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Circulating Tumour DNA as a Sensitive and Specific Marker of Response to Therapy and of Occult Disease in Colorectal Cancer

ABSTRACT: Interventions: This is a prospective study involving the collection of blood samples for the purposes of measuring circulating DNA from patients with resectable colorectal cancer liver metastases. Two distinct cohorts of patients, those undergoing initial liver resection followed by 12 cycles of FOLFOX and those given pre and postoperative chemotherapy will be treated and followed according to standard protocols. 60 mls of blood will be collected at specified timpoints. - 60 mls will be collected at each timepoint. COHORT 1 - Initial Surgery the timepoints are: Timepoint 1 - Screening Timepoint 2 - 4 weeks post surgery Timepoint 3 Post cycle 6 adjuvant chemotherapy (Day 1 Cycle 7) Timepoint 4 - Post cycle 12 (Days 3 at CADD disconnect) Timepoint 5 - 10 every 3 months (3 mth follow up; 6mth follow up; 12 mth follow up; 18 mth follow up and 24 mth follow up) COHORT 2 - Pre-op Chemo timpoints are: Timepoint 1 - Screening Timepoint 2 - Post cycle 1 (day 1 cycle 2) Timepoint 3 - Post cycle 2 (day 1 cycle 3) Timepoint 4 - post cycle 4 (day 1 cycle 5) Timepoint 5 - 4 weeks post surgery Timepoint 6 - Post cycle 12 (day 3 at CADD disconnect) Timepoint 7 -10 - 3 monthly follow - ups ( 3 mths; 6 mths; 9 mths; 12 mnths) Timepoint 11 & 12 - 6 monthly follow - ups (18 mths and 24 mths) Primary outcome(s): To demonstrate that the persistence of tumour DNA in peripheral blood immediately following clinically and radiologically complete resection of liver metastases is a sensitive and specific predictor of subsequent disease recurrence.[Final analysis of blood, plasma and tissue specimens. COHORT 1 - Initial Surgery the timepoints are: Timepoint 1 - Screening Timepoint 2 - 4 weeks post surgery Timepoint 3 Post cycle 6 adjuvant chemotherapy (Day 1 Cycle 7) Timepoint 4 - Post cycle 12 (Days 3 at CADD disconnect) Timepoint 5 - 10 every 3 months (3 mth follow up; 6mth follow up; 12 mth follow up; 18 mth follow up and 24 mth follow up) COHORT 2 - Pre-op Chemo timpoints are: Timepoint 1 - Screening Timepoint 2 - Post cycle 1 (day 1 cycle 2) Timepoint 3 - Post cycle 2 (day 1 cycle 3) Timepoint 4 - post cycle 4 (day 1 cycle 5) Timepoint 5 - 4 weeks post surgery Timepoint 6 - Post cycle 12 (day 3 at CADD disconnect) Timepoint 7 -10 - 3 monthly follow - ups ( 3 mths; 6 mths; 9 mths; 12 mnths) Timepoint 11 & 12 - 6 monthly follow - ups (18 mths and 24 mths)]

DISEASE(S): Cancer-bowel-back Passage (rectum) Or Large Bowel (colon),Patients With Resectable Colorectal Cancer Liver Metastases

