Phase II Study Evaluating Holmium-166 TARE Followed by Maintenance Therapy in Liver Limited Unresectable Colorectal Cancer Patients After First-line Chemotherapy and Target Agents
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 4
- 试验地点
- 1
- 主要终点
- Progression-free survival (PFS) Rate
研究概览
简要总结
The aim of this study is to assess the efficacy of 166Ho-TARE followed by maintenance therapy with fluoropyrimidine and anti-EGFR or bevacizumab in liver-limited unresectable colorectal cancer patients, in terms of progression free rate 9- and 8-months for cohort A and B, respectively.
详细描述
HAITI is a phase II, single-arm trial of 166Ho-TARE followed by maintenance therapy in liver-limited unresectable colorectal cancer patients, achieving partial response or stable disease according to RECIST 1.1 criteria after 6-12 cycles of induction first-line chemotherapy.
Two cohorts of patients are included:
- left sided RAS/BRAF wild-type (cohort A)
- right-sided and/or RAS mutated (cohort B)
Enrolled patients will be treated with different maintenance therapy according to study cohort (fluoropyrimidine + anti-EGFR or bevacizumab).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Written informed consent to study procedures;
- •Age ≥18 years;
- •Histologically proven diagnosis of colorectal adenocarcinoma, with or without primary tumour in situ;
- •Liver-only disease at radiological exams involving less than 50% of liver volume;
- •Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤2;
- •Patients with partial response or stable disease according to RECIST 1.1 criteria deemed unresectable after 6-12 cycles of induction first-line chemotherapy;
- •Life expectancy of at least 12 weeks;
- •Hematopoietic function: absolute neutrophil count ≥ 1,500/mm3; platelet count
- •≥100,000/mm3; haemoglobin level ≥ 9 g/dL;
- •Liver function: total bilirubin ≤ 1.5 times upper limit of normal (ULN); alkaline phosphatase
- •≤ 5 times ULN; AST ≤ 5 times ULN;
- •Renal function: creatinine clearance > 50 mL/min or serum creatinine 1.5 x UNL; no renal disease that would preclude study treatment or follow-up;
- •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 as outlined in Section 7.5 - 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
- •Inclusion criteria for Cohort A:
- •RAS/BRAF wild-type and left sided primary tumor
- •First-line induction chemotherapy regimen permitted up to 6-12 cycles with:
- •FOLFOX or FOLFIRI + anti-EGFR (cetuximab or panitumumab). Patients who interrupted anti-EGFR target therapy during induction phase due to toxicity or other reasons, candidate to maintenance with fluoropyridine alone therapy can be enrolled.
- •Inclusion criteria for Cohort B:
- •RAS mutated and/or right-sided primary tumor
- •First-line induction chemotherapy regimen admitted up to 6-12 cycles with:
- •FOLFOX/FOLFIRI/XELOX + bevacizumab or FOLFOXIRI + bevacizumab. Patients who interrupted bevacizumab during induction phase due to toxicity or other reasons, candidate to maintenance with fluoropyridine alone therapy can be enrolled.
排除标准
- •Patients with radiological evidence of extra liver distant metastases.
- •Evidence of ascites, cirrhosis, portal hypertension, main portal venous tumour involvement or thrombosis, or any other contraindications to radioembolization treatment;
- •Previous radiotherapy delivered to the liver;
- •Patients with BRAF mutated and/or MSI-high tumours;
- •Previous history of malignancy within the last 5 years will be excluded with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ;
- •Treatment with any investigational drug within 30 days prior to enrolment or 2 investigational agent half-lives (whichever is longer);
- •Active uncontrolled infections or other clinically relevant concomitant illness contraindicating study procedures and treatment administration Clinically significant (e.g. 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 (CHF), serious cardiac arrhythmia requiring medication
- •Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at baseline. Sexually active males and females (of childbearing potential) unwilling to practice contraception during the study and until 180 days after the last trial treatment;
- •History of a previous allergic reaction to contrast media that would preclude safe angiography of the hepatic arteries, in the opinion of the treating Interventional Radiologist;
- •Known hypersensitivity to fluoropyrimidine, anti-VEGF or anti-EGFR MoAb.
- •Psychiatric or addictive disorders, or other conditions that, in the opinion of the investigator, would preclude study participation;
- •Withdrawal of the consent to take part to the study
研究组 & 干预措施
COHORT A/B
Eligible patients will receive Scout dose procedure. After 1-2 weeks, patients eligible for radioembolization will receive 166Ho-TARE and at least after 3 weeks, maintenance treatment with fluoropyrimidine plus target agents (anti-EGFR or bevacizumab) according to the respective study cohort.
