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

Study Overview
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Brief Summary
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A open label 1:1 randomized phase II exploratory study investigating adjuvant therapy in patients with molecular biologically detectable residual disease after primary resection for localized colorectal tumors.

Detailed Description
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The main clinical hypothesis is that patients having undergone radical resection from CRC do not present with detectable tumor DNA in the plasma, whereas patients with detectable tumor DNA two weeks' post surgery have residual microscopic disease, and consequently a high risk of diseases recurrence which can be prevented with adjuvant chemotherapy. The primary aim of the present study is to investigate - in a randomized trial - if use of standard adjuvant chemotherapy therapy improves the disease free survival in patients with molecular biological residual disease where adjuvant chemotherapy is not standard treatment . Secondary aims include investigating molecular biological response to adjuvant chemotherapy in patients with post-operative ctDNA.

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

Conditions
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Colorectal Cancer, Circulating Tumor DNA, Adjuvant Chemotherapy, Progression Free Survival

Intervention / Treatment
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* Drug: Capox (or FOLFOX) including flouropyrimidine and oxaliplatin combination chemotherapy
* Other: Intensified Follow-up Schedule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Surgically removed Adenocarcinoma of the colon or rectum Pathologically stage I or II disease, and radical resection Detectable ctDNA in two weeks postoperative plasma sample No indication for adjuvant chemotherapy according to DCCG guidelines (website) Age at least 18 years ECOG performance status 0-2 Clinically eligible for adjuvant chemotherapy at investigators decision. Adequate bone marrow, liver and renal function allowing systemic chemotherapy (Absolute neutrophil count ≥1.5x109/l and thrombocytes ≥ 100x109/l. Bilirubin ≤ 1.5 x upper normal value and alanine aminotransferase ≤ 3 x upper normal value, and Calculated or measured renal glomerular filtration rate at least 30 mL/min) Anticonception for fertile women and for male patients with a fertile partner. Intrauterine device, vasectomy of a female subject's male partner or hormonal contraceptive are acceptable • Written and verbally informed consent Exclusion Criteria: Radiological evidence of distant metastasis, by CT- chest and abdomen Incapacity, frailty, disability and comorbidity to a degree that according to the investigator is not compatible with combination chemotherapy Previous treatment with 5FU or oxaliplatin Neuropathy NCI grade > 1 Other malignant tumor within 5 years except non-melanoma skin cancer or carcinoma in situ cervicis uteri Pregnant (positive pregnancy test) or breast feeding women

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A open label 1:1 randomized phase II exploratory study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: A<br>Intensified follow-up schedule | Other: Intensified Follow-up Schedule<br>* Close monitoring with Imaging during follow-up Patients included in this trial will undergo intensified follow-up with CT-chest and abdomen every four months after surgery for the first 2 years, then every 6 months for 1 years and finally once yearly for the last 2 years up to 5 years follow-up is completed.<br>|
| Experimental: B<br>Adjuvant chemotherapy + intensified follow-up schedule | Drug: Capox (or FOLFOX) including flouropyrimidine and oxaliplatin combination chemotherapy<br>* Six months of adjuvant combination chemotherapy with Capox (or FOLFOX) Patients will receive adjuvant chemotherapy with eight cycles of CAPOX (oxaliplatin 130 mg/m2 day 1 and capecitabine 1000 mg/m2 b.i.d. days 1-14, repeated every 3 weeks. (Patients with an ileostomy are only eligible for FOLFOX and will be treated with 12 cycles of FOLFOX (oxaliplatin 85 mg/m2 day 1, leucovorin 400 mg/m2 day 1, 5FU 400 mg/m2 bolus day 1 and 5FU 2400 mg/ m2 over 46-48 hours day 1-3, repeated every second weeks)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DFS | Disease free survival | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Molecular biological response | Molecular biological response at 6 months | 6 months | 
| MB-DFS | Molecular biological disease free survival at 1 year | 1 year | 
| TT-MBR | Time to molecular biological recurrence | 3 years | 
| TTR | Time to radiological recurrence | 3 years | 
| LRR | Local recurrence rate | 3 years | 
| DRR | Distant recurrence rate | 3 years | 
| OS | Overall survival | 5 years | 
| TR | Translational research exploratory | 3 years |