Ignite Creation Date:
2024-05-06 @ 3:36 PM
Last Modification Date:
2024-10-26 @ 1:52 PM
Study NCT ID:
NCT04689347
Status:
UNKNOWN
Last Update Posted:
2022-04-04
First Post:
2020-12-22
Brief Title:
5FULV Irinotecan Temozolomide and Bevacizumab for MGMT Silenced Microsatellite Stable Metastatic Colorectal Cancer
Sponsor:
Fondazione IRCCS Istituto Nazionale dei Tumori Milano
Organization:
Fondazione IRCCS Istituto Nazionale dei Tumori Milano
Study Overview
Official Title:
Phase 1b Trial of 5-fluorouracil Leucovorin Irinotecan in Combination With Temozolomide FLIRT and Bevacizumab for the First-line Treatment of Patients With MGMT Silenced Microsatellite Stable Metastatic Colorectal Cancer
Status:
UNKNOWN
Status Verified Date:
2022-03
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:
An upfront-intensified treatment combining all the three active cytotoxic agents in metastatic colorectal cancer mCRC including fluoropyrimidines oxaliplatin irinotecan FOLFOXIRI plus antiangiogenic blockade with bevacizumab significantly improved survival No biomarkers are available for predicting sensitivityresistance to single chemotherapeutic drugs the simultaneous delivery of all active chemotherapeutic agents might overcome resistance to single drugs
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 Clinical and preclinical synergy has been reported for combination of temozolomide with irinotecan and fluoropyrimidines Temozolomide could be regarded as a targeted chemotherapy for patients with MSS and MGMT silenced tumors In this subgroup of patients an intensified triplet upfront regimen including temozolomide fluoropyrimidines irinotecan associated with bevacizumab could be a novel combination in molecularly super-selected mCRC patients
Moving from this the investigators designed this open-label monocentric phase 1b study evaluating the safety of the combination regimen 5-fluorouracil leucovorin irinotecan temozolomide and bevacizumab in patients with MGMT silenced and MSS mCRC
The study will consist in a dose-escalation assessment of the safety of the treatment in subjects with previously untreated MGMT silenced MSS mCRC A 3 3 design will be used to assess the maximum tolerated dose MTD or maximum tested dose of the combination FLIRT-bevacizumab
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 Clinical and preclinical synergy has been reported for combination of temozolomide with irinotecan and fluoropyrimidines Temozolomide could be regarded as a targeted chemotherapy for patients with MSS and MGMT silenced tumors In this subgroup of patients an intensified triplet upfront regimen including temozolomide fluoropyrimidines irinotecan associated with bevacizumab could be a novel combination in molecularly super-selected mCRC patients
Moving from this the investigators designed this open-label monocentric phase 1b study evaluating the safety of the combination regimen 5-fluorouracil leucovorin irinotecan temozolomide and bevacizumab in patients with MGMT silenced and MSS mCRC
The study will consist in a dose-escalation assessment of the safety of the treatment in subjects with previously untreated MGMT silenced MSS mCRC A 3 3 design will be used to assess the maximum tolerated dose MTD or maximum tested dose of the combination FLIRT-bevacizumab
Detailed Description:
An upfront-intensified treatment combining all the three active cytotoxic agents in mCRC including fluoropyrimidines oxaliplatin irinotecan FOLFOXIRI plus antiangiogenic blockade with bevacizumab significantly improved progression-free survival PFS overall survival OS and objective response rate ORR compared to standard FOLFIRI and bevacizumab irrespective to RASBRAF status at price of higher rate of specific toxicities Advantages of an intensified regimen include 1 exposure to all active available drugs since more than 10-15 of patients would not receive any second-line therapy due to early performance status deterioration 2 the chance of achieving a high rate around 36 of secondary R0R1 resection of metastases in patients with liver-limited and initially unresectable liver metastases
Furthermore results from the phase 3 TRIBE2 study showed that the intensified upfront regimen FOLFOXIRI-bevacizumab followed by the pre-planned reintroduction of the same agents after progressive disease provided a statistically significant and clinically relevant survival benefit when compared with the pre-planned sequential administration of FOLFOX-bevacizumab and FOLFIRI-bevacizumab in unresectable patients with mCRC Therefore FOLFOXIRI-bevacizumab regimen is recommended by all major guidelines as one of the possible upfront treatment options for mCRC and is used in the clinical practice mainly for patients with highly aggressive disease such as those with right sided andor RAS or BRAF mutated Notably since no biomarkers are available for predicting sensitivityresistance to single chemotherapeutic drugs the simultaneous delivery of all active chemotherapeutic agents might overcome resistance to single drugs
