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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT00291486
Registration number
NCT00291486
Ethics application status
Date submitted
10/02/2006
Date registered
14/02/2006
Date last updated
10/10/2022
Titles & IDs
Public title
Capecitabine and 131I-huA33 in Patients With Metastatic Colorectal Cancer
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Scientific title
Phase I Trial of Oral Capecitabine Combined With 131I-huA33 in Patients With Metastatic Colorectal Cancer
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Secondary ID [1]
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R21CA108145-01A1
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Secondary ID [2]
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LUD2002-017
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Colorectal Neoplasms
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Condition category
Condition code
Cancer
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Bowel - Back passage (rectum) or large bowel (colon)
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Capecitabine
Treatment: Drugs - 131I-huA33 (131-Iodine on humanised monoclonal antibody A33)
Experimental: 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.
Experimental: 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.
Experimental: 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.
Experimental: 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.
Experimental: 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.
Treatment: Drugs: Capecitabine
Capecitabine was administered orally at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle. Daily doses were rounded to the nearest 150 mg.
Treatment: Drugs: 131I-huA33 (131-Iodine on humanised monoclonal antibody A33)
All patients received a dose of 5 mg huA33 conjugated to 5-8 mCi 131I. The therapy dose of 131I-huA33 comprised a constant protein dose of 10 mg/m2 huA33 regardless of dose level. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I).
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Number of Patients With Dose-Limiting Toxicities (DLT)
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Assessment method [1]
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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.
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Timepoint [1]
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7 weeks
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Secondary outcome [1]
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Number of Patients With Tumour Response Assessed by Response Evaluation Criteria in Solid Tumors (RECIST).
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Assessment method [1]
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Tumor responses were evaluated using appropriate imaging and categorized according to RECIST at Screening (within 2 weeks of the first dose of study treatment), and at week 13. Per RECIST, target lesions are categorized as follows: complete response (CR): disappearance of all target lesions; partial response (PR): = 30% decrease in the sum of the longest diameter of target lesions; progressive disease (PD): = 20% increase in the sum of the longest diameter of target lesions; stable disease (SD): small changes that do not meet above criteria (Therasse et al 2000).
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Timepoint [1]
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13 weeks
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Secondary outcome [2]
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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
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Assessment method [2]
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T1/2 biological is the clearance of the isotope from the whole body. Following the initial 131I-huA33 infusion, gamma camera scans were acquired over a 1 week period (1-4 hours, Day 1, Day 2 or 3, and Day 4 or 5). Whole body clearance, or biological half time, T1/2 biological, was calculated from the whole body anterior and posterior planar images. A region of interest (ROI) was calculated to encompass the whole body, and for each ROI at each time point, the mean counts per pixel per minute was normalised to imaging time point Day 1.
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Timepoint [2]
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1 week
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Secondary outcome [3]
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Mean Specific Absorbed Dose of 131I-huA33 for Normal Organs Calculated From the Initial Infusion
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Assessment method [3]
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Gamma camera imaging with anterior and posterior whole body scans using conjugate view methodology were performed on four occasions (1-4 hours, Day 1, Day 2 or 3, and Day 4 or 5) following completion of the intravenous initial infusion.
Dosimetric analysis was performed on the series of gamma camera whole-body planar images acquired in all patients following the first infusion.
Organ radioactivity content was estimated from the geometric mean of anterior and posterior regions of interest counts. The counts for each organ were corrected for background using regions of interest drawn adjacent to each organ where whole body thickness was comparable.
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Timepoint [3]
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1 week
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Secondary outcome [4]
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Mean Total Tumor Dose of 131I-huA33
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Assessment method [4]
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Gamma camera imaging were performed on four occasions (1-4 hours, Day 1, Day 2 or 3, and Day 4 or 5) following completion of the initial infusion and 7+2 days post-therapy infusion in week 2, and again in week 3 or 4 and week 5 following the therapy infusion.
Dosimetry analysis was performed on the series of gamma camera whole-body planar images.