Maintenance treatment:
Cohort A:
- CETUXIMAB iv day1, over 1 hours, 500 mg/sqm or PANITUMUMAB iv over 1 hours, 6 mg/kg, every 14 days
- LED 200 mg/sqm iv over 1 hour, day 1
- 5-FLUOROURACIL ic 48 h, starting on day 1 every 14 days; 2400 mg/sqm and 400 mg/sqm bolus if FOLFOX/FOLFIRI in the induction treatment
Cohort B:
- BEVACIZUMAB 5 mg/kg iv biweekly day1, over 30 minutes
- LED 200 mg/sqm iv over 1 hour, day 1
- 5-FLUOROURACIL ic 48 h, starting on day 1 every 14 days; 2400 mg/sqm and 400 mg/sqm bolus if FOLFOX/FOLFIRI in the induction treatment
CAPECITABINE, 1000 mg/sqm orally twice daily, day 1-14, plus bevacizumab 7,5 mg/kg iv every 21 days is allowed.
干预措施: 166Holmium TARE (Procedure)
COHORT A/B
Eligible patients will receive Scout dose procedure. After 1-2 weeks, patients eligible for radioembolization will receive 166Ho-TARE and at least after 3 weeks, maintenance treatment with fluoropyrimidine plus target agents (anti-EGFR or bevacizumab) according to the respective study cohort.
Maintenance treatment:
Cohort A:
- CETUXIMAB iv day1, over 1 hours, 500 mg/sqm or PANITUMUMAB iv over 1 hours, 6 mg/kg, every 14 days
- LED 200 mg/sqm iv over 1 hour, day 1
- 5-FLUOROURACIL ic 48 h, starting on day 1 every 14 days; 2400 mg/sqm and 400 mg/sqm bolus if FOLFOX/FOLFIRI in the induction treatment
Cohort B:
- BEVACIZUMAB 5 mg/kg iv biweekly day1, over 30 minutes
- LED 200 mg/sqm iv over 1 hour, day 1
- 5-FLUOROURACIL ic 48 h, starting on day 1 every 14 days; 2400 mg/sqm and 400 mg/sqm bolus if FOLFOX/FOLFIRI in the induction treatment
CAPECITABINE, 1000 mg/sqm orally twice daily, day 1-14, plus bevacizumab 7,5 mg/kg iv every 21 days is allowed.
干预措施: Cetuximab (Drug)
COHORT A/B
Eligible patients will receive Scout dose procedure. After 1-2 weeks, patients eligible for radioembolization will receive 166Ho-TARE and at least after 3 weeks, maintenance treatment with fluoropyrimidine plus target agents (anti-EGFR or bevacizumab) according to the respective study cohort.
Maintenance treatment:
Cohort A:
- CETUXIMAB iv day1, over 1 hours, 500 mg/sqm or PANITUMUMAB iv over 1 hours, 6 mg/kg, every 14 days
- LED 200 mg/sqm iv over 1 hour, day 1
- 5-FLUOROURACIL ic 48 h, starting on day 1 every 14 days; 2400 mg/sqm and 400 mg/sqm bolus if FOLFOX/FOLFIRI in the induction treatment
Cohort B:
- BEVACIZUMAB 5 mg/kg iv biweekly day1, over 30 minutes
- LED 200 mg/sqm iv over 1 hour, day 1
- 5-FLUOROURACIL ic 48 h, starting on day 1 every 14 days; 2400 mg/sqm and 400 mg/sqm bolus if FOLFOX/FOLFIRI in the induction treatment
CAPECITABINE, 1000 mg/sqm orally twice daily, day 1-14, plus bevacizumab 7,5 mg/kg iv every 21 days is allowed.
干预措施: Panitumumab (Drug)
COHORT A/B
Eligible patients will receive Scout dose procedure. After 1-2 weeks, patients eligible for radioembolization will receive 166Ho-TARE and at least after 3 weeks, maintenance treatment with fluoropyrimidine plus target agents (anti-EGFR or bevacizumab) according to the respective study cohort.
