Capecitabine and 131I-huA33 in Patients With Metastatic Colorectal Cancer

• Sponsor: Ludwig Institute for Cancer Research (Other)
• Overall Status: Completed
• CT.gov ID: NCT00291486
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 19
• Location: 1
• Arms: 5
• Actual Duration (Months): 106.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Colorectal Neoplasms	Drug: Capecitabine; Drug: 131I-huA33 (131-Iodine on humanised monoclonal antibody A33)	Phase 1

Detailed Description

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.

Blood samples will be taken just before the treatment infusion and then weekly for 13 weeks. There will be weekly physical examinations until 9 weeks after the treatment infusion and again at 12 weeks. Total study duration is 13 weeks from the trace-labelled infusion of 131I-huA33, that is 12 weeks from the treatment infusion of 131I-huA33. Patients will only receive one treatment infusion of 131I-huA33 antibody.

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I Trial of Oral Capecitabine Combined With 131I-huA33 in Patients With Metastatic Colorectal Cancer
• Actual Study Start Date: Oct 1, 2003
• Actual Primary Completion Date: Jan 3, 2008
• Actual Study Completion Date: Aug 29, 2012

Arms and Interventions

Arm	Intervention/Treatment
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.	Drug: 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.; Other Names: Xeloda ; Drug: 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).
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.	Drug: 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.; Other Names: Xeloda ; Drug: 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).
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.	Drug: 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.; Other Names: Xeloda ; Drug: 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).
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.	Drug: 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.; Other Names: Xeloda ; Drug: 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).
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.	Drug: 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.; Other Names: Xeloda ; Drug: 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).

Outcome Measures

Primary Outcome Measures

1. Number of Patients With Dose-Limiting Toxicities (DLT) [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.

Secondary Outcome Measures

1. Number of Patients With Tumour Response Assessed by Response Evaluation Criteria in Solid Tumors (RECIST). [13 weeks]

   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).

2. 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]

   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.

3. Mean Specific Absorbed Dose of 131I-huA33 for Normal Organs Calculated From the Initial Infusion [1 week]

   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.

4. Mean Total Tumor Dose of 131I-huA33 [5 weeks]

   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.

5. Pharmacokinetics (PK) of 131I-huA33 as Measured by T½α and T½β (Half Lives of the Initial and Terminal Phases of Disposition, Respectively) [5 weeks]

   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).

6. Pharmacokinetics (PK) of 131I-huA33 as Measured by Clearance (CL) [5 weeks]

   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).

7. Impact of Capecitabine on 131I-huA33 Clearance (CL) as Measured by Initial and Therapy Dose Clearance (CL) [5 weeks]

   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).

8. Pharmacokinetics (PK) of 131I-huA33 as Measured by the Volume of the Central Compartment (V1) [5 weeks]

   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).

9. Pharmacokinetics (PK) of 131I-huA33 as Measured by Maximum Serum Concentration (Cmax) [5 weeks]

   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).

10. Pharmacokinetics (PK) of 131I-huA33 as Measured by Area Under the Serum Concentration Curve Extrapolated to Infinite Time (AUC) [5 weeks]

    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).

11. Number of Patients With Human Anti-human Antibodies (HAHA) to 131I-huA33 [13 weeks]

    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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ludwig Institute Oncology Unit and Tumor Targeting Program, Austin Health	Heidelberg	Victoria	Australia	3084

Sponsors and Collaborators

• Ludwig Institute for Cancer Research
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Prof. Andrew M Scott, MBBS, DDU MD, Ludwig Institute for Cancer Research

Study Documents (Full-Text)

None provided.

More Information

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.

