cross resistant strategies aimed at clearing micrometastatic disease
Temozolomide has modest but non-negligible activity about 10 in chemo-refractory patients with MGMT methylated mCRC The response rate to temozolomide-based therapy in pretreated patients is increased to up to 20 when restricting the focus on those with MGMT IHC-negativeMGMT methylated and MSS cancers Significant activity ORR 26 and favorable safety profile were reported by the combination of temozolomide and irinotecan TEMIRI regimen in patients with pretreated MGMT methylatedMSS mCRC thus suggesting that the two agents may have synergist activity in line with preclinical data
Based on all these considerations there is a strong rationale for investigating TEMIRI regimen as consolidation non-cross resistant therapy in a liquid-biopsy driven interventional trial
Eligible patients with MGMT-silenced MSS radically resected CRC and detectable ctDNA after standard chemotherapy will be enrolled and will receive 6-month post-adjuvantconsolidation TEMIRI given for up to 6 monthly cycles
Circulating tumor DNA ctDNA detected after surgical resection reflects the presence of micrometastatic disease and pivotal observational studies addressed the prognostic value of ctDNA in the post-surgical setting Adjuvant chemotherapy can promote the clearance of ctDNA and ctDNA clearance after adjuvant chemotherapy is prognostic for better DFS in patients with stage III resected cancers and post-operative positive ctDNA
ctDNA may be investigated as a potential real-time surrogate biomarker of the efficacy of adjuvant therapy but suggest that patients with ctDNA persistence after standard chemotherapy might be molecularly metastatic and may benefit from additional consolidation non-cross resistant strategies aimed at clearing micrometastatic disease
Temozolomide has modest but non-negligible activity about 10 in chemo-refractory patients with MGMT methylated mCRC The response rate to temozolomide-based therapy in pretreated patients is increased to up to 20 when restricting the focus on those with MGMT IHC-negativeMGMT methylated and MSS cancers Significant activity ORR 26 and favorable safety profile were reported by the combination of temozolomide and irinotecan TEMIRI regimen in patients with pretreated MGMT methylatedMSS mCRC thus suggesting that the two agents may have synergist activity in line with preclinical data
Based on all these considerations there is a strong rationale for investigating TEMIRI regimen as consolidation non-cross resistant therapy in a liquid-biopsy driven interventional trial
Eligible patients with MGMT-silenced MSS radically resected CRC and detectable ctDNA after standard chemotherapy will be enrolled and will receive 6-month post-adjuvantconsolidation TEMIRI given for up to 6 monthly cycles
Detailed Description:
Surgical resection is curative for 75 of stage II and 50 of stage III colon cancer patients The magnitude of benefit of adjuvant chemotherapy in terms of disease-free DFS and overall survival OS varies according to TNM stage and microsatellite status Specifically in patients with stage II microsatellite stable MSS tumors and high risk clinical features ie pT4 lymphovascular invasion perineural invasion bowel obstruction positive surgical margins and inadequately sampled lymph nodes adjuvant therapy with fluoropyrimidines conditioned a modest but significant DFS benefit while oxaliplatin-based therapy may be offered to patients with poor prognosis such as those with pT4 disease In patients with stage III disease adjuvant therapy with oxaliplatin and fluoropyrimidine combinations significantly improved DFS and OS in phase 3 randomized trials However oxaliplatin is burdened by dose-cumulative and potentially long-lasting neurotoxicity Therefore three-month duration of oxaliplatin-based chemotherapy was compared to six-month in six randomized trials including patients with resected stage IIIII colon cancer In the pooled analysis of such trials IDEA Collaboration the non-inferiority for DFS of three months adjuvant oxaliplatin-based chemotherapy was not formally demonstrated However absolute DFS loss with 3- month therapy was clearly unsignificant from a clinical point-of-view and 3-month duration of oxaliplatin-based adjuvant chemotherapy is now recommended in patients with low risk disease pT3N1 and particularly when adopting a capecitabine-based regimen CAPOX
Circulating tumor DNA ctDNA detected after surgical resection reflects the presence of micrometastatic disease and pivotal observational studies addressed the prognostic value of ctDNA in the post-surgical setting Detectable ctDNA after surgery is prognostic for DFS in patients with resected colon cancer with high specificity in predicting recurrence -100 reinforcing its promising role for guiding trials on post-surgical intensification strategies but ctDNA is also endowed with suboptimal sensitivity 70 thus limiting its potential usefulness to guide the complete omission of adjuvant chemotherapy Regarding the impact of adjuvant chemotherapy on micrometastatic disease adjuvant chemotherapy was able to clear ctDNA in individual patients with resected stage II tumors Moreover ctDNA clearance after adjuvant chemotherapy was prognostic for better DFS in patients with stage III resected cancers and post-operative positive ctDNA Collectively these data highlight that ctDNA may be investigated as a potential real-time surrogate biomarker of the efficacy of adjuvant therapy but suggest that patients with ctDNA persistence after standard chemotherapy might be molecularly metastatic and may benefit from additional consolidation non-cross resistant strategies aimed at clearing micrometastatic disease
