A Precision Medicine Trial Leveraging Blood-Based Tumor Genomics to Optimize Treatment in Operable Stage III and High-Risk Stage II Colon Cancer Patients
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 700
- 试验地点
- 26
- 主要终点
- 2-Year Recurrence-Free Survival (RFS)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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-
- •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.
排除标准
- •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
- •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.
研究组 & 干预措施
Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Standard Therapy
CAPOX/FOLFOX for 6 months or until toxicity
干预措施: Oxaliplatin (Drug)
Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Standard Therapy
CAPOX/FOLFOX for 6 months or until toxicity
干预措施: Capecitabine (Drug)
Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Standard Therapy
CAPOX/FOLFOX for 6 months or until toxicity
干预措施: Folinic acid (Drug)
Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Standard Therapy
CAPOX/FOLFOX for 6 months or until toxicity
干预措施: Fluorouracil (Drug)
Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Standard Therapy
CAPOX/FOLFOX for 6 months or until toxicity
干预措施: Capecitabine (Drug)
Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Tailored Therapy
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.
干预措施: Oxaliplatin (Drug)
Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Tailored Therapy
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.
干预措施: Capecitabine (Drug)
Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Tailored Therapy
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.
干预措施: Folinic acid (Drug)
Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Tailored Therapy
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.
干预措施: Fluorouracil (Drug)
Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Tailored Therapy
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.
干预措施: Temozolomide (Drug)
Trial-1 (ctDNA+) Strata-1 (MSS/MMRp extendend RAS/RAFmut) Tailored Therapy
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.
干预措施: Irinotecan (Drug)
Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Standard Therapy
CAPOX/FOLFOX for 6 months or until toxicity
干预措施: Oxaliplatin (Drug)
Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Standard Therapy
CAPOX/FOLFOX for 6 months or until toxicity
干预措施: Folinic acid (Drug)
Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Standard Therapy
CAPOX/FOLFOX for 6 months or until toxicity
干预措施: Fluorouracil (Drug)
Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Tailored Therapy
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.
干预措施: Nivolumab (Drug)
Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Tailored Therapy
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.
干预措施: Ipilimumab (Drug)
Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Tailored Therapy
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.
干预措施: Trastuzumab (Drug)
Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Tailored Therapy
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.
干预措施: Pertuzumab (Drug)
Trial-1 (ctDNA+) Strata-2 (MSI-H/MMRd & MSS/MMRp extended RAS/RAFwt) Tailored Therapy
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.
干预措施: Panitumumab (Drug)
Trial-2 (ctDNA-) Standard Therapy
Chemotherapy regimen at prior declared physician choice (CAPE/CAPOX/FOLFOX/5-FU±LV).
干预措施: Oxaliplatin (Drug)
Trial-2 (ctDNA-) Standard Therapy
Chemotherapy regimen at prior declared physician choice (CAPE/CAPOX/FOLFOX/5-FU±LV).
干预措施: Capecitabine (Drug)
Trial-2 (ctDNA-) Standard Therapy
Chemotherapy regimen at prior declared physician choice (CAPE/CAPOX/FOLFOX/5-FU±LV).
干预措施: Folinic acid (Drug)
Trial-2 (ctDNA-) Standard Therapy
Chemotherapy regimen at prior declared physician choice (CAPE/CAPOX/FOLFOX/5-FU±LV).
干预措施: Fluorouracil (Drug)
结局指标
主要结局
2-Year Recurrence-Free Survival (RFS)
时间窗: Assessed at 2 years post-surgery
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.
次要结局
- 3-Year Recurrence-Free Survival (RFS)(Assessed at 3 years post-surgery)
- Treatment Safety and Tolerability(Assessed throughout the treatment period, up to 6 months)
- 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)
- Assessment of Quality of Life Using EQ-5D-5L 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)
- 5-Year Overall Survival (OS)(Assessed at 5 years post-surgery)
- Sensitivity and Specificity of Liquid Biopsy in Detecting Residual Disease(Assessed at regular intervals post-surgery, up to 2 years)