The Sagittarius Trial

NCT06490536 | Recruiting Phase 3

• 2 other identifiers: IFOM-CPT009/2022/PO0082023-509851-15-00
• Study Type: interventional
• Target: 700
• Locations: 3 countries
• Sites: 26

Brief Summary

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. 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. Prior neoadjuvant treatment administered before surgery. 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.

Conditions

Colon Cancer Stage II; Colon Cancer Stage III

Outcome Measures

Primary Outcomes (1)

• 2-Year Recurrence-Free Survival (RFS)

  The primary outcome measure is the 2-year recurrence-free survival (RFS) rate, defined as the proportion of patients who remain free of disease recurrence two years after surgery. This metric is assessed using regular clinical evaluations and imaging studies. Recurrence is determined by the reappearance of colon cancer as confirmed by histological, radiological, or clinical findings.

  Assessed at 2 years post-surgery

Secondary Outcomes (6)

• 3-Year Recurrence-Free Survival (RFS)

  Assessed at 3 years post-surgery

• 5-Year Overall Survival (OS)

  Assessed at 5 years post-surgery

• Treatment Safety and Tolerability

  Assessed throughout the treatment period, up to 6 months

• Sensitivity and Specificity of Liquid Biopsy in Detecting Residual Disease

  Assessed at regular intervals post-surgery, up to 2 years

• Assessment of Quality of Life Using FACT-C Questionnaire

  Assessed at regular intervals during the treatment period and during follow-up, up to 3 years or up to the date of first documented progression or the date of consent withdrawal

Study Arms (6)

Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Standard Therapy

ACTIVE COMPARATOR

CAPOX/FOLFOX for 6 months or until toxicity

Drug: Oxaliplatin; Drug: Capecitabine; Drug: Folinic acid; Drug: Fluorouracil

Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Tailored Therapy

EXPERIMENTAL

CAPOX for 3 months with an interventional liquid biopsy at the end of the treatment. Patients still resulting ctDNA+ will be switched to a tailored therapy (FOLFIRI for RAS/RAF-mutated and MGMT-positive tumors or TEMIRI for RAS/RAF-mutated and MGMT-negative tumors) for 6 months or until toxicity. On the other hand, ctDNA- patients will continue CAPOX up to 3 months, and their ctDNA status will be re-assessed at the end of the treatment. Patients remaining ctDNA- will enter into follow-up, while patients resulting ctDNA+ will be switched to the tailored therapy.

Drug: Oxaliplatin; Drug: Capecitabine; Drug: Folinic acid; Drug: Fluorouracil; Drug: Temozolomide; Drug: Irinotecan

Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Standard Therapy

ACTIVE COMPARATOR

CAPOX/FOLFOX for 6 months or until toxicity

Drug: Oxaliplatin; Drug: Capecitabine; Drug: Folinic acid; Drug: Fluorouracil

Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Tailored Therapy

EXPERIMENTAL

Tailored therapy (nivolumab+ipilimumab for MSI-H/MMRd: MSI-H/MMRd tumors and MSS/MMRp tumors with POLE mutations and a high TMB or trastuzumab + pertuzumab for MSS/MMRp HER2-amplified tumors or panitumumab+folfox for MSS/MMRp RAS/RAF/HER2 wild-type) for 3 months, at the end, the ctDNA status of patients will be reassessed to further guide their subsequent treatments. Patients still ctDNA+ at will be switched to standard therapy. On the other hand, patients undergoing seroconversion will continue the same therapy for 3 further months and will be then re-assessed at the end of the treatment. Patients resulting ctDNA- will enter into Follow-up, while patients resulting ctDNA+ will be switched to the standard therapy.

Drug: Nivolumab; Drug: Ipilimumab; Drug: Trastuzumab; Drug: Pertuzumab; Drug: Panitumumab

Trial-2 (ctDNA-) Standard Therapy

ACTIVE COMPARATOR

Chemotherapy regimen at prior declared physician choice (CAPE/CAPOX/FOLFOX/5-FU±LV).

Drug: Oxaliplatin; Drug: Capecitabine; Drug: Folinic acid; Drug: Fluorouracil

Trial-2 (ctDNA-) Intensive Follow-up

NO INTERVENTION

Intensive follow-up for 6 months (except for MSS Stage III High-risk patients which will be treated with CAPE).

Interventions

Oxaliplatin DRUG

Oxaliplatin is used as part of the chemotherapy regimens for patients with ctDNA+ results in the SAGITTARIUS trial. It is administered in the following ways: CAPOX Regimen: Oxaliplatin 130 mg/m² is given intravenously on day 1, in combination with capecitabine 1000 mg/m² taken orally twice daily on days 1-14 of each 21-day cycle. FOLFOX Regimen: Oxaliplatin 85 mg/m² is administered intravenously on day 1, alongside folinic acid 400 mg/m² and fluorouracil 400 mg/m² IV bolus, followed by 2400 mg/m² IV infusion over 46 hours, in each 14-day cycle. Dosages are standardized, while the duration of treatment can be adjusted based on patient response and liquid biopsy results, typically up to 6 months.

Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Standard Therapy; Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Tailored Therapy; Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Standard Therapy; Trial-2 (ctDNA-) Standard Therapy

Capecitabine DRUG

Capecitabine is used as part of the chemotherapy regimens for patients with ctDNA+ and ctDNA- results in the SAGITTARIUS trial. It is administered in the following ways: CAPOX Regimen: Capecitabine 1000 mg/m² is taken orally twice daily on days 1-14 of each 21-day cycle, in combination with oxaliplatin 130 mg/m² given intravenously on day 1. Capecitabine Monotherapy for High-Risk ctDNA- Patients: Capecitabine 1250 mg/m² is taken orally twice daily on days 1-14 of each 21-day cycle for patients identified as high-risk but with negative ctDNA results. The dosage of capecitabine is standardized, while the duration of treatment varies based on patient response and monitoring results, typically up to 6 months.

Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Standard Therapy; Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Tailored Therapy; Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Standard Therapy; Trial-2 (ctDNA-) Standard Therapy

Folinic acid DRUG

Folinic acid is used as part of the FOLFOX chemotherapy regimen for patients with ctDNA+ results in the SAGITTARIUS trial. It is administered in the following way: FOLFOX Regimen: Folinic acid (leucovorin) 400 mg/m² is given intravenously on day 1, in combination with oxaliplatin 85 mg/m² IV on day 1 and fluorouracil 400 mg/m² IV bolus followed by 2400 mg/m² IV infusion over 46 hours, in each 14-day cycle. The dosage of folinic acid is standardized, while the duration of treatment can be adjusted based on patient response and liquid biopsy results, typically up to 6 months.

Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Standard Therapy; Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Tailored Therapy; Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Standard Therapy; Trial-2 (ctDNA-) Standard Therapy

Fluorouracil DRUG

Fluorouracil is used as part of the FOLFOX chemotherapy regimen for patients with ctDNA+ results in the SAGITTARIUS trial. It is administered in the following way: FOLFOX Regimen: Fluorouracil 400 mg/m² is given as an intravenous (IV) bolus on day 1, followed by 2400 mg/m² as a continuous IV infusion over 46 hours, in combination with folinic acid (leucovorin) 400 mg/m² IV on day 1 and oxaliplatin 85 mg/m² IV on day 1. This regimen is repeated every 14 days. The dosage of fluorouracil is standardized, while the duration of treatment is typically up to 6 months, adjusted based on patient response and liquid biopsy results.

Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Standard Therapy; Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Tailored Therapy; Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Standard Therapy; Trial-2 (ctDNA-) Standard Therapy

Temozolomide DRUG

Temozolomide is used as part of the tailored chemotherapy regimen for patients with ctDNA+ results in the SAGITTARIUS trial, specifically for those with MGMT-negative tumors. It is administered in the following way: TEMIRI Regimen: Temozolomide 150-200 mg/m² is taken orally once daily on days 1-5 of each 28-day cycle, in combination with irinotecan 250 mg/m² administered intravenously on day 1 of each cycle. The dosage of temozolomide is standardized, while the duration of treatment can be adjusted based on patient response and liquid biopsy results.

Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Tailored Therapy

Irinotecan DRUG

Irinotecan is used as part of the tailored chemotherapy regimen for patients with ctDNA+ results in the SAGITTARIUS trial. It is administered in the following ways: TEMIRI Regimen: Irinotecan 250 mg/m² is administered intravenously on day 1 of each 28-day cycle, in combination with temozolomide 150-200 mg/m² taken orally once daily on days 1-5. FOLFIRI Regimen: Irinotecan 180 mg/m² is given intravenously on day 1, in combination with folinic acid (leucovorin) 400 mg/m² IV, fluorouracil 400 mg/m² IV bolus, followed by 2400 mg/m² IV infusion over 46 hours, in each 14-day cycle. The dosage of irinotecan is standardized, while the duration of treatment can be adjusted based on patient response and liquid biopsy results.

Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Tailored Therapy

Nivolumab DRUG

Nivolumab is used as part of the tailored immunotherapy regimen for patients with ctDNA+ results, specifically for those with MSI-H/MMRd tumors in the SAGITTARIUS trial. It is administered in the following way: Nivolumab: 3 mg/kg is given intravenously every 2 weeks. This dosage is standardized, while the duration of treatment can be adjusted based on patient response and liquid biopsy results.

Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Tailored Therapy

Ipilimumab DRUG

Ipilimumab is used as part of the tailored immunotherapy regimen for patients with ctDNA+ results, specifically for those with MSI-H/MMRd tumors in the SAGITTARIUS trial. It is administered in the following way: Ipilimumab: 1 mg/kg is given intravenously every 6 weeks. This dosage is standardized, while the duration of treatment can be adjusted based on patient response and liquid biopsy results.

Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Tailored Therapy

Trastuzumab DRUG

Trastuzumab is used as part of the tailored targeted therapy regimen for patients with ctDNA+ results, specifically for those with HER2-amplified tumors in the SAGITTARIUS trial. It is administered in the following way: Trastuzumab: 8 mg/kg as an initial intravenous (IV) loading dose, followed by 6 mg/kg IV every 3 weeks. The dosage is standardized, while the duration of treatment can be adjusted based on patient response and liquid biopsy results.

Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Tailored Therapy

Pertuzumab DRUG

Pertuzumab is used as part of the tailored targeted therapy regimen for patients with ctDNA+ results, specifically for those with HER2-amplified tumors in the SAGITTARIUS trial. It is administered in the following way: Pertuzumab: 840 mg as an initial intravenous (IV) loading dose, followed by 420 mg IV every 3 weeks. The dosage is standardized, while the duration of treatment can be adjusted based on patient response and liquid biopsy results.

Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Tailored Therapy

Panitumumab DRUG

Panitumumab is used as part of the tailored targeted therapy regimen for patients with ctDNA+ results, specifically for those with multiple wild-type tumors (MSS/MMRp extended RAS/RAF wild-type) in the SAGITTARIUS trial. It is administered in the following way: Panitumumab: 6 mg/kg is given intravenously every 2 weeks. The dosage is standardized, while the duration of treatment can be adjusted based on patient response and liquid biopsy results.

Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Tailored Therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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 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.
• Prior neoadjuvant treatment administered before surgery.

Sponsors & Collaborators

• IFOM ETS - The AIRC Institute of Molecular Oncology: lead

Study Sites (26)

Charité - Universitätsmedizin Berlin

Berlin, 10117, Germany

RECRUITING

Azienda Sanitaria Locale di Biella

Biella, Biella, 13875, Italy

RECRUITING

Fondazione Poliambulanza

Brescia, Brescia, 25124, Italy

RECRUITING

Azienda Ospedaliera Universitaria San Martino

Genova, Genova, 16132, Italy

RECRUITING

Istituto Europeo di Oncologia

Milan, Milano, 20141, Italy

RECRUITING

Istituto Clinico Humanitas

Rozzano, Milano, 20089, Italy

RECRUITING

Ospedale Niguarda

Milan, Milan, 20162, Italy

RECRUITING

Ospedale Maggiore di Novara

Novara, Novara, 28100, Italy

RECRUITING

Azienda Ospedaliera Universitaria di Parma

Parma, Parma, 43126, Italy

RECRUITING

Ospedale Santa Maria della Misericordia

Perugia, Perugia, 06129, Italy

RECRUITING

Azienda Unità Sanitaria Locale della Romagna

Ravenna, Ravenna, 48121, Italy

RECRUITING

Policlinico Universitario Gemelli

Roma, Roma, 00168, Italy

RECRUITING

Istituto di Candiolo

Candiolo, Torino, 10060, Italy

RECRUITING

Hospital del Mar

Barcelona, Barcelona, 08003, Spain

RECRUITING

Hospital Universitari Vall d'Hebron

Barcelona, Barcelona, 08035, Spain

RECRUITING

INCLIVA Instituto de Investigación Sanitaria

Valencia, Spain, 46010, Spain

RECRUITING

Hospital Sant Pau Barcelona

Barcelona, 08041, Spain

RECRUITING

Consorci Corporació Sanitària Parc Taulí

Barcelona, 08208, Spain

RECRUITING

Instituto Catalán de Oncologia

Barcelona, 08908, Spain

RECRUITING

Hospital Universitario Reina Sofia

Córdoba, 14004, Spain

RECRUITING

Hospital Clinico Universitario San Carlos

Madrid, 28040, Spain

RECRUITING

Complejo Hospitalario de Navarra

Pamplona, 31008, Spain

RECRUITING

Hospital Universitario Marqués de Valdecilla

Santander, 39008, Spain

RECRUITING

Hospital Clínico Universitario de Santiago

Santiago de Compostela, 15706, Spain

RECRUITING

Hospital General Universitario de Valencia

Valencia, 46014, Spain

RECRUITING

Hospital Universitario Miguel Servet

Zaragoza, 50009, Spain

RECRUITING

MeSH Terms

Conditions

Colonic Neoplasms

Interventions

Oxaliplatin; Capecitabine; Leucovorin; Fluorouracil; Temozolomide; Irinotecan; Nivolumab; Ipilimumab; Trastuzumab; pertuzumab; Panitumumab

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Dacarbazine; Triazenes; Imidazoles; Azoles; Camptothecin; Alkaloids; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Clara Montagut

  Hospital del Mar

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Silvia Marsoni

CONTACT

+39 02.574303862; sagittarius@ifom.eu

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 11, 2024
• First Posted: July 8, 2024
• Study Start: October 22, 2024
• Primary Completion: March 1, 2026
• Study Completion (Estimated): September 1, 2028
• Last Updated: August 29, 2025

Record last verified: 2025-08

Locations

ES (13); DE (1); IT (12)