• Responsible Party: Ludwig Institute for Cancer Research
• ClinicalTrials.gov Identifier: NCT00291486
• Other Study ID Numbers: LUD2002-017; R21CA108145-01A1
• First Posted: Feb 14, 2006
• Last Update Posted: Feb 7, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Colorectal Neoplasms; Capecitabine; Antibodies; Antibodies, Monoclonal

Study Results

Participant Flow

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Cohort 5
Arm/Group Description	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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.	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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.	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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.	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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.	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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.
Period Title: Overall Study
STARTED	3	6	3	3	4
COMPLETED	2	3	2	2	3
NOT COMPLETED	1	3	1	1	1

Baseline Characteristics

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Cohort 5	Total
Arm/Group Description	20 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.	30 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150mg.	30 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.	40 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.	40 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.	Total of all reporting groups
Overall Participants	3	6	3	3	4	19
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	3 100%	2 33.3%	3 100%	3 100%	2 50%	13 68.4%
>=65 years	0 0%	4 66.7%	0 0%	0 0%	2 50%	6 31.6%
Sex: Female, Male (Count of Participants)
Female	1 33.3%	2 33.3%	2 66.7%	0 0%	1 25%	6 31.6%
Male	2 66.7%	4 66.7%	1 33.3%	3 100%	3 75%	13 68.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	1 33.3%	1 16.7%	0 0%	0 0%	0 0%	2 10.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
White	2 66.7%	5 83.3%	3 100%	3 100%	4 100%	17 89.5%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Australia	3 100%	6 100%	3 100%	3 100%	4 100%	19 100%

Outcome Measures

1. Primary Outcome

Title	Number of Patients With Dose-Limiting Toxicities (DLT)
Description	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.
Time Frame	7 weeks

Outcome Measure Data

Analysis Population Description

All patients who received at least one dose of study treatment.

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Cohort 5
Arm/Group Description	20 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.	30 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.	30 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.	40 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.	40 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.
Measure Participants	3	6	3	3	4
Count of Participants [Participants]	0 0%	2 33.3%	0 0%	0 0%	0 0%

2. Secondary Outcome

Title	Number of Patients With Tumour Response Assessed by Response Evaluation Criteria in Solid Tumors (RECIST).
Description	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).
Time Frame	13 weeks

Outcome Measure Data

Analysis Population Description

All patients who received at least one dose of study treatment and were evaluable for response. One patient in Cohort 5 was not evaluable due to the patient's request to discontinue the study prior to this evaluation.

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Cohort 5
Arm/Group Description	20 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.	30 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.	30 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.	40 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.	40 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.
Measure Participants	3	6	3	3	3
CR	0 0%	0 0%	0 0%	0 0%	0 0%
PR	0 0%	1 16.7%	0 0%	0 0%	0 0%
SD	1 33.3%	3 50%	2 66.7%	1 33.3%	3 75%
PD	2 66.7%	2 33.3%	1 33.3%	2 66.7%	0 0%

3. Secondary Outcome

Title	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
Description	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.
Time Frame	1 week

Outcome Measure Data

Analysis Population Description

All patients who received the initial infusion of 131I-huA33.

Arm/Group Title	Cohorts 1-5
Arm/Group Description	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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.
Measure Participants	19
Whole Body Clearance (T1/2 biologic)	219.56 (62.81)
Normal Organ Clearance in the Liver (T1/2 biological - liver)	62.29 (22.05)
Normal Organ Clearance in the kidney (T1/2 biological - kidney)	104.89 (56.22)

4. Secondary Outcome

Title	Mean Specific Absorbed Dose of 131I-huA33 for Normal Organs Calculated From the Initial Infusion
Description	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.
Time Frame	1 week

Outcome Measure Data

Analysis Population Description

All patients who received the initial infusion of 131I-huA33.

Arm/Group Title	Cohorts 1-5
Arm/Group Description	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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.
Measure Participants	19
Liver	0.12 (0.03)
Spleen	0.18 (0.06)
Kidney	0.14 (0.05)
Lung	0.09 (0.03)
Red Marrow	0.056 (0.011)

5. Secondary Outcome

Title	Mean Total Tumor Dose of 131I-huA33
Description	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.
Time Frame	5 weeks

Outcome Measure Data

Analysis Population Description

All patients who received the initial and therapy infusions and had tumors of sufficient size for accurate tumor quantitation and dosimetry. Nine patients had tumors too small to be analyzed. Results are presented by the radiolabeled dose of huA33 given as well as all patients.