MGMT promoter methylation is found in about 40 of colorectal tumors MGMT deficiency impairs DNA repair following administration of several alkylating agents including temozolomide Temozolomide has limited single-agent activity around 10 in patients with pretreated MGMT methylated mCRC Promising activity has been reported for temozolomide in combination with the potentially synergic drug irinotecan TEMIRI regimen in clinically and molecularly selected patients In a recent phase 2 randomized trial capecitabine in combination with temozolomide CAPTEM regimen displayed similar activity and efficacy with respect to standard FOLFIRI as second-line therapy for MGMT methylated RAS mutated mCRC
Heterogeneity of MGMT promoter methylation and residual MGMT protein expression might account for lack of activity of temozolomide in patients with MGMT promoter methylation assessed by means of a qualitative-only assay ie methylation-specific PCR MSP which has been used as selection assay for patients enrollment in published trials Exploratory analyses have consistently shown the role of quantitative assessment of MGMT promoter methylation by means of digital PCR methylBEAMing and MGMT protein expression by immunohistochemistry IHC as potential predictive factors in mCRC patients treated with temozolomide In the randomized phase 2 CAPTEM versus FOLFIRI second-line trial patients with retained MGMT positivity by IHC had poorer outcomes in terms of PFS OS and disease control rate DCR interaction test with arm P0028 Any residual MGMT protein expression has been associated with lack of response to temozolomide across different trials further supporting the restriction of temozolomide-based therapies for patients with MGMT IHC negativity coupled with gene methylation MGMT silencing
Mismatch repair deficiencymicrosatellite instability MSI has been linked to innate resistance to several alkylating chemotherapeutic agents including temozolomide since cytotoxicity of these agents strictly relies on functional mismatch repair Therefore patients with MSI-high mCRC are excluded from temozolomide-based therapy
Temozolomide could be regarded as a targeted chemotherapy for patients with MSS and MGMT silenced tumors In this subgroup of patients an intensified triplet upfront regimen including temozolomide fluoropyrimidines irinotecan associated with bevacizumab could be a novel combination in molecularly hyperselected mCRC patients
Moving from this rationale the investigators designed this phase 1b trial assessing safety recommended dose and preliminary activity of 5-fluoruracil irinotecan temozolomide and bevacizumab FLIRT-bevacizumab as a biomarker-guided initial therapy for patients with MGMT silenced and MSS mCRC
The study will consist in a dose-escalation assessment of the safety of the treatment in subjects with previously untreated MGMT silenced MSS mCRC
A 3 3 design will be used to assess the maximum tolerated dose MTD or maximum tested dose of the combination FLIRT-bevacizumab
The MTD will be defined as the dose level at which 23 or 26 subjects experience a dose-limiting toxicity DLT When the MTD or maximum tested dose has been determined or reached the RP2D to be tested in a future phase II trial will be one dose level below the MTD or the maximum tested dose if MTD will not be reached At least 6 patients should be treated at the RD during the dose escalation
The treatment will consist of an induction period of four 28-day cycles of FLIRT- bevacizumab followed by maintenance regimen of 5-FULV-bevacizumab administered every 14 days in combination with per os temozolomide according to dose level over days 1-5 every 28 days in patients without progressive disease at the end of the induction period Patients will undergo tumor assessment at baseline and every 8 1 weeks until confirmed disease progression unacceptable toxicity withdrawal of consent death whichever occurs first The treatment will continue until progressive disease unacceptable toxicities or consent withdrawal
