Evaluation of ctDNA Clearance in Stage III and High-Risk Stage II Resected Colon Cancer Using FOLFOXIRI, Trifluridine/Tipiracil, and Drug Combinations
- Trial ID
- 2024-515152-20-00
- Protocol
- ERASE-CRC
- Sponsor
- Fondazione GONO G.I.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the rate of **circulating tumor DNA (ct-DNA)** clearance at the end of adjuvant and post-adjuvant treatments in patients with stage III or high-risk stage II resected colon cancer. Specifically, the study aims to compare the efficacy of FOLFOXIRI versus FOLFOX/CAPOX in patients with positive ct-DNA after surgery, and FOLFOX plus Trastuzumab and Tucatinib in HER2+/RAS wild-type patients. Additionally, the study assesses the rate of ct-DNA clearance following post-adjuvant treatment with trifluridine/tipiracil versus observation in patients with positive ct-DNA after fluoropyrimidine and oxaliplatin-based adjuvant therapy. The clinical relevance of this objective lies in its potential to guide treatment intensification strategies based on ct-DNA status, which may improve patient outcomes by tailoring therapy to individual molecular profiles.
Secondary objectives include assessing the safety profiles of the study treatments, the duration of Disease-free Survival (DFS) and Overall Survival (OS), and the prognostic impact of post-surgery and post-adjuvant detection of ct-DNA. The study also evaluates the prognostic significance of ct-DNA clearance at the end of adjuvant and post-adjuvant therapies, and its potential as a surrogate marker of adjuvant therapy efficacy. Additionally, the study measures quality of life using Patient-Reported Outcomes (PROs) questionnaires, including EORTC QLQ-C30, EORTC QLQ-CR29, and EuroQol EQ-5D.
Participants
The clinical trial involves participants diagnosed with **stage III and high-risk stage II resected colon cancer**. The study population includes both male and female subjects, aged between 18 and 75 years. Participants are required to have a histologically confirmed diagnosis of stage III or high-risk stage II adenocarcinoma of the colon, including intraperitoneal rectal cancer. The trial does not specify the total number of participants, as this information was not provided by the sponsor. The selection criteria include individuals who have undergone curative surgery and have positive circulating tumor DNA (ct-DNA) after surgery. Participants must have completed a fluoropyrimidine and oxaliplatin-based adjuvant treatment for a specified duration. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, depending on age. Lifestyle considerations such as diet and physical activity are not detailed in the available data. The trial population includes vulnerable groups, and both genders are represented. Key inclusion criteria involve the availability of formalin-fixed, paraffin-embedded tumor tissue for translational analysis and the willingness to comply with the protocol, including the use of adequate contraception for participants of childbearing potential.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of adjuvant and post-adjuvant treatments in patients with **stage III and high-risk stage II resected colon cancer**. This is a Phase II, randomized, double-blind, controlled trial. The primary objective is to assess the rate of circulating tumor DNA (ct-DNA) clearance at the end of the adjuvant and post-adjuvant treatments. The trial is expected to last until July 2028, with recruitment starting in March 2023.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as age, performance status, and laboratory values. The trial includes two main parts: Part 1 focuses on adjuvant treatment with FOLFOXIRI or FOLFOX/CAPOX, and Part 2 involves post-adjuvant treatment with trifluridine/tipiracil versus observation. Each part will have follow-up visits to monitor treatment response and adverse events, with the primary endpoint being the ct-DNA clearance rate. The end-of-study visit will assess overall outcomes, including disease-free survival and overall survival.
Participant involvement is expected to last up to 24 months, depending on the treatment arm and response. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial will adhere to rigorous ethical standards, ensuring that all participants provide informed consent and that their safety is continuously monitored throughout the study duration.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Trifluridine** is provided as a film-coated tablet for **oral use**. The maximum daily dose is 70 mg/m², with a total maximum dose of 420 mg/m² over a treatment period of 24 weeks. Trifluridine is a thymidine-based antineoplastic nucleoside analogue.
**Irinotecan** is administered as a concentrate for solution for infusion via **intravenous use**. The maximum daily dose is 165 mg/m², with a total maximum dose of 990 mg/m² over 24 weeks. Irinotecan is a semi-synthetic derivative of camptothecin.
**Capecitabine** is available as a film-coated tablet for **oral use**. The maximum daily dose is 2000 mg/m², with a total maximum dose of 224,000 mg/m² over 24 weeks. Capecitabine is classified as a pyrimidine analogue.
**Fluorouracil** is administered via **intravenous use** with a maximum daily dose of 200 mg/m² and a total maximum dose of 1200 mg/m² over 24 weeks. It serves as a detoxifying antidote in the treatment regimen.
**Tucatinib** is provided as a film-coated tablet for **oral use**. The maximum daily dose is 600 mg, with a total maximum dose of 3600 mg over 24 weeks. Tucatinib functions as a tyrosine kinase inhibitor.
**Calcium Levofolinate** is administered via **intravenous use** with a maximum daily dose of 200 mg/m² and a total maximum dose of 1200 mg/m² over 24 weeks. It acts as a detoxifying antidote.
