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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Gastrointestinal Neoplasms; Colonic Diseases; Colorectal Neoplasms; Rectal Diseases; Colorectal Cancer; Rectal Cancer; Rectal Neoplasms; Colonic Neoplasms; Gastrointestinal Cancer; Colo-rectal Cancer; Colonic Cancer; Digestive System Neoplasm; Digestive System Disease; Gastro-Intestinal Disorder; ctDNA
• Intervention / Treatment: Diagnostic test: ctDNA-analysis; Other: Intensified Follow-up Schedule

• Study Type: Interventional
• Enrollment (Estimated): 340
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Kaare A Gotschalck, PhD; Phone Number: +45 78423786; Email: kaarsune@rm.dk
• Study Contact Backup: Name: Claus L Andersen, PhD; Phone Number: +45 78455319; Email: cla@clin.au.dk

Study Locations

• Denmark
  • Randers, Denmark, 8930
    • Recruiting
    • Surgical Department, Randers Regional Hospital
    • Contact: Kaare Andersson Gotschalck, MD, PhD; Email: kaarsune@rm.dk
    • Contact: Jesper Nors, MD; Phone Number: +45 c; Email: jenors@rm.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ctDNA guided surveillance; 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; Minimally-invasive blood-based analysis of circulating tumor DNA (ctDNA).; Other: Intensified Follow-up Schedule; PET/CT-scans every 3. month
No Intervention: Standard Danish follow-up program; 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?

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

Collaborators and Investigators

• Sponsor: Claus Lindbjerg Andersen
• Collaborators: University of Aarhus
• Investigators: Principal Investigator: Claus L Andersen, PhD, Department of Molecular Medicin, Aarhus University Hospital

Publications and helpful links

General Publications

• Nors J, Henriksen TV, Gotschalck KA, Juul T, Sogaard J, Iversen LH, Andersen CL. IMPROVE-IT2: implementing noninvasive circulating tumor DNA analysis to optimize the operative and postoperative treatment for patients with colorectal cancer - intervention trial 2. Study protocol. Acta Oncol. 2020 Mar;59(3):336-341. doi: 10.1080/0284186X.2019.1711170. Epub 2020 Jan 10. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2020
• Primary Completion (Estimated): June 30, 2028
• Study Completion (Estimated): June 30, 2028

Study Registration Dates

• First Submitted: September 4, 2019
• First Submitted That Met QC Criteria: September 6, 2019
• First Posted (Actual): September 10, 2019

Study Record Updates

• Last Update Posted (Estimated): December 8, 2023
• Last Update Submitted That Met QC Criteria: December 1, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Intestinal Neoplasms; Neoplasms; Colorectal Neoplasms; Rectal Neoplasms; Gastrointestinal Diseases; Digestive System Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Intestinal Diseases; Colonic Neoplasms; Colonic Diseases; Rectal Diseases
• Other Study ID Numbers: IMPROVE-IT2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No