Temozolomide displayed limited activity overall response rate ORR 9 in patients with heavily pretreated metastatic colorectal cancer mCRC with MGMT promoter methylation assessed by means of a qualitative assay - methylation-specific PCR However even if MGMT promoter methylation is found in up to 40 of patients with colorectal cancer in-silico analyses and translational analyses showed that only a subset of these tumors - 10 of all comers display lack of MGMT expression and negative MGMT IHC staining In keeping with findings correlative studies of phase 2 trials showed that MGMT immunohistochemical negativity and higher MGMT methylation by quantitative assays are associated with temozolomide activity Finally proficiency of the mismatch repair is needed for alkylators activity Therefore temozolomide might be considered a tailored chemotherapy in patients with MGMT silenced tumors ie those with MGMT negative expression and MGMT promoter methylation and microsatellite stable MSS tumors Significant activity ORR 26 and favorable safety profile were reported by the combination of temozolomide and irinotecan TEMIRI regimen in patients with pretreated MGMT methylatedMSS mCRC thus suggesting that the two agents may have synergist activity in line with preclinical data
Moving from this rationale we designed a phase 2 proof-of-concept trial aimed at evaluating the activity in terms of ctDNA clearance or seroreversion after TEMIRI regimen as a post-adjuvant strategy in patients with MGMT silenced MSS colorectal cancer CRC with positive ctDNA after oxaliplatin-based adjuvant standard chemotherapy
Eligible patients with MGMT-silenced MSS radically resected CRC and detectable ctDNA after standard chemotherapy will be enrolled and will receive 6-month post-adjuvantconsolidation TEMIRI given for up to 6 monthly cycles
Circulating tumor DNA ctDNA detected after surgical resection reflects the presence of micrometastatic disease and pivotal observational studies addressed the prognostic value of ctDNA in the post-surgical setting Detectable ctDNA after surgery is prognostic for DFS in patients with resected colon cancer with high specificity in predicting recurrence -100 reinforcing its promising role for guiding trials on post-surgical intensification strategies but ctDNA is also endowed with suboptimal sensitivity 70 thus limiting its potential usefulness to guide the complete omission of adjuvant chemotherapy Regarding the impact of adjuvant chemotherapy on micrometastatic disease adjuvant chemotherapy was able to clear ctDNA in individual patients with resected stage II tumors Moreover ctDNA clearance after adjuvant chemotherapy was prognostic for better DFS in patients with stage III resected cancers and post-operative positive ctDNA Collectively these data highlight that ctDNA may be investigated as a potential real-time surrogate biomarker of the efficacy of adjuvant therapy but suggest that patients with ctDNA persistence after standard chemotherapy might be molecularly metastatic and may benefit from additional consolidation non-cross resistant strategies aimed at clearing micrometastatic disease
Temozolomide displayed limited activity overall response rate ORR 9 in patients with heavily pretreated metastatic colorectal cancer mCRC with MGMT promoter methylation assessed by means of a qualitative assay - methylation-specific PCR However even if MGMT promoter methylation is found in up to 40 of patients with colorectal cancer in-silico analyses and translational analyses showed that only a subset of these tumors - 10 of all comers display lack of MGMT expression and negative MGMT IHC staining In keeping with findings correlative studies of phase 2 trials showed that MGMT immunohistochemical negativity and higher MGMT methylation by quantitative assays are associated with temozolomide activity Finally proficiency of the mismatch repair is needed for alkylators activity Therefore temozolomide might be considered a tailored chemotherapy in patients with MGMT silenced tumors ie those with MGMT negative expression and MGMT promoter methylation and microsatellite stable MSS tumors Significant activity ORR 26 and favorable safety profile were reported by the combination of temozolomide and irinotecan TEMIRI regimen in patients with pretreated MGMT methylatedMSS mCRC thus suggesting that the two agents may have synergist activity in line with preclinical data
Moving from this rationale we designed a phase 2 proof-of-concept trial aimed at evaluating the activity in terms of ctDNA clearance or seroreversion after TEMIRI regimen as a post-adjuvant strategy in patients with MGMT silenced MSS colorectal cancer CRC with positive ctDNA after oxaliplatin-based adjuvant standard chemotherapy
Eligible patients with MGMT-silenced MSS radically resected CRC and detectable ctDNA after standard chemotherapy will be enrolled and will receive 6-month post-adjuvantconsolidation TEMIRI given for up to 6 monthly cycles
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