Ignite Creation Date:
2024-06-16 @ 11:51 AM
Last Modification Date:
2024-10-26 @ 3:31 PM
Study NCT ID:
NCT06446557
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-06-06
First Post:
2024-02-26
Brief Title:
De-scalation or swItch of Treatment According to Circulating tuMOr DNA Variation After 2 Cycles of Doublet Chemotherapy Plus Targeted Agent in Metastatic Unresectable Colorectal Cancer
Sponsor:
University Hospital Rouen
Organization:
University Hospital Rouen
Study Overview
Official Title:
De-scalation or swItch of Treatment According to Circulating tuMOr DNA Variation After 2 Cycles of Doublet Chemotherapy Plus Targeted Agent in Metastatic Unresectable Colorectal Cancer DIAMOND Study A Randomized Phase III of PRODIGE Intergroup
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-02
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:
DIAMOND
Brief Summary:
Background In unresectable mCRC a de-escalation strategy using maintenance or chemotherapy CT discontinuation in selected cases is considered as a valid option in non-progressive patients after a first-line induction of doublet CT targeted agent TA 1-7
In this context circulating tumor DNA ctDNA is considered very promising to optimize decision making Indeed ctDNA harbour the same main alterations of the tumor and has been recognized as biologically relevant to reflect tumor dynamics and therapeutic efficacy 8
As we and other groups reported in mCRC that early variation of ctDNA during CT may be relevant to predict outcome 9-11 Indeed patients with a ctDNA decrease from the first C1 to the third C3 cycles of CT 80 or ctDNA01 ngml at C3 or without ctDNA detectable at C1 and C3 have significant better survival as compared to patients with less decrease or with ctDNA increase 10 ctDNA monitoring had never been prospectively evaluated to guide early adaptation in the treatment strategy in mCRC
Aim A randomized phase III open label strategy trial of the superiority in overall survival OS adjusted on quality of life of an early treatment adaptation guided by ctDNA variation versus a standard management in unresectable left-side MSS-BRAFV600E non-mutated mCRC treated by first-line doublet CT TA
Patients and methods
-Main inclusion criteria will be i unresectable left-side and non-pre-treated mCRC ii MSS and non-mutated BRAFV600E tumor iii at least one measurable lesion iv ECOG 0-1 and adequate biological functions for first-line doublet CT TA antiEGFR if RAS WT bevacizumab BV if RAS MUT
Randomization 11 between an experimental strategy guided by ctDNA variation with de-escalation Arm A1 or A2 or switch of treatment Arm A3 versus standard strategy Arm B The analysis of variation of ctDNA from C1-C3 will be centralized and detected using Digital PCR targeting hypermethylation of WIF1NPY genes 10 in real-time in arm A and in second step in arm B
Randomization in Arm A after 4 cycles of doublet TA non-progressive patients will be allocated to a strategy according to ctDNA value and variation from C1-C3
Arm A1 CT discontinuation ctDNA normalization 01 ngml or ctDNA not detectable Arm A2 maintenance with fluoropyrimidine TA ctDNA 01 ngml and ctDNA 80
Arm A3 ctDNA non-responders ctDNA 80 or increase switch of CT - TA
Randomisation in Arm B at least 8 cycles of doublet CT TA before adaptation of sequence at physician choice
Statistical considerations with an expected median OS at 32 months mean 376 months a mean QoL at 700 in first-line mCRC corresponding to 0700 x 376 263 QALM or 219 QALY SD 118 QALY 408 patients are required randomization 11 to show a gain of 4 months of quality-adjusted OS 4 QALM or 033 QALY in experimental ctDNA strategy versus standard strategy 5 two-sided type I error rate 81 power and 118 QALY SD
The secondary objectives will be
To compare strategies standard vs ctDNA guided overall and in the subgroups of ctDNA response on 18 24 and 36-months restricted mean of QoL-adjusted OS OS PFS response rate toxicity Quality of Life and cost utility
Bio-collection for further ctDNA analysis Only cost of samples collection and their transportation to the resource center is requested Further ancillary analysis will be subject to independent funding requests to evaluate
