The Sagittarius Trial

Background \& Rationale:

Colon cancer is a leading cause of cancer deaths, with a high recurrence rate in stage II high-risk and stage III patients due to undetectable micro-metastases. Liquid biopsy (LB) detects residual cancer DNA post-surgery and monitors treatment response.

Primary Objective:

Show that therapy based on tumor genetics and LB improves outcomes and quality of life for high-risk stage II and stage III colon cancer patients compared to conventional therapy.

Secondary Objectives:

Compare recurrence times. Evaluate side effects and quality of life. Assess cost differences. Validate LB accuracy.

Study Design: Patients are randomized into standard or personalized treatment groups based on LB results.

For positive LB results:

Randomized to standard or customized therapy. Monitor treatment response with LB.

For negative LB results:

Randomized to standard chemotherapy or follow-ups, starting treatment if a positive result appears.

Treatments:

Standard Chemotherapy:

CAPOX (capecitabine and oxaliplatin) FOLFOX (folinic acid, fluorouracil, and oxaliplatin)

Personalized Treatments:

Customized chemotherapy with CAPOX. Immunotherapy with nivolumab and ipilimumab. Targeted therapy with trastuzumab and pertuzumab. FOLFOX with anti-EGFR (epidermal growth factor receptor) therapy (panitumumab).

Population: 700 patients with operable stage III and high-risk stage II colon cancer.

Inclusion Criteria:

Aged 18 or older. Confirmed diagnosis. Tumor tissue sample available.

Exclusion Criteria:

History of other tumors within five years. Incomplete colonoscopy or recent polyp removal. Metastatic disease or recent experimental study participation. Major cardiovascular diseases, intestinal obstruction, autoimmune diseases, neuropathy, HIV (Human Immunodeficiency Virus), active TB (Tuberculosis), or hepatitis B/C infection.

Medical conditions contraindicating treatment.

Endpoints:

Primary:

Evaluate disease recurrence after two years.

Secondary:

Assess disease recurrence and overall survival at 3 and 5 years. Measure treatment safety and tolerability. Validate LB accuracy. Monitor quality of life using questionnaires.

The study will last 5 years and be conducted in 25-30 hospitals across Italy, Spain, and Germany.

Background \& Rationale:

Colon cancer (CC) is the second most lethal malignancy, accounting for nearly 10% of all cancer-related deaths. Despite over two-thirds of CC patients undergoing surgical resection, 50% of stage III patients relapse within 5 years. Adjuvant chemotherapy (ACT), typically involving oxaliplatin combined with a fluoropyrimidine, offers only a 10-15% survival advantage over 5-fluorouracil alone. The benefit from ACT is predicted by clinical and pathological parameters rather than metastatic propensity or biological sensitivity, and its success is limited by high toxicity levels, particularly oxaliplatin-induced peripheral sensory neuropathy.

Liquid biopsy (LB) profiling circulating tumor DNA (ctDNA) has emerged as an effective diagnostic tool for early cancer detection, staging, prognosis, monitoring drug resistance, and detecting minimal residual disease (MRD). Retrospective studies show that ctDNA detection post-surgery and post-ACT is associated with high recurrence risk and worse recurrence-free survival (RFS) in stage I-III colorectal cancer (CRC) patients. Prospective studies confirm ctDNA's prognostic value post-surgery and ACT.

SAGITTARIUS Trial Objectives:

Diagnosing MRD After Surgery: Utilize post-surgical LB to identify high-risk tumors and stratify stage II high-risk and stage III CC patients, enabling targeted treatments and reducing unnecessary chemotoxicity.

Establishing the Efficacy of Adjuvant Chemotherapy and Targeted Therapies: Tailor treatment based on the individual tumor genomic landscape to improve clinical outcomes and quality of life compared to conventional chemotherapy.