**Oxaliplatin** is administered via **intravenous use** with a maximum daily dose of 130 mg/m² and a total maximum dose of 1020 mg/m² over 24 weeks. It is a platin derivative used in the treatment protocol.
**Trastuzumab** is administered via **intravenous use** with a maximum daily dose of 4 mg/kg and a total maximum dose of 24 mg/kg over 24 weeks. Trastuzumab is a monoclonal antibody used in the trial.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen. The trial also includes non-experimental treatments such as standard-of-care therapy, which may involve the use of a placebo or comparator treatment, depending on the specific study arm. The administration of these medications is conducted under strict clinical supervision to ensure participant safety and data integrity.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the measurement of **ct-DNA clearance rate**. This endpoint is defined as the percentage of patients with undetectable circulating tumor DNA (ct-DNA) at the end of the treatment phases. Specifically, the trial will evaluate the ct-DNA clearance rate after the completion of adjuvant treatment in Part 1 and target-driven Part 1, as well as after post-adjuvant treatment in Part 2. The analysis will focus on patients with stage III or high-risk stage II colon cancer who have positive ct-DNA following surgery.
Secondary endpoints include the assessment of overall toxicity rates, defined as the percentage of patients experiencing any adverse event or specific adverse events of grade 3 or higher, according to the National Cancer Institute Common Toxicity Criteria (version 5.0). Additionally, the trial will evaluate **Disease-Free Survival (DFS)** and **Overall Survival (OS)**. DFS is defined as the time from randomization to the first documentation of disease relapse or death due to any cause, while OS is defined as the time from randomization to the date of death due to any cause. Patient-reported outcomes (PROs) will also be analyzed using the EORTC QLQ-C30, EORTC QLQ-CR29, and EuroQol EQ-5D questionnaires, with scores and subscales compared between treatment arms.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Part 1 and target-driven part 1, adjuvant phase II study: Written informed consent to study procedures;
- 18 – 70 years of age ECOG PS ≤ 1 or 71-75 years of age with ECOG PS 0;
- Histologically confirmed stage III or high-risk stage II adenocarcinoma of colon including intraperitoneal rectal cancer. Stage II colon cancers are defined at high risk if at least one major prognostic factor (pT4, less than 12 nodes examined, clinical presentation with bowel perforation) or at least two minor prognostic factors (grade 3 or 4, clinical presentation with bowel obstruction, histological signs of vascular or lymphatic or perineural invasion, high preoperative CEA levels) are reported.
- For target-driven Part 1 only: HER2+ and RAS wt disease as determined by a tissue-based assay (central laboratory assessment)
- Curative surgery performed no less than 4 and no more than 12 weeks prior to randomization (pending results of ct-DNA analysis, up to 2 cycles of FOLFOX/CAPOX are allowed to start the adjuvant treatment within 8-10 weeks after surgery)
- Contrast-enhanced chest and abdominal CT scan (or abdomen MRI and chest CT if contrast-enhanced CT scan is contraindicated) performed after the surgery and prior to randomization with no evidence of metastatic disease.
- Availability of formalin-fixed, paraffin-embedded (FFPE) tumor tissue from the surgical specimen and blood sample for ct-DNA analysis within 28 days prior randomization.
- Positive ct-DNA after surgery (central assessment). The blood sample should be collected 2-6 weeks after the surgery.
- Neutrophils ≥1.5 x 109/L, Platelets ≥100 x 109/L, Hgb ≥ 9 g/dl.
- Total bilirubin ≤1.5 fold the upper-normal limits (UNL), ASAT (SGOT) and/or ALAT (SGPT) ≤2.5 x UNL, alkaline phosphatase ≤2.5 x UNL .
- Creatinine clearance ≥50 mL/min or serum creatinine ≤1.5 x UNL.
- For target-driven Part 1 only: Left ventricular ejection fraction (LVEF) ≥50% as assessed by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan.
- For patients eligible for protocol treatment, availability of formalin-fixed, paraffinembedded (FFPE) tumor tissue from the surgical specimen for translational analysis.
- Women of childbearing potential must have a negative blood pregnancy test at the screening visit. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least 12 months, are surgically sterile, or are sexually inactive. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient;
- Subjects and their partners must be willing to avoid pregnancy during the trial. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception. Contraception, starting during study screening visit throughout the study period up to 180 days after the last dose of chemotherapy;
- Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject;
- Will and ability to comply with the protocol.
- Part 2, post-adjuvant phase II study: Written informed consent to study procedures;
- ≥ 18 years of age;
- Histologically confirmed stage III or high-risk stage II adenocarcinoma of colon including intraperitoneal rectal cancer. Stage II colon cancers are defined at high risk if at least one major prognostic factor (pT4, less than 12 nodes examined, clinical presentation with bowel perforation) or at least two minor prognostic factors (grade 3 or 4, clinical presentation with bowel obstruction, histological signs of vascular or lymphatic or perineural invasion, high preoperative CEA levels) are reported.
