Kidney Cancer
Conditions
Keywords
stage IV renal cell cancer, recurrent renal cell cancer
Brief summary
RATIONALE: Monoclonal antibodies can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. PURPOSE: Phase I/II trial to study the effectiveness of monoclonal antibody therapy in treating patients with advanced kidney cancer.
Detailed description
This is a dose-escalation study. Initially patients receive a scout dose of iodine-131 radiolabeled chimeric monoclonal antibody G250 (131I-cG250) administered intravenously (IV) over 10 minutes to determine whole body clearance. One week later, patients receive incremental doses of 131I-cG250 IV over 10 minutes at 2-3 day intervals for 2-6 weeks,. Dose escalation begins at least 8 weeks after the last infusion of 131I-cG250. In the absence of dose-limiting toxicity in the first 3 patients treated, subsequent cohorts of 3 patients each receive escalating doses of 131I-cG250 on the same schedule. If dose-limiting toxicity occurs in 2 of 6 patients treated at a given dose level, then dose escalation ceases and the next lower dose is declared the maximum tolerated dose (MTD). Treatment continues once recovery from all toxic effects occurs, beginning 8 to 12 weeks following the last dose of 131I-cG250. Patients achieving complete remission, partial remission, or stable disease were eligible to receive up to 3 courses of treatment.
Interventions
BIOLOGICALIodine-131 radiolabeled chimeric monoclonal antibody G250 (131I-cG250)
cG250 is an IgG1 chimeric monoclonal antibody. It was supplied as a sterile solution at a concentration of 1.0 mg/mL in either a 2 mL or a 5 mL vial. cG250 was radiolabeled with Iodine-131 prior to use.
Sponsors
National Cancer Institute (NCI)
Ludwig Institute for Cancer Research
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Histologically proven renal cell carcinoma. Clinical presentation consistent with metastatic renal cell carcinoma. Bidimensionally measurable disease by conventional imaging. Patients must have been off chemotherapy or immunotherapy for at least 6 weeks prior to study entry. Women of child-bearing age must have had a negative pregnancy test carried out the day of and prior to receiving therapy, and were asked to use effective contraception during the study. Patients were required to be ambulatory with a Karnofsky Performance Status at least 70, Serum creatinine ≤ 2mg/dl, Serum bilirubin ≤ 1mg/d, White Blood Cells (WBC) ≥ 3,500/mm\^3, Platelet count ≥ 100,000/mm\^3, Prothrombin time \< 1.3 x control.
Exclusion criteria
Significant prior radiation therapy to the entire pelvis and/or lumbosacral spine. Clinically significant cardiac disease. Serious infection requiring treatment with antibiotics, or other serious illness. Women who are pregnant or lactating. Central Nervous System (CNS) tumor involvement. Life expectancy less than 6 weeks. Hypercalcemia greater than 12.5 mg/dL or symptomatic.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Adverse Events (AEs) | Up to 12 months | All adverse events occurring during the study were to be recorded on the patient's case report form, and include the following information: a description; date of onset and resolution; severity; relationship to an investigational agent; action taken and outcome. Toxicity was graded in accordance with the NCI CTCAE version 3.0. |
| Number of Patients With Dose-Limiting Toxicities (DLTs) | up to 12 months | Subjects were monitored for Adverse Events (AEs) for at least 8 weeks after the last infusion of 131I-cG250, or until recovery from all toxicity, and prior to dose escalation. Toxicity was graded in accordance with the Common Toxicity Criteria (CTC) of the National Cancer Institute (NCI) Version 3.0. Dose-Limiting Toxicity (DLT) was defined as grade 3 or greater toxicity related to study therapy. The maximum tolerated dose was defined as the highest safely tolerated dose where at most one of six patients experiences a DLT with the next higher dose having at least two patients who experience a DLT. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Best Overall Tumor Response | Up to 12 weeks | Tumor responses were evaluated using computed tomography and categorized according to World Health Organization (WHO) criteria at baseline and at no more than 6 weeks after the last dose, or not more than 12 weeks after entry into the study. Complete Response (CR): disappearance of all measurable disease lasting at least 1 month; Partial Response (PR): ≥ 50% decrease in the size of the product of 2 perpendicular diameters of any measurable lesions and no new lesions, lasting at least one month; Progressive Disease (PD): ≥ 25% increase in the size of any measurable lesions or the appearance of any new lesions; Stable Disease (SD): small changes that do not meet above criteria. |
| Number of Patients With Human Anti-chimeric Antibodies (HACA) | Up to 6 months | Blood samples were taken at baseline and in weeks 2, 3, 4, 5, and 6 as well as month 6. HACA was measured by an enzyme-linked immunosorbent assay (ELISA) using the double antibody sandwich technique and pretreatment serum as negative control. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 50cGy Radiation On day 1, patients received a single dose of 131I-cG250 (5 mCi/5 mg) administered as an intravenous infusion over 10 minutes.