Study Design:

The SAGITTARIUS trial is a randomized phase III study designed to demonstrate the efficacy of ctDNA detection in guiding adjuvant clinical management of stage III and high-risk stage II CC patients. The trial employs the CE-IVD marked tumor-informed MRD assay Signatera (NATERA® Inc.) and comprehensive tumor genomic profiling (TruSight Oncology Comprehensive (EU), TSOComp, Illumina, Inc.). These tools will provide a detailed molecular genomic landscape of each patient's tumor, with results available within 8 weeks post-surgery for timely adjuvant treatment initiation.

Patient Stratification and Randomization:

Patients are stratified based on ctDNA status into two main trials:

Trial-1 (ctDNA Positive Patients): Includes further stratification based on MSS/MMRp extended RAS/RAF mutation status and MSI-H/MMRd status. Treatment arms include standard chemotherapy (CAPOX/FOLFOX) or personalized treatments with reassessment of ctDNA status guiding subsequent therapies.

Trial-2 (ctDNA Negative Patients): Patients are randomized to either a physician-choice chemotherapy regimen or intensive follow-up, with interventional LBs at specified intervals.

Therapeutic Approaches:

Standard Chemotherapy Regimens: CAPOX (capecitabine and oxaliplatin) and FOLFOX (folinic acid, fluorouracil, and oxaliplatin).

Personalized Therapies: Include options such as FOLFIRI or TEMIRI for RAS/RAF-mutated tumors, double immunotherapy (nivolumab and ipilimumab) for MSI-H/MMRd, anti-HER2 therapy (trastuzumab and pertuzumab) for HER2-amplified tumors, and FOLFOX combined with anti-EGFR (panitumumab) for multiple wild-type tumors.

Data Collection and Analysis:

Data will be collected through regular clinical evaluations, imaging studies, and questionnaires to assess various endpoints, including RFS, overall survival, treatment safety, tolerability, and quality of life. The primary endpoint is the 2-year RFS in ctDNA positive patients, while secondary endpoints include 3 and 5-year RFS, overall survival, and the accuracy of LB in detecting residual disease. Statistical analyses will follow the intention-to-treat principle, utilizing the Kaplan-Meier method for time-to-event data and stratified log-rank tests for comparison.

Eligibility Criteria:
Inclusion Criteria:

* SAGITTARIUS trial written informed consent.
* Age ≥ 18 years.
* Histologically confirmed diagnosis of operable stage III and High-Risk stage II CC located at least 12 cm from the anal verge by endoscopy and above the peritoneal reflection at surgery.
* Availability of the original FFPE tumor tissue.
* ECOG performance status 0-1.
* Normal organ functions (as defined in section 9.3).
* Women with childbearing potential (WOCBP) should complete a pregnancy test and be willing to use highly effective contraceptive methods.

Exclusion Criteria:

* History of another neoplastic disease, unless in remission for ≥ 5 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
* Had an incomplete diagnostic colonoscopy.
* Recent polyps' removal (within one month).
* Macroscopic or microscopic evidence of residual tumor (R1 or R2 resections). Patients should never have had any evidence of metastatic disease (including presence of tumor cells in the peritoneal lavage).
* Current or recent treatment with another investigational drug or participation in another investigational study.
* Patient unable to comply with the study protocol owing to psychological, social or geographical reasons.
* Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study.
* Inadequate contraception (male or female patients) if of childbearing or procreational potential.
* Clinically relevant cardiovascular disease.
* Acute or subacute intestinal occlusion or history of inflammatory bowel disease or any other autoimmune disease.
* Pre-existing neuropathy \> grade 1. Known grade 3 or 4 allergic reaction to any of the components of the treatment.
* Has a known DPD (DihydroPyrimidine Dehydrogenase) deficiency.
* Has a known Gilbert Syndrome or UGT1A1 homozygous \*28/\*28 germline variant.
* Has a known history of Human Immunodeficiency Virus (HIV).
* Has a known history of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C virus infection.
* Has a known history of active TB (Bacillus Tuberculosis).
* Has a medical condition that contraindicate the use of the investigational medicinal product (IMP) according to product indications.