Furthermore results from the phase 3 TRIBE2 study showed that the intensified upfront regimen FOLFOXIRI-bevacizumab followed by the pre-planned reintroduction of the same agents after progressive disease provided a statistically significant and clinically relevant survival benefit when compared with the pre-planned sequential administration of FOLFOX-bevacizumab and FOLFIRI-bevacizumab in unresectable patients with mCRC Therefore FOLFOXIRI-bevacizumab regimen is recommended by all major guidelines as one of the possible upfront treatment options for mCRC and is used in the clinical practice mainly for patients with highly aggressive disease such as those with right sided andor RAS or BRAF mutated Notably since no biomarkers are available for predicting sensitivityresistance to single chemotherapeutic drugs the simultaneous delivery of all active chemotherapeutic agents might overcome resistance to single drugs
MGMT promoter methylation is found in about 40 of colorectal tumors MGMT deficiency impairs DNA repair following administration of several alkylating agents including temozolomide Temozolomide has limited single-agent activity around 10 in patients with pretreated MGMT methylated mCRC Promising activity has been reported for temozolomide in combination with the potentially synergic drug irinotecan TEMIRI regimen in clinically and molecularly selected patients In a recent phase 2 randomized trial capecitabine in combination with temozolomide CAPTEM regimen displayed similar activity and efficacy with respect to standard FOLFIRI as second-line therapy for MGMT methylated RAS mutated mCRC
Heterogeneity of MGMT promoter methylation and residual MGMT protein expression might account for lack of activity of temozolomide in patients with MGMT promoter methylation assessed by means of a qualitative-only assay ie methylation-specific PCR MSP which has been used as selection assay for patients enrollment in published trials Exploratory analyses have consistently shown the role of quantitative assessment of MGMT promoter methylation by means of digital PCR methylBEAMing and MGMT protein expression by immunohistochemistry IHC as potential predictive factors in mCRC patients treated with temozolomide In the randomized phase 2 CAPTEM versus FOLFIRI second-line trial patients with retained MGMT positivity by IHC had poorer outcomes in terms of PFS OS and disease control rate DCR interaction test with arm P0028 Any residual MGMT protein expression has been associated with lack of response to temozolomide across different trials further supporting the restriction of temozolomide-based therapies for patients with MGMT IHC negativity coupled with gene methylation MGMT silencing
Mismatch repair deficiencymicrosatellite instability MSI has been linked to innate resistance to several alkylating chemotherapeutic agents including temozolomide since cytotoxicity of these agents strictly relies on functional mismatch repair Therefore patients with MSI-high mCRC are excluded from temozolomide-based therapy
Temozolomide could be regarded as a targeted chemotherapy for patients with MSS and MGMT silenced tumors In this subgroup of patients an intensified triplet upfront regimen including temozolomide fluoropyrimidines irinotecan associated with bevacizumab could be a novel combination in molecularly hyperselected mCRC patients
Moving from this rationale the investigators designed this phase 1b trial assessing safety recommended dose and preliminary activity of 5-fluoruracil irinotecan temozolomide and bevacizumab FLIRT-bevacizumab as a biomarker-guided initial therapy for patients with MGMT silenced and MSS mCRC
The study will consist in a dose-escalation assessment of the safety of the treatment in subjects with previously untreated MGMT silenced MSS mCRC
A 3 3 design will be used to assess the maximum tolerated dose MTD or maximum tested dose of the combination FLIRT-bevacizumab
The MTD will be defined as the dose level at which 23 or 26 subjects experience a dose-limiting toxicity DLT When the MTD or maximum tested dose has been determined or reached the RP2D to be tested in a future phase II trial will be one dose level below the MTD or the maximum tested dose if MTD will not be reached At least 6 patients should be treated at the RD during the dose escalation
The treatment will consist of an induction period of four 28-day cycles of FLIRT- bevacizumab followed by maintenance regimen of 5-FULV-bevacizumab administered every 14 days in combination with per os temozolomide according to dose level over days 1-5 every 28 days in patients without progressive disease at the end of the induction period Patients will undergo tumor assessment at baseline and every 8 1 weeks until confirmed disease progression unacceptable toxicity withdrawal of consent death whichever occurs first The treatment will continue until progressive disease unacceptable toxicities or consent withdrawal
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