The Sagittarius Trial
A Precision Medicine Trial Leveraging Blood-Based Tumor Genomics to Optimize Treatment in Operable Stage III and High-Risk Stage II Colon Cancer Patients
IFOM ETS - The AIRC Institute of Molecular Oncology
700 participants
Oct 22, 2024
INTERVENTIONAL
Conditions
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.
Eligibility
Inclusion Criteria7
- 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 Criteria14
- 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.
Interventions
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Locations(26)
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NCT06490536