ctDNA kinetics during the induction and its impact on outcome in overall population and in each arm
ctDNA changes between time points during de-escalation arms to determine thresholds of variations predictive of clinical andor radiological progression
Conclusion DIAMOND is a randomized phase III strategy trial to show the superiority in OS adjusted on quality of life of an early treatment adaptation guided by ctDNA versus a standard management in unresectable left-side MSS-BRAFV600E non-mutated mCRC treated by first-line doublet CT TA
In this context circulating tumor DNA ctDNA is considered very promising to optimize decision making Indeed ctDNA harbour the same main alterations of the tumor and has been recognized as biologically relevant to reflect tumor dynamics and therapeutic efficacy 8
As we and other groups reported in mCRC that early variation of ctDNA during CT may be relevant to predict outcome 9-11 Indeed patients with a ctDNA decrease from the first C1 to the third C3 cycles of CT 80 or ctDNA01 ngml at C3 or without ctDNA detectable at C1 and C3 have significant better survival as compared to patients with less decrease or with ctDNA increase 10 ctDNA monitoring had never been prospectively evaluated to guide early adaptation in the treatment strategy in mCRC
Aim A randomized phase III open label strategy trial of the superiority in overall survival OS adjusted on quality of life of an early treatment adaptation guided by ctDNA variation versus a standard management in unresectable left-side MSS-BRAFV600E non-mutated mCRC treated by first-line doublet CT TA
Patients and methods
-Main inclusion criteria will be i unresectable left-side and non-pre-treated mCRC ii MSS and non-mutated BRAFV600E tumor iii at least one measurable lesion iv ECOG 0-1 and adequate biological functions for first-line doublet CT TA antiEGFR if RAS WT bevacizumab BV if RAS MUT
Randomization 11 between an experimental strategy guided by ctDNA variation with de-escalation Arm A1 or A2 or switch of treatment Arm A3 versus standard strategy Arm B The analysis of variation of ctDNA from C1-C3 will be centralized and detected using Digital PCR targeting hypermethylation of WIF1NPY genes 10 in real-time in arm A and in second step in arm B
Randomization in Arm A after 4 cycles of doublet TA non-progressive patients will be allocated to a strategy according to ctDNA value and variation from C1-C3
Arm A1 CT discontinuation ctDNA normalization 01 ngml or ctDNA not detectable Arm A2 maintenance with fluoropyrimidine TA ctDNA 01 ngml and ctDNA 80
Arm A3 ctDNA non-responders ctDNA 80 or increase switch of CT - TA
Randomisation in Arm B at least 8 cycles of doublet CT TA before adaptation of sequence at physician choice
Statistical considerations with an expected median OS at 32 months mean 376 months a mean QoL at 700 in first-line mCRC corresponding to 0700 x 376 263 QALM or 219 QALY SD 118 QALY 408 patients are required randomization 11 to show a gain of 4 months of quality-adjusted OS 4 QALM or 033 QALY in experimental ctDNA strategy versus standard strategy 5 two-sided type I error rate 81 power and 118 QALY SD
The secondary objectives will be
To compare strategies standard vs ctDNA guided overall and in the subgroups of ctDNA response on 18 24 and 36-months restricted mean of QoL-adjusted OS OS PFS response rate toxicity Quality of Life and cost utility
Bio-collection for further ctDNA analysis Only cost of samples collection and their transportation to the resource center is requested Further ancillary analysis will be subject to independent funding requests to evaluate
ctDNA kinetics during the induction and its impact on outcome in overall population and in each arm
ctDNA changes between time points during de-escalation arms to determine thresholds of variations predictive of clinical andor radiological progression
Conclusion DIAMOND is a randomized phase III strategy trial to show the superiority in OS adjusted on quality of life of an early treatment adaptation guided by ctDNA versus a standard management in unresectable left-side MSS-BRAFV600E non-mutated mCRC treated by first-line doublet CT TA
Detailed Description:
None
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