PROVIDER: 2458057 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Interventions: This is a prospective study involving the collection of blood samples for the purposes of measuring circulating tumour DNA from two distinct cohorts of patients: COHORT A: Patients with curatively resected stage II colon cancer- subgroups will be enrolled according to whether adjuvant chemotherapy is recommended by patient’s treating oncologist. Group A - Chemotherpay; Group B - No Chemo (serial blood collection) and Group C - No chemotherapy (baseline sample). Timepoints for each group in COHORT A are as follows: Group A - 60mls of blood will be collected at 11 timepoints- Timepoint 1 - Baseline (4-8 weeks post operation) Timepoint 2 - Post 3 month of chemotherapy Timepoint 3 - Completion of chemotherapy Timepoint (4 - 11) -3 monthly follow ups post completion of treatment (3mths; 6mths; 9mths; 12mths; 15mths; 18 mths; 21 mnths and 24mths) Group B - 60mls of blood will be collected at 9 timepoints - Timepoint 1 - Baseline (4-8 weeks post operation) Timepoint (2 - 9) -3 monthly follow ups post completion of treatment (3mths; 6mths; 9mths; 12mths; 15mths; 18 mths; 21 mnths and 24mths) Group C - 60mls of blood will be collected at 1 timepoint - Timepoint 1 Baseline (4-8 weeks post operation) COHORT B - Patients with metastatic (stage IV) colorectal cancer undergoing first line chemotherapy. 60 mls of blood will be collected at 3 timepoints - Timepoint 1 - Priot to Cycle 1 Day 1 chemotherapy Timepoint 2 - Cycle 1 Day 3 chemotherapy Timepoint 3 - Cycle 2 Day 1 cemotherapy Primary outcome(s): COHORT A Stage II Colrectal Cancer - to demonstrate that persistence of tumour derived DNA in peripheral blood following complete resection of the primary tumour is a sensitive and specific arker of subsequent disease recurrence.[COHORT A - At the completion of the analysis of blood, plasma and tissue samples. COHORT A are as follows: Group A - 60mls of blood will be collected at 11 timepoints- Timepoint 1 - Baseline (4-8 weeks post operation) Timepoint 2 - Post 3 month of chemotherapy Timepoint 3 - Completion of chemotherapy Timepoint (4 - 11) -3 monthly follow ups post completion of treatment (3mths; 6mths; 9mths; 12mths; 15mths; 18 mths; 21 mnths and 24mths) Group B - 60mls of blood will be collected at 9 timepoints - Timepoint 1 - Baseline (4-8 weeks post operation) Timepoint (2 - 9) -3 monthly follow ups post completion of treatment (3mths; 6mths; 9mths; 12mths; 15mths; 18 mths; 21 mnths and 24mths) Group C - 60mls of blood will be collected at 1 timepoint - Timepoint 1 Baseline (4-8 weeks post operation)];COHORT B Stage IV Colorectal Cancer - To confirm that early changes in the level of circulating tumour DNA are a sensitive and specific marker of treatment response or resistance.[COHORT B - At the completion of the analysis of blood, plasma and tissue samples. COHORT B - Patients with metastatic (stage IV) colorectal cancer undergoing first line chemotherapy. 60 mls of blood will be collected at 3 timepoints - Timepoint 1 - Priot to Cycle 1 Day 1 chemotherapy Timepoint 2 - Cycle 1 Day 3 chemotherapy Timepoint 3 - Cycle 2 Day 1 cemotherapy] Study Design: Timing: Prospective

Project description:This is a model built by COPASI4.24(Build 197) This a model from the article: Computational design of improved standardized chemotherapy protocols for grade II oligodendrogliomas Víctor M. Pérez-García, Luis E. Ayala-Hernández, Juan Belmonte-Beitia, Philippe Schucht, Michael Murek, Andreas Raabe, Juan Sepúlveda. PLoS Comput Biol. 2019 Jul; 15(7): e1006778. Abstract: Here we put forward a mathematical model describing the response of low-grade (WHO grade II) oligodendrogliomas (LGO) to temozolomide (TMZ). The model describes the longitudinal volumetric dynamics of tumor response to TMZ of a cohort of 11 LGO patients treated with TMZ. After finding patient-specific parameters, different therapeutic strategies were tried computationally on the ‘in-silico twins’ of those patients. Chemotherapy schedules with larger-than-standard rest periods between consecutive cycles had either the same or better long-term efficacy than the standard 28-day cycles. The results were confirmed in a large trial of 2000 virtual patients. These long-cycle schemes would also have reduced toxicity and defer the appearance of resistances. On the basis of those results, a combination scheme consisting of five induction TMZ cycles given monthly plus 12 maintenance cycles given every three months was found to provide substantial survival benefits for the in-silico twins of the 11 LGO patients (median 5.69 years, range: 0.67 to 68.45 years) and in a large virtual trial including 2000 patients. We used 220 sets of experiments in-silico to show that a clinical trial incorporating 100 patients per arm (standard intensive treatment versus 5 + 12 scheme) could demonstrate the superiority of the novel scheme after a follow-up period of 10 years. Thus, the proposed treatment plan could be the basis for a standardized TMZ treatment for LGO patients with survival benefits. This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. For more information see the terms of use. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92

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Circulating Tumour DNA as a Sensitive and Specific Marker of Response to Therapy and of Occult Disease in Colorectal Cancer

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