Tumor radioactivity content after the initial infusion was estimated from the geometric mean of anterior and posterior regions of interest counts. The counts for each organ were corrected for background using regions of interest drawn adjacent to each tumor. Resultant counts were converted to activity using a camera sensitivity factor calculated from a gamma camera standard of known activity which was scanned at the same time.
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Timepoint [4]
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5 weeks
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Secondary outcome [5]
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Pharmacokinetics (PK) of 131I-huA33 as Measured by T½a and T½ß (Half Lives of the Initial and Terminal Phases of Disposition, Respectively)
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Assessment method [5]
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Blood samples for pharmacokinetics (PK) were drawn in week 0 immediately pre-initial 131I-huA33 infusion; then 5 minutes, 60 minutes and 2 hours post-initial 131I-huA33 infusion, Day 1, Day 2 or Day 3, Day 4 or Day 5. In week 1, PK samples were collected immediately pre-therapy 131I-huA33 infusion, 5 minutes, 24 ± 2 hours and approximately 7 days post-therapy 131I-huA33 infusion, then weekly until 4 weeks post therapy.
Pharmacokinetic calculations were performed on serum 131I-huA33 data using a curve fitting Program (WinNonLin version 5.2; Pharsight Co., Mountain View, CA).
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Timepoint [5]
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5 weeks
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Secondary outcome [6]
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Pharmacokinetics (PK) of 131I-huA33 as Measured by Clearance (CL)
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Assessment method [6]
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Blood samples for pharmacokinetics (PK) were drawn in week 0 immediately pre-initial 131I-huA33 infusion; then 5 minutes, 60 minutes and 2 hours post-initial 131I-huA33 infusion, Day 1, Day 2 or Day 3, Day 4 or Day 5. In week 1, PK samples were collected immediately pre-therapy 131I-huA33 infusion, 5 minutes, 24 ± 2 hours and approximately 7 days post-therapy 13II-huA33 infusion, then weekly until 4 weeks post therapy.
Pharmacokinetic calculations were performed on serum 131I-huA33 data using a curve fitting Program (WinNonLin version 5.2; Pharsight Co., Mountain View, CA).
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Timepoint [6]
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5 weeks
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Secondary outcome [7]
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Impact of Capecitabine on 131I-huA33 Clearance (CL) as Measured by Initial and Therapy Dose Clearance (CL)
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Assessment method [7]
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Blood samples for pharmacokinetics (PK) were drawn in week 0 immediately pre-initial 131I-huA33 infusion; then 5 minutes, 60 minutes and 2 hours post-initial 131I-huA33 infusion, Day 1, Day 2 or Day 3, Day 4 or Day 5. In week 1, PK samples were collected immediately pre-therapy 131I-huA33 infusion, 5 minutes, 24 ± 2 hours and approximately 7 days post-therapy 13II-huA33 infusion, then weekly until 4 weeks post therapy.
Pharmacokinetic calculations were performed on serum 131I-huA33 data using a curve fitting Program (WinNonLin version 5.2; Pharsight Co., Mountain View, CA).
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Timepoint [7]
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5 weeks
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Secondary outcome [8]
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Pharmacokinetics (PK) of 131I-huA33 as Measured by the Volume of the Central Compartment (V1)
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Assessment method [8]
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Blood samples for pharmacokinetics (PK) were drawn in week 0 immediately pre-initial 131I-huA33 infusion; then 5 minutes, 60 minutes and 2 hours post-initial 131I-huA33 infusion, Day 1, Day 2 or Day 3, Day 4 or Day 5. In week 1, PK samples were collected immediately pre-therapy 131I-huA33 infusion, 5 minutes, 24 ± 2 hours and approximately 7 days post-therapy 131I-huA33 infusion, then weekly until 4 weeks post therapy.
Pharmacokinetic calculations were performed on serum 131I-huA33 data using a curve fitting Program (WinNonLin version 5.2; Pharsight Co., Mountain View, CA).
