Systemic Neoadjuvant and Adjuvant Control by Precision Medicine in Rectal Cancer (SYNCOPE)

Systemic Neoadjuvant and Adjuvant Control by Precision Medicine in Rectal Cancer (SYNCOPE) - Approach on High-risk Group to Reduce Metastases

Rectal cancer represents the most complex area of multidisciplinary treatment in bowel surgery. In 2017, there were 1221 new rectal cancers in Finland. The prognosis of colorectal cancer (CRC) patients these days is almost exclusively driven by the occurrence of the metastatic form of the disease.

The treatment of rectal cancer often includes a long delay between diagnosis and the initiation of systemic chemotherapy, increasing risk for systemic metastases for those at high risk. On the other hand, the waiting time during pretreatment before surgery enables comprehensive systematic characterization of the primary tumor status before the decisions on adjuvant chemotherapy, opening a window to the use of precision in decision-making.

In this randomized controlled treatment trial, outcomes of novel precision methods to select right rectal cancer patients for treatment that they need will be compared to conventional treatment. The study aims to reduce over-treatment of those that most likely do not benefit from additional treatments. With the overall aim to reduce metastatic form of the disease, patients with high-risk features will be randomized to a treatment strategy with early systemic control by chemotherapy followed by circulating tumor DNA (ctDNA) and organoid-guided adjuvant therapy, or to conventional treatment strategy. Both state-of-the-art laboratory practice and routine diagnostic clinical pipelines are introduced to bring future diagnostic models of minimal residual disease and chemoresistance closer to current practice. The outcomes will reveal the clinical benefit of such strategy by recurrence-free survival at highest level of evidence, and produce important clinical outcome data on the application of ctDNA in everyday cancer treatment practice. The translational data on the use of ctDNA organoids to inform treatment decision and regimen selection will build knowledge of the use of such biomarkers as tools for clinical practice and clinical research. The results will be scalable worldwide in the practice of rectal cancer treatment.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: Total neoadjuvant therapy (TNT); Diagnostic test: Minimal residual disease (MRD); Radiation: Long radiation therapy

• Study Type: Interventional
• Enrollment (Anticipated): 93
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Toni T Seppälä, MD, PhD; Phone Number: +358444722846; Email: toni.seppala@tuni.fi

Study Locations

• Finland
  • Tampere, Finland, 33520
    • Recruiting
    • Tampere University Hospital
    • Contact: Toni Seppala, Prof; Phone Number: +358444722846; Email: toni.seppala@pirha.fi
  • Uusimaa
    • Helsinki, Uusimaa, Finland, 00029
      • Recruiting
      • Helsinki University Central Hospital
      • Contact: Toni T Seppala, MD, PhD; Phone Number: +358444722846; Email: toni.t.seppala@hus.fi

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. rectal adenocarcinoma,
2. World Health Organization (WHO) performance status 0-1, assessed by the MDT to be able to undergo capecitabine and oxaliplatin (CAPOX) treatment, 3) extramural vein invasion by magnetic resonance imaging (mrEMVI+) and

4) assessed by the multi-disciplinary team (MDT) to require either radiotherapy (RT) or long chemoradiotherapy (CRT) by the current standards.

Exclusion Criteria:

1. deficient mismatch repair (MMR) status,
2. non-dihydropyrimidine dehydrogenase (DPYD) genotype,
3. a contraindication to capecitabine, oxaliplatin or RT, or
4. failing in blood tests that describe the adequate circulatory, liver and kidney function for chemotherapy.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TNT + precision	Drug: Total neoadjuvant therapy (TNT); Short radiotherapy (5X5 Gy) and capecitabine/oxaliplatin; Diagnostic test: Minimal residual disease (MRD); Postoperative MRD on circulating cell-free DNA
Active Comparator: Conventional	Radiation: Long radiation therapy; Long-course 50.4 Gy radiation with capecitabine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recurrence-free survival		3 years from surgery
Recurrence-free survival		5 years from surgery
Postoperative ctDNA	number of patients with detectable ctDNA at postoperative sample in the conventional treatment arm that are not assigned to chemotherapy	3 weeks postoperatively

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
overall survival		5 years
overall survival		3 years
CRC-specific survival		3 years
CRC-specific survival		5 years
number of surgically resected patients resected patients		1 year
R0-resection rate		1 year
local recurrence rate		5 years postoperatively
complete pathological response response rate		12 weeks after initiation of pretreatment
complete clinical response rate		12 weeks after initiation of pretreatment
total uptake of chemotherapy		1year
total uptake of chemotherapy		3 years
total uptake of chemotherapy		5 years
adverse effects of surgery effects of surgery		1 year
adverse effects of chemotherapy		1 year
adverse effects of chemotherapy		3 years
Treatment response by patient-derived organoid (PDO) therapy response	population distribution of PDO treatment response is compared to their corresponding clinical response by response MRI and pathological response and compared to organoid in vitro response	1 year

Collaborators and Investigators

• Sponsor: Helsinki University Central Hospital
• Investigators: Principal Investigator: Toni T Seppälä, MD, PhD, Tampere University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): December 20, 2021
• Primary Completion (Anticipated): August 31, 2028
• Study Completion (Anticipated): December 31, 2031

Study Registration Dates

• First Submitted: February 8, 2021
• First Submitted That Met QC Criteria: April 9, 2021
• First Posted (Actual): April 12, 2021

Study Record Updates

• Last Update Posted (Estimate): March 6, 2023
• Last Update Submitted That Met QC Criteria: March 3, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms
• Other Study ID Numbers: HUS/155/2021

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
• product manufactured in and exported from the U.S.: No