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

Phase I Trial of Oral Capecitabine Combined With 131I-huA33 in Patients With Metastatic Colorectal Cancer

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).

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.

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.

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.

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.

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.

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.

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.

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).

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.

Number of Patients With Tumour Response Assessed by Response Evaluation Criteria in Solid Tumors (RECIST).

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).

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

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.

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.

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.

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

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).

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).

Impact of Capecitabine on 131I-huA33 Clearance (CL) as Measured by Initial and Therapy Dose Clearance (CL)

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).

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).

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).

Pharmacokinetics (PK) of 131I-huA33 as Measured by Area Under the Serum Concentration Curve Extrapolated to Infinite Time (AUC)

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).

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).

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: Neutrophils >/= 1.5 x 10^9/L; Platelets >/= 150 x 10^9/L; Serum bilirubin </= 34 micromol/L; Calculated creatinine clearance > 50 ml/min. Age >/= 18 years. Able and willing to give valid written informed consent. 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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