- Fluoropyrimidine and oxaliplatin-containing adjuvant treatment for at least 3 months (6 cycles of 5-fluorouracil and oxaliplatin-based therapy or 4 cycles of capecitabine and oxaliplatin-based-therapy) and no more than 6 months (12 cycles of 5-fluorouracil and oxaliplatin-based therapy or 8 cycles of capecitabine and oxaliplatin-based-therapy).
- Contrast-enhanced chest and abdominal CT scan (or abdomen MRI and chest CT if contrast-enhanced CT scan is contraindicated) performed within 4 weeks from the end of adjuvant therapy and 28 days prior to randomization.
- Availability of FFPE tumor tissue from the surgical specimen and blood sample for ct- DNA analysis within 28 days prior to randomization ((only for patients who received adjuvant as per clinical practice and not in the Part 1 of the study).
- Positive ct-DNA after the end of adjuvant treatment (centrally laboratory assessment).
- ECOG PS ≤ 1.
- Neutrophils ≥1.5 x 109/L, Platelets ≥100 x 109/L, Hgb ≥9 g/dl.
- Total bilirubin ≤1.5 fold the upper-normal limits (UNL), ASAT (SGOT) and/or ALAT (SGPT) ≤2.5 x UNL, alkaline phosphatase ≤2.5 x UNL.
- Creatinine clearance ≥ 50 mL/min or serum creatinine ≤1.5 x UNL.
- Availability of formalin-fixed, paraffin-embedded (FFPE) tumor tissue from the surgical specimen for translational analyses (only for patients who received adjuvant as per clinical practice and not in the Part 1 of the study).
- Women of childbearing potential must have a negative blood pregnancy test at the screening visit. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least 12 months, are surgically sterile, or are sexually inactive. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient
- Subjects and their partners must be willing to avoid pregnancy during the trial. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception. Contraception, starting during study screening visit throughout the study period up to 180 days after the last dose of chemotherapy;
- Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject;
- Will and ability to comply with the protocol.
Exclusion Criteria
- Part 1, adjuvant phase II study and Part 2, post-adjuvant phase II study: Any evidence of metastatic disease (radiological or pathological metastasis);
- Macroscopic or microscopic evidence of residual tumor (R1 or R2 resections) after surgery;
- Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ;
- For Part 1 and target-driven Part 1 only: patient with complete dihydropyrimidine dehydrogenase (DPYD) deficiency (homozygous of the following DPYD polymorphisms: c1679GG, c1905+1AA, c2846TT);
- History or evidence upon physical examination of CNS disease unless adequately treated.
- Clinical signs of malnutrition.
- Active uncontrolled infections or other clinically relevant concomitant illness contraindicating chemotherapy administration.
- Evidence of bleeding diathesis or coagulopathy
- Clinically significant (i.e. active) cardiovascular disease for example cerebrovascular accidents (≤6 months), myocardial infarction (≤6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication
- Significant vascular disease (i.e. aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of study enrolment.
- Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication.
- Treatment with any investigational drug within 30 days prior to enrolment or 2 investigational agent half-lives (whichever is longer);
- Known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs.
- Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies.
- Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at screening; Sexually active males and females (of childbearing potential) unwilling to practice contraception (as defined in section 5.5) during the study and until 180 days after the last trial treatment.
- For Target-driven Part 1 population only:Has ongoing ≥ Grade 2 diarrhea of any etiology at screening;
- Presence of known chronic liver disease;
- Known to be positive for hepatitis C infection (positive by polymerase chain reaction [PCR]). Subjects who have been treated for hepatitis C infection are permitted if they have documented sustained virologic response of at least 12 weeks.
- Known to be positive for hepatitis B (HBV) by surface antigen (HBsAg) expression. Subjects who are positive for either hepatitis B surface antibody (HBsAB) or antibodies to the hepatitis B core antigen (HBcAB) should be screened using PCR measurement of hepatitis B DNA levels. Subjects with hepatitis B DNA levels by PCR that require nucleoside analogue therapy are not eligible for the trial. The latest local guidelines should be followed regarding the monitoring of hepatitis B DNA levels by PCR for subjects on study treatment.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Yet Recruiting | 10 Mar 2023 | 477 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
TRIFLURIDINE | Test | — | ORAL USE | 70 | 24 | SUB11291MIG |
IRINOTECAN | Test | — | INTRAVENOUS USE | 165 | 24 | SUB08295MIG |
TRIFLURIDINE | Test | — | ORAL USE | 70 | 24 | SUB11291MIG |
CAPECITABINE | Comparator | — | ORAL USE | 2000 | 24 | SUB12474MIG |
FLUOROURACIL | Test | PHF00231MIG | INTRAVENOUS USE | 200 | 24 | SCP1165178 |
TUCATINIB | Test | — | ORAL USE | 600 | 24 | SUB177913 |
CAPECITABINE | Comparator | — | ORAL USE | 2000 | 24 | SUB12474MIG |
TUCATINIB | Test | — | ORAL USE | 600 | 24 | SUB177913 |
CALCIUM LEVOFOLINATE | Test | PHF00231MIG | INTRAVENOUS USE | 200 | 24 | SCP139914 |
OXALIPLATIN | Test | PHF00230MIG | INTRAVENOUS USE | 130 | 24 | SCP128961 |