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Timepoint [8]
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5 weeks
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Secondary outcome [9]
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Pharmacokinetics (PK) of 131I-huA33 as Measured by Maximum Serum Concentration (Cmax)
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Assessment method [9]
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Blood samples for pharmacokinetics (PK) were drawn in week 0 immediately pre-initial 131I-huA33 infusion; then 5 minutes, 60 minutes and 2 hours post-initial 131I-huA33 infusion, Day 1, Day 2 or Day 3, Day 4 or Day 5. In week 1, PK samples were collected immediately pre-therapy 131I-huA33 infusion, 5 minutes, 24 ± 2 hours and approximately 7 days post-therapy 131I-huA33 infusion, then weekly until 4 weeks post therapy.
Pharmacokinetic calculations were performed on serum 131I-huA33 data using a curve fitting Program (WinNonLin version 5.2; Pharsight Co., Mountain View, CA).
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Timepoint [9]
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5 weeks
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Secondary outcome [10]
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Pharmacokinetics (PK) of 131I-huA33 as Measured by Area Under the Serum Concentration Curve Extrapolated to Infinite Time (AUC)
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Assessment method [10]
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Blood samples for pharmacokinetics (PK) were drawn in week 0 immediately pre-initial 131I-huA33 infusion; then 5 minutes, 60 minutes and 2 hours post-initial 131I-huA33 infusion, Day 1, Day 2 or Day 3, Day 4 or Day 5. In week 1, PK samples were collected immediately pre-therapy 131I-huA33 infusion, 5 minutes, 24 ± 2 hours and approximately 7 days post-therapy 131I-huA33 infusion, then weekly until 4 weeks post therapy.
Pharmacokinetic calculations were performed on serum 131I-huA33 data using a curve fitting Program (WinNonLin version 5.2; Pharsight Co., Mountain View, CA).
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Timepoint [10]
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5 weeks
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Secondary outcome [11]
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Number of Patients With Human Anti-human Antibodies (HAHA) to 131I-huA33
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Assessment method [11]
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Serum samples for human anti-human antibody (HAHA) assessment were collected prior to each 131I-huA33 infusion, at weekly intervals during weeks 0-7, then alternate weeks until the end-of-study visit. Measurement of immune responses to huA33 in patients serum was performed using a BIAcore 2000 biosensor (Biacore AB, Uppsala, Sweden).
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Timepoint [11]
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13 weeks
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Eligibility
Key inclusion criteria
- 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 0-2.
- Vital laboratory parameters should be within normal range including:
1. Neutrophils >/= 1.5 x 10^9/L;
2. Platelets >/= 150 x 10^9/L;
3. Serum bilirubin </= 34 micromol/L;
4. Calculated creatinine clearance > 50 ml/min.
- Age >/= 18 years.
- Able and willing to give valid written informed consent.
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
- 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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Other
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Other design features
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Phase
Phase 1
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
1/10/2003
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
29/08/2012
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Sample size
Target
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Accrual to date
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Final
19
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Recruitment in Australia
Recruitment state(s)
VIC
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Recruitment hospital [1]
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Ludwig Institute Oncology Unit and Tumor Targeting Program, Austin Health - Heidelberg
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Recruitment postcode(s) [1]
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3084 - Heidelberg
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Funding & Sponsors
Primary sponsor type
Other
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Name
Ludwig Institute for Cancer Research
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Address
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Country
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Other collaborator category [1]
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Government body
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Name [1]
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National Cancer Institute (NCI)
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Address [1]
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Ethics approval
Ethics application status
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Summary
Brief summary
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).
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Trial website
https://clinicaltrials.gov/ct2/show/NCT00291486
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Trial related presentations / publications
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000 Feb 2;92(3):205-16. doi: 10.1093/jnci/92.3.205.
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Public notes
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Contacts
Principal investigator
Name
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Prof. Andrew M Scott, MBBS, DDU MD
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Address
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Ludwig Institute for Cancer Research
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT00291486
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