Arm/Group Title	All Patients	Cohort 1; 20 mCi 131I-huA33	Cohorts 2 and 3; 30 mCi 131I-huA33	Cohorts 4 and 5: 40 mCi 131I-huA33
Arm/Group Description	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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.	20 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg	30 mCi 131I-huA33, 1500 mg/m2/day or 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.	40 mCi 131I-huA33, 1000 mg/m2/day or 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.
Measure Participants	10	0	6	4
Mean (Standard Deviation) [Gy]	13.83 (7.61)	13.15 (7.26)	14.89 (9.08)

6. Secondary Outcome

Title	Pharmacokinetics (PK) of 131I-huA33 as Measured by T½α and T½β (Half Lives of the Initial and Terminal Phases of Disposition, Respectively)
Description	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).
Time Frame	5 weeks

Outcome Measure Data

Analysis Population Description

In all cohorts, both doses of huA33 were the same. The amount of radioactivity administered does not impact the PK of the protein. The results are presented for all patients who received study therapy and had PK samples taken. Two patients were not included in the determination of mean parameter values due to curve fit instability (one after initial infusion and one after therapy infusion) and one due to a positive human anti-human antibody (HAHA) response in Week 1 (therapy infusion).

Arm/Group Title	Cohorts 1-5
Arm/Group Description	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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered 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.
Measure Participants	19
T½α after initial 131I-huA33 infusion	15.78 (4.68)
T½α after therapy 131I-huA33 infusion	28.63 (8.93)
T½β after initial 131I-huA33 infusion	100.24 (20.92)
T½β after therapy 131I-huA33 infusion	152.60 (49.59)

7. Secondary Outcome

Title	Pharmacokinetics (PK) of 131I-huA33 as Measured by Clearance (CL)
Description	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).
Time Frame	5 weeks

Outcome Measure Data

Analysis Population Description

In all cohorts, the doses of huA33 were the same. The amount of radioactivity administered does not impact the PK of the protein. The results are presented for all patients who received study therapy and had PK samples taken. The results excluded the following patients due to curve fit instability; 1 after the initial infusion, and 1 after the therapy infusion. Another was excluded from the results measured after the therapy infusion due to a positive human anti-human antibody (HAHA) in Week 1.

Arm/Group Title	Cohorts 1-5
Arm/Group Description	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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.
Measure Participants	19
CL after initial 131I-huA33 infusion	36.72 (8.01)
CL after therapy 131I-huA33 infusion	32.60 (8.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1
	Comments	Comparison of CL between initial infusion and therapy infusion
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.144
	Comments
	Method	t-test, 1 sided
	Comments

8. Secondary Outcome

Title	Impact of Capecitabine on 131I-huA33 Clearance (CL) as Measured by Initial and Therapy Dose Clearance (CL)
Description	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).
Time Frame	5 weeks

Outcome Measure Data

Analysis Population Description

CL is a key parameter to assess the impact of capecitabine on huA33 therapy. The doses of huA33 were the same, results are presented by capecitabine dose level in patients who received study therapy and had PK samples taken. The results excluded the following patients due to curve fit instability; 1 after the initial infusion, and 1 after the therapy infusion. Another was excluded from the results measured after the therapy infusion due to a positive human anti-human antibody (HAHA) in Week 1.

Arm/Group Title	Cohorts 1 and 2; 1500 mg/m2/Day Capecitabine	Cohorts 3 and 4; 1000 mg/m2/Day Capecitabine	Cohort 5; 1250 mg/m2/Day Capecitabine
Arm/Group Description	20 or 30 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.	30 or 40 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.	40 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg
Measure Participants	9	6	4
Initial dose CL	34.88 (9.81)	40.54 (7.41)	34.65 (1.85)
Therapy dose CL	26.88 (6.66)	39.41 (5.55)	35.53 (4.76)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1, Cohort 2, Cohort 3
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.361
	Comments
	Method	ANOVA
	Comments

9. Secondary Outcome

Title	Pharmacokinetics (PK) of 131I-huA33 as Measured by the Volume of the Central Compartment (V1)
Description	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).
Time Frame	5 weeks

Outcome Measure Data

Analysis Population Description

In all cohorts, both doses of huA33 were the same. The amount of radioactivity administered does not impact the PK of the protein. The results excluded the following patients due to curve fit instability; 1 after the initial infusion, and 1 after the therapy infusion. Another was excluded from the results measured after the therapy infusion due to a positive human anti-human antibody (HAHA) in Week 1.