Therapeutic doses of 131I-cG250 were administered the following week as fractionated outpatient doses, starting with 30 mCi/5 mg 131I-cG250. Subsequent doses of 131I-cG250 were administered at 2-3 day intervals with the total amount of 131I-cG250 administered based on the calculated clearance of the initial dose administered on day 1. Whole body activity was maintained at no more than 30 mCi iodine-131.
In the absence of disease progression and after recovery from toxicity, patients could be re-treated beginning 8 weeks after the last treatment of the initial series, for a total of not more than 3 treatments.
Iiodine-131 radiolabeled chimeric monoclonal antibody G250 (131I-cG250): cG250 is an IgG1 chimeric monoclonal antibody. It was supplied as a sterile solution at a concentration of 1.0 mg/mL in either a 2 mL or a 5 mL vial. cG250 was radiolabeled with Iodine-131 prior to use. | 3 |
| Cohort 2 75cGy Radiation On day 1, patients received a single dose of 131I-cG250 (5 mCi/5 mg) administered as an intravenous infusion over 10 minutes.
Therapeutic doses of 131I-cG250 were administered the following week as fractionated outpatient doses, starting with 30 mCi/5 mg 131I-cG250. Subsequent doses of 131I-cG250 were administered at 2-3 day intervals with the total amount of 131I-cG250 administered based on the calculated clearance of the initial dose administered on day 1. Whole body activity was maintained at no more than 30 mCi iodine-131.
In the absence of disease progression and after recovery from toxicity, patients could be re-treated beginning 8 weeks after the last treatment of the initial series, for a total of not more than 3 treatments.
Iodine-131 radiolabeled chimeric monoclonal antibody G250 (131I-cG250): cG250 is an IgG1 chimeric monoclonal antibody. It was supplied as a sterile solution at a concentration of 1.0 mg/mL in either a 2 mL or a 5 mL vial. cG250 was radiolabeled with Iodine-131 prior to use. | 9 |
| Cohort 3 100cGy Radiation On day 1, patients received a single dose of 131I-cG250 (5 mCi/5 mg) administered as an intravenous infusion over 10 minutes.
Therapeutic doses of 131I-cG250 were administered the following week as fractionated outpatient doses, starting with 30 mCi/5 mg 131I-cG250. Subsequent doses of 131I-cG250 were administered at 2-3 day intervals with the total amount of 131I-cG250 administered based on the calculated clearance of the initial dose administered on day 1. Whole body activity was maintained at no more than 30 mCi iodine-131.
In the absence of disease progression and after recovery from toxicity, patients could be re-treated beginning 8 weeks after the last treatment of the initial series, for a total of not more than 3 treatments.
Iodine-131 radiolabeled chimeric monoclonal antibody G250 (131I-cG250): cG250 is an IgG1 chimeric monoclonal antibody. It was supplied as a sterile solution at a concentration of 1.0 mg/mL in either a 2 mL or a 5 mL vial. cG250 was radiolabeled with Iodine-131 prior to use. | 3 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 1 |
| Overall Study | Death | 0 | 0 | 1 |
| Overall Study | Physician Decision | 1 | 1 | 0 |
| Overall Study | Progressive Disease | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Cohort 1 50cGy Radiation | Cohort 2 75cGy Radiation | Cohort 3 100cGy Radiation | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 8 Participants | 2 Participants | 13 Participants |
| Region of Enrollment United States | 3 participants | 9 participants | 3 participants | 15 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 2 Participants | 8 Participants | 1 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 9 | 2 / 3 |
| other Total, other adverse events | 3 / 3 | 8 / 9 | 3 / 3 |
| serious Total, serious adverse events | 1 / 3 | 2 / 9 | 3 / 3 |
Outcome results
Primary
Number of Patients With Adverse Events (AEs)
All adverse events occurring during the study were to be recorded on the patient's case report form, and include the following information: a description; date of onset and resolution; severity; relationship to an investigational agent; action taken and outcome. Toxicity was graded in accordance with the NCI CTCAE version 3.0.
Time frame: Up to 12 months
Population: All patients who received at least one dose of 131I-cG250.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 50cGy Radiation | Number of Patients With Adverse Events (AEs) | 3 Participants |
| Cohort 2 75cGy Radiation | Number of Patients With Adverse Events (AEs) | 8 Participants |
| Cohort 3 100cGy Radiation | Number of Patients With Adverse Events (AEs) | 3 Participants |
Primary
Number of Patients With Dose-Limiting Toxicities (DLTs)
Subjects were monitored for Adverse Events (AEs) for at least 8 weeks after the last infusion of 131I-cG250, or until recovery from all toxicity, and prior to dose escalation. Toxicity was graded in accordance with the Common Toxicity Criteria (CTC) of the National Cancer Institute (NCI) Version 3.0. Dose-Limiting Toxicity (DLT) was defined as grade 3 or greater toxicity related to study therapy. The maximum tolerated dose was defined as the highest safely tolerated dose where at most one of six patients experiences a DLT with the next higher dose having at least two patients who experience a DLT.
