Phase I Trial of Oral Capecitabine Combined With 131I-huA33 in Patients With Metastatic Colorectal Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 19
- 试验地点
- 1
- 主要终点
- Number of Patients With Dose-Limiting Toxicities (DLT)
研究概览
简要总结
The purpose of this clinical trial is to determine whether it is safe to treat patients with advanced colorectal cancer, with humanised A33 antibody tagged with radioactive iodine (131I-huA33) in combination with chemotherapy (capecitabine).
详细描述
This clinical trial tests the combination of humanised A33 monoclonal antibody tagged with radioactive iodine 131 (131I-huA33) together with capecitabine chemotherapy in patients with advanced colorectal cancer.
When colorectal cancer has spread to other organs, it is generally considered incurable but with a limited number of treatment options. Colorectal cancer cells express proteins on their surface known as antigens, and one of these is called the A33 antigen. An antibody which targets the A33 antigen was initially developed in the mouse and found to bind to human colorectal cancer cells. Because humans developed immune reactions when given the mouse antibody, an antibody, which is more like normal human antibodies, was developed (humanised A33 antibody). In order to increase its effectiveness, radioactive iodine (131I) has been attached to the antibody so that the antibody can deliver radiation directly to colorectal cancer cells. Previous studies have shown that both the unlabelled humanised A33 antibody as well as the humanised A33 antibody tagged with radioactive iodine can be administered safely to humans with no major allergic reactions. The addition of chemotherapy to radiolabelled 131I-huA33 may result in a treatment that is more effective for the treatment of colorectal cancer than either agent alone.
The purpose of this study is to determine whether it is safe to give humanised A33 antibody tagged with radioactive iodine together with chemotherapy. Different dose levels of radioactive iodine attached to a constant dose of antibody will be given together with a fixed total daily capecitabine chemotherapy dose. Providing humanised A33 antibody tagged with radioactive iodine and chemotherapy is tolerated well without major side effects, the dose of capecitabine chemotherapy given with 131I-huA33 will also be increased in order to determine the highest dose that can be given safely in combination with radio-labelled 131I-huA33. The effectiveness of the treatment combination against advanced colorectal cancer will also be assessed.
Patients with advanced colorectal cancer who have never previously received chemotherapy using capecitabine may be eligible to participate in the study. A total of between 15 and 30 patients are expected to be recruited.
Screening blood tests will be performed to determine eligibility, as well as baseline heart and lung function tests and appropriate scans to measure tumour size and assess radiation within the body. Patients will be given a trace-labelled (small radiation dose) infusion of 131I-huA33 into a vein followed a week later by the treatment infusion of 131I-huA33. The first infusion will be given as an outpatient, but for the second, patients will be hospitalized and confined to a radiation-shielded room until radiation levels fall to safe limits. Oral iodine drops will also be given for 28 days in order to protect the thyroid gland from the effects of radioactive iodine. Capecitabine chemotherapy will be taken orally and will commence at the time of the treatment infusion. Each cycle of capecitabine chemotherapy involves the medication being taken twice per day for a total of 14 days followed by 7 days rest. A total of 4 cycles of capecitabine will be given after the treatment infusion.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Metastatic colorectal cancer.
- •Histologically or cytologically proven colorectal cancer.
- •Measurable disease on CT scan with at least one lesion >/= 2cm diameter (to allow adequate infusion imaging).
- •Expected survival of at least 4 months.
- •ECOG performance status 0-
- •Vital laboratory parameters should be within normal range including:
- •Neutrophils >/= 1.5 x 10^9/L;
- •Platelets >/= 150 x 10^9/L;
- •Serum bilirubin </= 34 micromol/L;
- •Calculated creatinine clearance > 50 ml/min.
- •Age >/= 18 years.
- •Able and willing to give valid written informed consent.
排除标准
- •Previous treatment with capecitabine.
- •Untreated active metastatic disease to the central nervous system (new or enlarging lesions on CT or MRI), or within 3 months of treatment (ie surgery or radiotherapy) for brain metastases.
- •Other serious illnesses, eg, serious infections requiring antibiotics, bleeding disorders.
- •Liver involvement with metastatic disease > 50% liver volume.
- •Chemotherapy, radiation therapy, or immunotherapy within 4 weeks before study entry (6 weeks for nitrosoureas).
