IMPROVE-IT2: ctDNA-guided Surveillance for Stage III CRC, a Randomized Intervention Trial

Study Overview
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Brief Summary
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IMPROVE-IT2 is a randomized multicenter trial comparing the outcomes of ctDNA guided post-operative surveillance and standard-of-care CT-scan surveillance. The hypothesis of this study is that ctDNA guided post-operative surveillance combining ctDNA and radiological assessments could result in earlier detection of recurrent disease and identify more patients eligible for curative treatment.

Official Title
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Implementing Non-invasive Circulating Tumor DNA Analysis to Optimize the Operative and Postoperative Treatment for Patients With Colorectal Cancer - Intervention Trial 2

Conditions
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Colorectal Cancer, Colo-rectal Cancer, ctDNA, Gastro-Intestinal Disorder, Colorectal Neoplasms, Gastrointestinal Cancer, Gastrointestinal Neoplasms, Digestive System Disease, Digestive System Neoplasm, Colonic Diseases, Colonic Neoplasms, Colonic Cancer, Rectal Diseases, Rectal Neoplasms, Rectal Cancer

Intervention / Treatment
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* Diagnostic Test: ctDNA-analysis
* Other: Intensified Follow-up Schedule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Colon or rectal cancer, tumor stage III (pT1-4N1-2,cM0) or stage II high-risk (pT4N0,cM0 and pT3N0, cM0 with risk factors) Have received curative intend resection and be candidates for adjuvant chemotherapy Exclusion Criteria: Not treated with adjuvant chemotherapy Synchronous colorectal and non-colorectal cancer diagnosed per-operative (except skin cancer other than melanoma) Other cancers (excluding colorectal cancer or skin cancer other than melanoma) within 3 years from screening Patients who are unlikely to comply with the protocol (e.g. uncooperative attitude), inability to return for subsequent visits) and/or otherwise considered by the Investigator to be unlikely to complete the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ctDNA guided surveillance<br>ctDNA analysis will be performed every 4 months postoperatively (4, 8, 12, 16, 20 and 24). At time of first positive ctDNA, patients undergo a whole-body FDG-PET/CT-scan for radiological assessment and a colonoscopy. If the initial assessment is without evidence of recurrence, patients will be offered high-intensive radiological surveillance with FDG-PET/CT-scans every 3 months, until recurrence detection or 21 months has passed. At baseline and months 12, 18, 24 and 36 patients complete the QoL questionnaires including EORTC QLQ-C30, fear of cancer recurrence inventory (FCRI), and impact of events scale for cancer (IES-C). At every FDG-PET/CT-scans the patients also complete the questionnaire. | Diagnostic Test: ctDNA-analysis<br>* Minimally-invasive blood-based analysis of circulating tumor DNA (ctDNA).<br>Other: Intensified Follow-up Schedule<br>* PET/CT-scans every 3. month<br>|
| No Intervention: Standard Danish follow-up program<br>Patients will undergo surveillance according to current Danish Guidelines with CT-scans at months 12 and 36 postoperative and colonoscopy every 5 year until age 75. Longitudinal blood samples will be collected at same time-points as in the experimental group but not analyzed until end of trial. At baseline and months 12, 18, 24 and 36 patients complete the QoL questionnaires including EORTC QLQ-C30, fear of cancer recurrence inventory (FCRI), and impact of events scale for cancer (IES-C). | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FCI | Fraction of patients with relapse receiving intended curative resection or local treatment aiming at complete tumor destruction as defined at the relevant MDT conference. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3yr-OS | Overall survival at 3 years | 3 years | 
| 5yr-OS | Overall survival at 5 years | 5 years | 
| TTCR | Time to clinical recurrence | 3 years | 
| TTMR | Time to molecular recurrence | 2 years | 
| QoL | Quality of Life by use of EORTC QLQ-C30, version 3.0. The QoL outcome measure is differences in QLQ-C30 score at 12, 24 and 36 months between the experimental and control arm. | 3 years | 
| FCRI | Fear of Cancer Recurrence Inventory. The FCRI outcome measure is differences in FCRI at 12, 24 and 36 months between the experimental and control arm. | 3 years | 
| IES-C | Impact of Events Scale Cancer. The IES-C outcome measure is differences in IES-C at 12, 24 and 36 months between the experimental and control arm. | 3 years | 
| CE | Cost-effectiveness. QoL/Utility weights for the quality-adjusted life years parameter will be QLU-C10D based on EORTC QLQ-C30. | 5 years |