Arm/Group Title	Cohorts 1-5
Arm/Group Description	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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.
Measure Participants	19
V1 after initial 131I-huA33 infusion	3204.26 (605.59)
V1 after therapy 131I-huA33 infusion	3363.69 (649.64)

10. Secondary Outcome

Title	Pharmacokinetics (PK) of 131I-huA33 as Measured by Maximum Serum Concentration (Cmax)
Description	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).
Time Frame	5 weeks

Outcome Measure Data

Analysis Population Description

In all cohorts, both doses of huA33 were the same. The amount of radioactivity administered does not impact the PK of the protein. The results excluded the following patients due to curve fit instability; 1 after the initial infusion, and 1 after the therapy infusion. Another was excluded from the results measured after the therapy infusion due to a positive human anti-human antibody (HAHA) in Week 1.

Arm/Group Title	Cohorts 1-5
Arm/Group Description	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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.
Measure Participants	19
Cmax after initial 131I-huA33 infusion	1.53 (0.24)
Cmax after therapy 131I-huA33 infusion	5.52 (0.77)

11. Secondary Outcome

Title	Pharmacokinetics (PK) of 131I-huA33 as Measured by Area Under the Serum Concentration Curve Extrapolated to Infinite Time (AUC)
Description	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).
Time Frame	5 weeks

Outcome Measure Data

Analysis Population Description

In all cohorts, both doses of huA33 were the same. The amount of radioactivity administered does not impact the PK of the protein. The results excluded the following patients due to curve fit instability; 1 after the initial infusion, and 1 after the therapy infusion. Another was excluded from the results measured after the therapy infusion due to a positive human anti-human antibody (HAHA) in Week 1.

Arm/Group Title	Cohorts 1-5
Arm/Group Description	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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.
Measure Participants	19
AUC after initial 131I-huA33 infusion	130.43 (36.35)
AUC after therapy 131I-huA33 infusion	592.46 (161.33)

12. Secondary Outcome

Title	Number of Patients With Human Anti-human Antibodies (HAHA) to 131I-huA33
Description	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).
Time Frame	13 weeks

Outcome Measure Data

Analysis Population Description

All patients who received at least one dose of study therapy and had HAHA measured at the respective timepoint.

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Cohort 5
Arm/Group Description	20 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.	30 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.	30 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.	40 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.	40 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.
Measure Participants	3	6	3	3	4
Positive HAHA	0 0%	0 0%	0 0%	0 0%	0 0%
Negative HAHA	3 100%	6 100%	3 100%	3 100%	4 100%
Positive HAHA	0 0%	0 0%	0 0%	1 33.3%	0 0%
Negative HAHA	3 100%	6 100%	2 66.7%	2 66.7%	4 100%
Positive HAHA	0 0%	0 0%	0 0%	1 33.3%	2 50%
Negative HAHA	3 100%	6 100%	2 66.7%	2 66.7%	2 50%
Positive HAHA	0 0%	0 0%	0 0%	0 0%	1 25%
Negative HAHA	3 100%	6 100%	3 100%	3 100%	3 75%
Positive HAHA	0 0%	0 0%	1 33.3%	0 0%	0 0%
Negative HAHA	3 100%	6 100%	2 66.7%	3 100%	3 75%
Positive HAHA	0 0%	0 0%	1 33.3%	1 33.3%	0 0%
Negative HAHA	3 100%	6 100%	2 66.7%	2 66.7%	3 75%
Positive HAHA	0 0%	0 0%	1 33.3%	1 33.3%	0 0%
Negative HAHA	3 100%	6 100%	2 66.7%	2 66.7%	3 75%
Positive HAHA	0 0%	0 0%	0 0%	0 0%	0 0%
Negative HAHA	3 100%	4 66.7%	2 66.7%	3 100%	3 75%
Positive HAHA	0 0%	0 0%	2 66.7%	1 33.3%	0 0%
Negative HAHA	3 100%	3 50%	1 33.3%	2 66.7%	3 75%
Positive HAHA	0 0%	0 0%	0 0%	0 0%	0 0%
Negative HAHA	2 66.7%	3 50%	2 66.7%	3 100%	3 75%