Time frame: up to 12 months
Population: All patients who received at least one dose of 131I-cG250.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 50cGy Radiation | Number of Patients With Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Cohort 2 75cGy Radiation | Number of Patients With Dose-Limiting Toxicities (DLTs) | 1 Participants |
| Cohort 3 100cGy Radiation | Number of Patients With Dose-Limiting Toxicities (DLTs) | 3 Participants |
Secondary
Number of Patients With Best Overall Tumor Response
Tumor responses were evaluated using computed tomography and categorized according to World Health Organization (WHO) criteria at baseline and at no more than 6 weeks after the last dose, or not more than 12 weeks after entry into the study. Complete Response (CR): disappearance of all measurable disease lasting at least 1 month; Partial Response (PR): ≥ 50% decrease in the size of the product of 2 perpendicular diameters of any measurable lesions and no new lesions, lasting at least one month; Progressive Disease (PD): ≥ 25% increase in the size of any measurable lesions or the appearance of any new lesions; Stable Disease (SD): small changes that do not meet above criteria.
Time frame: Up to 12 weeks
Population: All patients who received study treatment and had at least one pre- and post-treatment tumor measurement.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 50cGy Radiation | Number of Patients With Best Overall Tumor Response | Complete Response (CR) | 0 Participants |
| Cohort 1 50cGy Radiation | Number of Patients With Best Overall Tumor Response | Stable Disease (SD) | 2 Participants |
| Cohort 1 50cGy Radiation | Number of Patients With Best Overall Tumor Response | Progressive Disease (PD) | 1 Participants |
| Cohort 1 50cGy Radiation | Number of Patients With Best Overall Tumor Response | Partial Response (PR) | 0 Participants |
| Cohort 2 75cGy Radiation | Number of Patients With Best Overall Tumor Response | Stable Disease (SD) | 6 Participants |
| Cohort 2 75cGy Radiation | Number of Patients With Best Overall Tumor Response | Complete Response (CR) | 0 Participants |
| Cohort 2 75cGy Radiation | Number of Patients With Best Overall Tumor Response | Progressive Disease (PD) | 1 Participants |
| Cohort 2 75cGy Radiation | Number of Patients With Best Overall Tumor Response | Partial Response (PR) | 0 Participants |
| Cohort 3 100cGy Radiation | Number of Patients With Best Overall Tumor Response | Progressive Disease (PD) | 1 Participants |
| Cohort 3 100cGy Radiation | Number of Patients With Best Overall Tumor Response | Stable Disease (SD) | 1 Participants |
| Cohort 3 100cGy Radiation | Number of Patients With Best Overall Tumor Response | Partial Response (PR) | 0 Participants |
| Cohort 3 100cGy Radiation | Number of Patients With Best Overall Tumor Response | Complete Response (CR) | 0 Participants |
Secondary
Number of Patients With Human Anti-chimeric Antibodies (HACA)
Blood samples were taken at baseline and in weeks 2, 3, 4, 5, and 6 as well as month 6. HACA was measured by an enzyme-linked immunosorbent assay (ELISA) using the double antibody sandwich technique and pretreatment serum as negative control.
Time frame: Up to 6 months
Population: All patients who received study therapy and had blood samples taken for HACA analyses before and after treatment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 50cGy Radiation | Number of Patients With Human Anti-chimeric Antibodies (HACA) | Number of subjects with negative HACA before and after treatment | 2 Participants |
| Cohort 1 50cGy Radiation | Number of Patients With Human Anti-chimeric Antibodies (HACA) | Number of subjects with negative HACA before treatment and positive HACA after treatment | 1 Participants |
| Cohort 2 75cGy Radiation | Number of Patients With Human Anti-chimeric Antibodies (HACA) | Number of subjects with negative HACA before and after treatment | 8 Participants |
| Cohort 2 75cGy Radiation | Number of Patients With Human Anti-chimeric Antibodies (HACA) | Number of subjects with negative HACA before treatment and positive HACA after treatment | 1 Participants |
| Cohort 3 100cGy Radiation | Number of Patients With Human Anti-chimeric Antibodies (HACA) | Number of subjects with negative HACA before treatment and positive HACA after treatment | 0 Participants |
| Cohort 3 100cGy Radiation | Number of Patients With Human Anti-chimeric Antibodies (HACA) | Number of subjects with negative HACA before and after treatment | 3 Participants |