Phase II Randomized Trial to Assess the Effect of Intensive vs Standard Adjuvant Chemotherapy in Localized Colon Cancer With Circulating Tumor DNA
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 45
- 试验地点
- 7
- 主要终点
- Proportion of patients with ctDNA clearance following FOLFOXIRI treatment
研究概览
简要总结
This trial has been designed to prove the feasibility of using liquid biopsy detection of minimal residual disease (MRD) to guide the postsurgical clinical management of early colon cancer patients. Moreover, it is important to define if conventional (CAPOX) versus intensive (FOLFOXIRI) adjuvant chemotherapy could convert plasma ctDNA positive into a ctDNA negative status.
详细描述
The detection of circulating tumor DNA immediately after surgery with curative-intent identifies minimal residual disease and has been demonstrated as a surrogate of disease-free survival. This finding could guide adjuvant postoperative treatment in early colon cancer patients.
The efficacy and safety of FOLFOXIRI were previously tested in metastatic colorectal cancer patients. The Investigators hypothesize that an intensive adjuvant chemotherapy with FOLFOXIRI regimen could convert patients with detectable ctDNA into ctDNA negative indicating appropriate control of minimal residual disease. Moreover, FOLFOXIRI could have a higher conversion rate than conventional CAPOX therapy.
The current trial proposes a two-step approach. In the first part, a maximum of 40 patients with positive plasma ctDNA will be receiving an intensive adjuvant treatment with FOLFOXIRI, which is considered at the moment standard of care for metastatic patients. This part will be taken as a go/no go decision. The aim is to get at least 14 patients with ctDNA negative after such adjuvant treatment. If these figures are not met, the trial will be stopped due to futility, recognizing that such adjuvant treatment cannot control MRD. On the other hand, if these numbers are reached, a second part is designed as an exploratory phase II study to further randomize 124 patients with ctDNA positive into CAPOX versus FOLFOXIRI for six months, assessing again ctDNA conversion into a negative status. The aim of this part is to estimate differences in converting plasma ctDNA into negative among the conventional versus intensive adjuvant treatment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •CIRCULATE-SPAIN-01 trial written informed consent.
- •Age ≥ 18 years and ≤ 75 years.
- •Histologically confirmed diagnosis of operable stage II or stage III Colon Cancer.
- •Postoperative, ctDNA positive.
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-
- •Normal organ functions, as follows:
- •Absolute neutrophil count (ANC) ≥ 1500/μL.
- •Platelets ≥ 100.000/μL.
- •Hemoglobin ≥ 9.0 g/dL OR ≥ 5.6 mmol/L.
- •Total bilirubin ≤ 1.5 x upper level of normality (ULN) OR direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 x ULN.
- •Aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) ≤ 2.5 x ULN.
- •Note: Synchronous primary tumours are accepted. Note: Patients with rectal cancer above the peritoneal reflection, who have not undergone postoperative chemotherapy or radiotherapy and who have risk factors, may be included in the trial.
排除标准
- •Patients having a MicroSatellite Instability High (MSI-H) or MisMatch Repair Deficient (MMRd) tumor are excluded from the study (done according to standard clinical practice).
- •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 and/or polyps' removal for patients in whom the remaining colon was not removed or explored. Note: Patients with intraoperative complete colonoscopy or early perioperative complete colonoscopy and/or patients with incomplete colonoscopy, but who do have a CT Colono or Intraoperative Colonoscopy, may be eligible to be recruited in the study.
- •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 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.
- •Current clinically unresolved cardiovascular disease.
- •Acute or subacute intestinal occlusion or history of inflammatory bowel disease.
- •Pre-existing neuropathy > grade
- •Known grade 3 or 4 allergic reaction to any of the components of the treatment.
- •Has a known DihydroPyrimidine Dehydrogenase (DPD) deficiency.
- •Has a known Gilbert Syndrome or UGT1A1 homozygous *28/*28 germline variant.
- •Has a known history of Human Immunodeficiency Virus (HIV). Note: No HIV testing is required.
- •Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus infection. Note: no testing for Hepatitis B and Hepatitis C is required.
- •Has a known history of active Bacillus Tuberculosis (TB).
研究组 & 干预措施
FOLFOXIRI
FOLFOXIRI intensive adjuvant chemotherapy
干预措施: FOLFOXIRI (Drug)
CAPOX
CAPOX standard adjuvant chemotherapy
干预措施: CAPOX (Drug)
结局指标
主要结局
Proportion of patients with ctDNA clearance following FOLFOXIRI treatment
时间窗: Prior to treatment initiation, immediately after adjuvant chemotherapy completion, and every 4 months for 2 years (phase IIa).
Proportion of patients with detectable circulating tumor DNA (ctDNA) prior to treatment who become ctDNA-negative following intensive adjuvant treatment with FOLFOXIRI.
Difference in ctDNA clearance rate between FOLFOXIRI and CAPOX(FOLFOXIRI) versus conventional adjuvant therapy (CAPOX).
时间窗: Prior to treatment initiation, immediately after adjuvant chemotherapy completion, and every 4 months for 2 years (phase IIb).
Proportion of patients with detectable circulating tumor DNA (ctDNA) prior to treatment who become ctDNA-negative following adjuvant chemotherapy, compared between the intensive treatment group (FOLFOXIRI) and the standard-of-care group (CAPOX).
次要结局
- Disease-free survival in patients with positive ctDNA(At 24 months after the end of treatment (phase IIb).)
- Disease-free survival according to ctDNA clearance status(At 12 months after the end of treatment (phase IIb).)
- Treatment-related toxicity of FOLFOXIRI compared with CAPOX(During the treatment period and immediately after adjuvant chemotherapy completion (phase IIb).)
- Quality of life assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)(At baseline, 3 months after treatment initiation, and immediately after adjuvant chemotherapy completion (phase IIb).)
- Quality of life assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Colorectal 29 (EORTC QLQ-CR29)(At baseline, 3 months after treatment initiation, and immediately after adjuvant chemotherapy completion (phase IIb).)