Adverse Events

Time Frame	up to 13 weeks
Adverse Event Reporting Description	Adverse Events (AEs) occurring during the study were to be documented in the source records and on the respective Case Report Form (CRF). All events, which occurred after signed informed consent but before first administration of study drug were to be documented on the Pre-existing Signs and Symptom page. Thereafter, they were to be documented on the AE page. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v3.0).
Arm/Group Title	Cohort 1		Cohort 2		Cohort 3		Cohort 4		Cohort 5
Arm/Group Description	20 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.		30 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.		30 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.		40 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.		40 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 the therapy dose given as a single infusion of 131I-huA33 with a constant protein dose of 10 mg/m2 huA33. The 131I-huA33 therapy dose was determined by the assigned dose level (i.e. 20, 30 or 40 mCi/m2 131I). Capecitabine was administered at doses between 1000 and 1500 mg/m2/day depending on assigned dose level for 14 days per 21-day cycle for 4 cycles. Daily doses were rounded to the nearest 150 mg.
All Cause Mortality
	Cohort 1		Cohort 2		Cohort 3		Cohort 4		Cohort 5
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Serious Adverse Events
	Cohort 1		Cohort 2		Cohort 3		Cohort 4		Cohort 5
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		3/6 (50%)		0/3 (0%)		1/3 (33.3%)		0/4 (0%)
Blood and lymphatic system disorders
Febrile Neutropenia	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Cardiac disorders
Angina	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Gastrointestinal disorders
Abdominal pain upper	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Diarrhoea	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Non-Hodgkin's Lymphoma	0/3 (0%)		0/6 (0%)		0/3 (0%)		1/3 (33.3%)		0/4 (0%)
Other (Not Including Serious) Adverse Events
	Cohort 1		Cohort 2		Cohort 3		Cohort 4		Cohort 5
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		6/6 (100%)		3/3 (100%)		3/3 (100%)		4/4 (100%)
Blood and lymphatic system disorders
Leukopenia	2/3 (66.7%)		3/6 (50%)		2/3 (66.7%)		1/3 (33.3%)		3/4 (75%)
Lymphopenia	3/3 (100%)		2/6 (33.3%)		0/3 (0%)		0/3 (0%)		1/4 (25%)
Monocytosis	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Neutropenia	2/3 (66.7%)		4/6 (66.7%)		2/3 (66.7%)		1/3 (33.3%)		4/4 (100%)
Thrombocytopenia	2/3 (66.7%)		4/6 (66.7%)		2/3 (66.7%)		2/3 (66.7%)		4/4 (100%)
Lymphadenopathy	0/3 (0%)		0/6 (0%)		0/3 (0%)		1/3 (33.3%)		0/4 (0%)
Anemia	3/3 (100%)		4/6 (66.7%)		2/3 (66.7%)		1/3 (33.3%)		0/4 (0%)
Cardiac disorders
Tachycardia	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Retrosternal chest pain	0/3 (0%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		1/4 (25%)
Supraventricular tachycardia	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Endocrine disorders
Hypoglycemia	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Eye disorders
Eye pain	0/3 (0%)		0/6 (0%)		1/3 (33.3%)		0/3 (0%)		0/4 (0%)
Gastrointestinal disorders
Abdominal discomfort	0/3 (0%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		1/4 (25%)
Abdominal distention	0/3 (0%)		0/6 (0%)		1/3 (33.3%)		0/3 (0%)		0/4 (0%)
Abdominal pain	0/3 (0%)		2/6 (33.3%)		1/3 (33.3%)		0/3 (0%)		0/4 (0%)
Anal discomfort	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Cheilitis	0/3 (0%)		0/6 (0%)		1/3 (33.3%)		0/3 (0%)		0/4 (0%)
Constipation	0/3 (0%)		1/6 (16.7%)		1/3 (33.3%)		0/3 (0%)		1/4 (25%)
Diarrhea	0/3 (0%)		5/6 (83.3%)		0/3 (0%)		2/3 (66.7%)		2/4 (50%)