Maintenance treatment:
Cohort A:
- CETUXIMAB iv day1, over 1 hours, 500 mg/sqm or PANITUMUMAB iv over 1 hours, 6 mg/kg, every 14 days
- LED 200 mg/sqm iv over 1 hour, day 1
- 5-FLUOROURACIL ic 48 h, starting on day 1 every 14 days; 2400 mg/sqm and 400 mg/sqm bolus if FOLFOX/FOLFIRI in the induction treatment
Cohort B:
- BEVACIZUMAB 5 mg/kg iv biweekly day1, over 30 minutes
- LED 200 mg/sqm iv over 1 hour, day 1
- 5-FLUOROURACIL ic 48 h, starting on day 1 every 14 days; 2400 mg/sqm and 400 mg/sqm bolus if FOLFOX/FOLFIRI in the induction treatment
CAPECITABINE, 1000 mg/sqm orally twice daily, day 1-14, plus bevacizumab 7,5 mg/kg iv every 21 days is allowed.
干预措施: 5-Fluorouracil (Drug)
COHORT A/B
Eligible patients will receive Scout dose procedure. After 1-2 weeks, patients eligible for radioembolization will receive 166Ho-TARE and at least after 3 weeks, maintenance treatment with fluoropyrimidine plus target agents (anti-EGFR or bevacizumab) according to the respective study cohort.
Maintenance treatment:
Cohort A:
- CETUXIMAB iv day1, over 1 hours, 500 mg/sqm or PANITUMUMAB iv over 1 hours, 6 mg/kg, every 14 days
- LED 200 mg/sqm iv over 1 hour, day 1
- 5-FLUOROURACIL ic 48 h, starting on day 1 every 14 days; 2400 mg/sqm and 400 mg/sqm bolus if FOLFOX/FOLFIRI in the induction treatment
Cohort B:
- BEVACIZUMAB 5 mg/kg iv biweekly day1, over 30 minutes
- LED 200 mg/sqm iv over 1 hour, day 1
- 5-FLUOROURACIL ic 48 h, starting on day 1 every 14 days; 2400 mg/sqm and 400 mg/sqm bolus if FOLFOX/FOLFIRI in the induction treatment
CAPECITABINE, 1000 mg/sqm orally twice daily, day 1-14, plus bevacizumab 7,5 mg/kg iv every 21 days is allowed.
干预措施: Bevacizumab (Drug)
COHORT A/B
Eligible patients will receive Scout dose procedure. After 1-2 weeks, patients eligible for radioembolization will receive 166Ho-TARE and at least after 3 weeks, maintenance treatment with fluoropyrimidine plus target agents (anti-EGFR or bevacizumab) according to the respective study cohort.
Maintenance treatment:
Cohort A:
- CETUXIMAB iv day1, over 1 hours, 500 mg/sqm or PANITUMUMAB iv over 1 hours, 6 mg/kg, every 14 days
- LED 200 mg/sqm iv over 1 hour, day 1
- 5-FLUOROURACIL ic 48 h, starting on day 1 every 14 days; 2400 mg/sqm and 400 mg/sqm bolus if FOLFOX/FOLFIRI in the induction treatment
Cohort B:
- BEVACIZUMAB 5 mg/kg iv biweekly day1, over 30 minutes
- LED 200 mg/sqm iv over 1 hour, day 1
- 5-FLUOROURACIL ic 48 h, starting on day 1 every 14 days; 2400 mg/sqm and 400 mg/sqm bolus if FOLFOX/FOLFIRI in the induction treatment
CAPECITABINE, 1000 mg/sqm orally twice daily, day 1-14, plus bevacizumab 7,5 mg/kg iv every 21 days is allowed.
干预措施: Capecitabine (Drug)
结局指标
主要结局
Progression-free survival (PFS) Rate
时间窗: 36 months
PFS is defined as the time from study enrolment to the first documentation of objective disease progression or death due to any cause, whichever occurs first. PFS will be censored on the date of the last evaluable on study tumor assessment documenting absence of progressive disease for patients who are alive, on study and progression free at the time of the analysis.
次要结局
- Quality of Life (QoL) assessed using the EuroQol EQ-5D questionnaire(36 months)
- Overall Toxicity rate(36 months)
- Grade 3/ Grade 4 Toxicity rate(36 months)
- Post-treatment Disease Control Rate (DCR)(36 months)
- Progression free survival(36 months)
- Overall Survival(36 months)
- Quality of Life (QoL) assessed using the EORTC QLQ-CR29 questionnaire(36 months)
- Dose-response relationships(36 months)
- Quality of Life (QoL) assessed using the EORTC QLQ-CR30 questionnaire(36 months)