- •Previous external beam irradiation except if: (i) it was for standard adjuvant pelvic radiation for rectal cancer; (ii) it was for localised irradiation for skin cancer; or (iii) the sum total of all previous external beam irradiation port areas is not greater than 25% of the total red marrow.
- •Previous treatment with a monoclonal antibody or antibody fragment AND a positive huA33 human anti-human antibody (HAHA) titre.
- •Concomitant treatment with systemic corticosteroids. Topical or inhalational corticosteroids are permitted.
- •Mental impairment that may compromise the ability to give informed consent and comply with the requirements of the study.
- •Lack of availability of the patient for clinical and laboratory follow-up assessment.
- •Participation in any other clinical trial involving another investigational agent within 4 weeks prior to enrollment.
- •Pregnancy or breastfeeding.
- •Women of childbearing potential: Refusal or inability to use effective means of contraception.
研究组 & 干预措施
Cohort 1
20 millicurie (mCi) 131I-huA33, 1500 mg/m2/day capecitabine
All patients received an initial dose of 5 mg huA33 conjugated to 5-8 mCi 131I on day 0.
This was followed 7 ± 2 days later by inpatient administration of a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33.
Capecitabine was administered in 2 divided doses per day on days 1-14 of each 21-day cycle for a total of 4 cycles. Daily doses were rounded to the nearest 150 mg.
干预措施: Capecitabine (Drug)
Cohort 1
20 millicurie (mCi) 131I-huA33, 1500 mg/m2/day capecitabine
All patients received an initial dose of 5 mg huA33 conjugated to 5-8 mCi 131I on day 0.
This was followed 7 ± 2 days later by inpatient administration of a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33.
Capecitabine was administered in 2 divided doses per day on days 1-14 of each 21-day cycle for a total of 4 cycles. Daily doses were rounded to the nearest 150 mg.
干预措施: 131I-huA33 (131-Iodine on humanised monoclonal antibody A33) (Drug)
Cohort 2
30 millicurie (mCi) 131I-huA33, 1500 mg/m2/day capecitabine
All patients received an initial dose of 5 mg huA33 conjugated to 5-8 mCi 131I on day 0.
This was followed 7 ± 2 days later by inpatient administration of a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33.
Capecitabine was administered in 2 divided doses per day on days 1-14 of each 21-day cycle for a total of 4 cycles. Daily doses were rounded to the nearest 150 mg.
干预措施: Capecitabine (Drug)
Cohort 2
30 millicurie (mCi) 131I-huA33, 1500 mg/m2/day capecitabine
All patients received an initial dose of 5 mg huA33 conjugated to 5-8 mCi 131I on day 0.
This was followed 7 ± 2 days later by inpatient administration of a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33.
Capecitabine was administered in 2 divided doses per day on days 1-14 of each 21-day cycle for a total of 4 cycles. Daily doses were rounded to the nearest 150 mg.
干预措施: 131I-huA33 (131-Iodine on humanised monoclonal antibody A33) (Drug)
Cohort 3
30 millicurie (mCi) 131I-huA33, 1000 mg/m2/day capecitabine
All patients received an initial dose of 5 mg huA33 conjugated to 5-8 mCi 131I on day 0.
This was followed 7 ± 2 days later by inpatient administration of a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33.
Capecitabine was administered in 2 divided doses per day on days 1-14 of each 21-day cycle for a total of 4 cycles. Daily doses were rounded to the nearest 150 mg.
干预措施: Capecitabine (Drug)
Cohort 3
30 millicurie (mCi) 131I-huA33, 1000 mg/m2/day capecitabine
All patients received an initial dose of 5 mg huA33 conjugated to 5-8 mCi 131I on day 0.
This was followed 7 ± 2 days later by inpatient administration of a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33.
Capecitabine was administered in 2 divided doses per day on days 1-14 of each 21-day cycle for a total of 4 cycles. Daily doses were rounded to the nearest 150 mg.
干预措施: 131I-huA33 (131-Iodine on humanised monoclonal antibody A33) (Drug)
Cohort 4
40 millicurie (mCi) 131I-huA33, 1000 mg/m2/day capecitabine
All patients received an initial dose of 5 mg huA33 conjugated to 5-8 mCi 131I on day 0.
This was followed 7 ± 2 days later by inpatient administration of a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33.