Dry mouth	0/3 (0%)		0/6 (0%)		0/3 (0%)		1/3 (33.3%)		1/4 (25%)
Dysgeusia	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		1/4 (25%)
Dyspepsia	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Epigastric discomfort	0/3 (0%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		1/4 (25%)
Gastroesophageal reflux disease	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		1/3 (33.3%)		0/4 (0%)
Lip dry	1/3 (33.3%)		0/6 (0%)		1/3 (33.3%)		0/3 (0%)		0/4 (0%)
Lip ulceration	1/3 (33.3%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Nausea	2/3 (66.7%)		5/6 (83.3%)		3/3 (100%)		0/3 (0%)		4/4 (100%)
Proctalgia	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Rectal hemorrhage	0/3 (0%)		2/6 (33.3%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Stomatitis	0/3 (0%)		2/6 (33.3%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Vomiting	0/3 (0%)		2/6 (33.3%)		0/3 (0%)		0/3 (0%)		2/4 (50%)
Abdominal pain upper	1/3 (33.3%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Flatulence	0/3 (0%)		0/6 (0%)		0/3 (0%)		1/3 (33.3%)		0/4 (0%)
Gastritis	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Oral pain	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
General disorders
Asthenia	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Chills	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		1/3 (33.3%)		0/4 (0%)
Edema Peripheral	0/3 (0%)		0/6 (0%)		1/3 (33.3%)		0/3 (0%)		0/4 (0%)
Hot flush	0/3 (0%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		1/4 (25%)
Lethargy	2/3 (66.7%)		6/6 (100%)		1/3 (33.3%)		2/3 (66.7%)		3/4 (75%)
Pyrexia	0/3 (0%)		2/6 (33.3%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Hepatobiliary disorders
Hyperbilirubinemia	1/3 (33.3%)		3/6 (50%)		1/3 (33.3%)		0/3 (0%)		2/4 (50%)
Infections and infestations
Herpes simplex	0/3 (0%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		1/4 (25%)
Herpes zoster	1/3 (33.3%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Oral candidiasis	0/3 (0%)		0/6 (0%)		0/3 (0%)		1/3 (33.3%)		0/4 (0%)
Rhinitis	0/3 (0%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		1/4 (25%)
Injury, poisoning and procedural complications
Animal bite	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Myopathy steroid	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Investigations
Alanine aminotransferase increased	0/3 (0%)		0/6 (0%)		1/3 (33.3%)		0/3 (0%)		0/4 (0%)
Blood alkaline phosphatase increased	0/3 (0%)		3/6 (50%)		1/3 (33.3%)		0/3 (0%)		0/4 (0%)
Blood creatinine increased	1/3 (33.3%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Blood thyroid stimulating hormone decreased	0/3 (0%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		1/4 (25%)
Gamma-glutamyl transferase increased	0/3 (0%)		1/6 (16.7%)		2/3 (66.7%)		0/3 (0%)		0/4 (0%)
Weight decreased	0/3 (0%)		2/6 (33.3%)		0/3 (0%)		1/3 (33.3%)		0/4 (0%)
Metabolism and nutrition disorders
Anorexia	0/3 (0%)		1/6 (16.7%)		2/3 (66.7%)		2/3 (66.7%)		2/4 (50%)
Hypoalbuminemia	1/3 (33.3%)		2/6 (33.3%)		1/3 (33.3%)		2/3 (66.7%)		0/4 (0%)
Hypokalemia	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Hyponatremia	0/3 (0%)		1/6 (16.7%)		1/3 (33.3%)		1/3 (33.3%)		1/4 (25%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/3 (33.3%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Back pain	1/3 (33.3%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Buttock pain	0/3 (0%)		0/6 (0%)		1/3 (33.3%)		0/3 (0%)		0/4 (0%)
Muscle spasms	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Musculoskeletal chest pain	1/3 (33.3%)		1/6 (16.7%)		0/3 (0%)		1/3 (33.3%)		0/4 (0%)
Myalgia	0/3 (0%)		0/6 (0%)		0/3 (0%)		1/3 (33.3%)		0/4 (0%)
Pain in extremity	0/3 (0%)		1/6 (16.7%)		1/3 (33.3%)		0/3 (0%)		0/4 (0%)