Capecitabine was administered in 2 divided doses per day on days 1-14 of each 21-day cycle for a total of 4 cycles. Daily doses were rounded to the nearest 150 mg.
干预措施: Capecitabine (Drug)
Cohort 4
40 millicurie (mCi) 131I-huA33, 1000 mg/m2/day capecitabine
All patients received an initial dose of 5 mg huA33 conjugated to 5-8 mCi 131I on day 0.
This was followed 7 ± 2 days later by inpatient administration of a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33.
Capecitabine was administered in 2 divided doses per day on days 1-14 of each 21-day cycle for a total of 4 cycles. Daily doses were rounded to the nearest 150 mg.
干预措施: 131I-huA33 (131-Iodine on humanised monoclonal antibody A33) (Drug)
Cohort 5
40 millicurie (mCi) 131I-huA33, 1250 mg/m2/day capecitabine
All patients received an initial dose of 5 mg huA33 conjugated to 5-8 mCi 131I on day 0.
This was followed 7 ± 2 days later by inpatient administration of a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33.
Capecitabine was administered in 2 divided doses per day on days 1-14 of each 21-day cycle for a total of 4 cycles. Daily doses were rounded to the nearest 150 mg.
干预措施: Capecitabine (Drug)
Cohort 5
40 millicurie (mCi) 131I-huA33, 1250 mg/m2/day capecitabine
All patients received an initial dose of 5 mg huA33 conjugated to 5-8 mCi 131I on day 0.
This was followed 7 ± 2 days later by inpatient administration of a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33.
Capecitabine was administered in 2 divided doses per day on days 1-14 of each 21-day cycle for a total of 4 cycles. Daily doses were rounded to the nearest 150 mg.
干预措施: 131I-huA33 (131-Iodine on humanised monoclonal antibody A33) (Drug)
结局指标
主要结局
Number of Patients With Dose-Limiting Toxicities (DLT)
时间窗: 7 weeks
Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v3.0). DLT was defined as any of the following related events: Any grade 2 or greater allergic reaction related to huA33. Any grade ≥ 3 non-haematological toxicity related to 131I-huA33 or capecitabine. * These toxicities included palmar plantar erythema, but skin rash thought to be related to huA33 protein was not a DLT as previous studies have shown no relation of this toxicity to dose of huA33 or radioiodine dose. * Capecitabine cardiotoxicity grade ≥ 3 - including vasospasm, acute coronary syndrome and arrhythmia, necessitated the cessation of study drug in the affected patient but were not considered DLT as these are recognized as idiosyncratic in nature and not known to be related to capecitabine dose. Any grade ≥ 4 neutropenia ≥ 7 days in duration or any thrombocytopenia with a platelet count \< 10 x 10\^9/L.
次要结局
- Pharmacokinetics (PK) of 131I-huA33 as Measured by T½α and T½β (Half Lives of the Initial and Terminal Phases of Disposition, Respectively)(5 weeks)
- Impact of Capecitabine on 131I-huA33 Clearance (CL) as Measured by Initial and Therapy Dose Clearance (CL)(5 weeks)
- Pharmacokinetics (PK) of 131I-huA33 as Measured by Area Under the Serum Concentration Curve Extrapolated to Infinite Time (AUC)(5 weeks)
- Number of Patients With Tumour Response Assessed by Response Evaluation Criteria in Solid Tumors (RECIST).(13 weeks)
- Mean Specific Absorbed Dose of 131I-huA33 for Normal Organs Calculated From the Initial Infusion(1 week)
- Biodistribution of 131I-huA33 Measured by Whole Body Clearance and Normal Organ Clearance Reported as Mean Biological Half-life (T1/2 Biological) After Initial 131I-huA33 Infusion(1 week)
- Pharmacokinetics (PK) of 131I-huA33 as Measured by Clearance (CL)(5 weeks)
- Pharmacokinetics (PK) of 131I-huA33 as Measured by the Volume of the Central Compartment (V1)(5 weeks)
- Number of Patients With Human Anti-human Antibodies (HAHA) to 131I-huA33(13 weeks)
- Mean Total Tumor Dose of 131I-huA33(5 weeks)
- Pharmacokinetics (PK) of 131I-huA33 as Measured by Maximum Serum Concentration (Cmax)(5 weeks)