Shoulder pain	1/3 (33.3%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Sensation of heaviness	0/3 (0%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		1/4 (25%)
Upper back pain	1/3 (33.3%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Nervous system disorders
Dizziness	0/3 (0%)		1/6 (16.7%)		2/3 (66.7%)		1/3 (33.3%)		1/4 (25%)
Extrapyramidal disorder	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Headache	0/3 (0%)		2/6 (33.3%)		0/3 (0%)		1/3 (33.3%)		1/4 (25%)
Hypoesthesia	0/3 (0%)		0/6 (0%)		1/3 (33.3%)		0/3 (0%)		0/4 (0%)
Insomnia	0/3 (0%)		1/6 (16.7%)		1/3 (33.3%)		1/3 (33.3%)		0/4 (0%)
Nerve root compression	0/3 (0%)		0/6 (0%)		1/3 (33.3%)		0/3 (0%)		0/4 (0%)
Neuropathy	1/3 (33.3%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Anosmia	1/3 (33.3%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Paresthesia	0/3 (0%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		1/4 (25%)
Peroneal nerve palsy	0/3 (0%)		0/6 (0%)		1/3 (33.3%)		0/3 (0%)		0/4 (0%)
Post herpetic neuralgia	1/3 (33.3%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Tremor	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		1/3 (33.3%)		0/4 (0%)
Weakness in extremity	0/3 (0%)		0/6 (0%)		1/3 (33.3%)		0/3 (0%)		0/4 (0%)
Psychiatric disorders
Agitation	0/3 (0%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		1/4 (25%)
Depressed mood	0/3 (0%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		1/4 (25%)
Mood altered	0/3 (0%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		1/4 (25%)
Renal and urinary disorders
Blood urea decreased	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Dysuria	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Renal colic	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Reproductive system and breast disorders
Vaginal pain	1/3 (33.3%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Pelvic pain	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Testicular pain	0/3 (0%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		1/4 (25%)
Respiratory, thoracic and mediastinal disorders
Cough	0/3 (0%)		1/6 (16.7%)		1/3 (33.3%)		3/3 (100%)		1/4 (25%)
Dysphonia	0/3 (0%)		0/6 (0%)		0/3 (0%)		1/3 (33.3%)		0/4 (0%)
Epistaxis	0/3 (0%)		0/6 (0%)		0/3 (0%)		1/3 (33.3%)		0/4 (0%)
Sinus congestion	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Pharyngeal pain	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		1/3 (33.3%)		0/4 (0%)
Pleuritic pain	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Rhinorrhea	0/3 (0%)		0/6 (0%)		1/3 (33.3%)		0/3 (0%)		0/4 (0%)
Upper respiratory tract infection NOS	1/3 (33.3%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Skin and subcutaneous tissue disorders
Contusion	1/3 (33.3%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Dry skin	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		1/4 (25%)
Erythema	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		1/4 (25%)
Hyperhidrosis	0/3 (0%)		0/6 (0%)		0/3 (0%)		1/3 (33.3%)		0/4 (0%)
Itchy skin	0/3 (0%)		0/6 (0%)		1/3 (33.3%)		0/3 (0%)		0/4 (0%)
Pruritus	1/3 (33.3%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Rash	0/3 (0%)		0/6 (0%)		0/3 (0%)		1/3 (33.3%)		1/4 (25%)
Rash erythematous	0/3 (0%)		0/6 (0%)		1/3 (33.3%)		0/3 (0%)		0/4 (0%)
Rash maculo-papular	1/3 (33.3%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Rash pruritic	0/3 (0%)		0/6 (0%)		0/3 (0%)		0/3 (0%)		1/4 (25%)
Skin exfoliation	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)
Pain of skin	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		1/4 (25%)
Vascular disorders
Hypertension	0/3 (0%)		0/6 (0%)		1/3 (33.3%)		0/3 (0%)		0/4 (0%)
Orthostatic hypotension	0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		0/4 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.