Treatment of Patients With Advanced Renal Cancer With a Radiolabeled Antibody, Yttrium-90 Conjugated Chimeric G250

Study Overview
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Brief Summary
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This was a Phase 1, open-label, dose-escalation study of yttrium-90 conjugated chimeric G250 (^90Y-DOTA-cG250) in patients with advanced, measurable clear cell renal cell carcinoma (RCC). Study objectives were to determine the safety, targeting, and dosimetry of ^90Y-DOTA-cG250, using indium-111 conjugated chimeric G250 (^111In-DOTA-cG250) as a surrogate, as well as to evaluate the immunogenicity of cG250.

Detailed Description
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Patients were enrolled sequentially into cohorts of 3 to 6 patients until determination of the maximum tolerated dose (MTD) of ^90Y-DOTA-cG250, defined as the dose level below the dose at which ≥ 2 patients experienced dose-limiting toxicity (DLT). In an attempt to mitigate liver uptake and toxicity, patients initially received a nontherapeutic injection with ^111In-DOTA-cG250 at an imaging dose of 5 mCi of ^111In + 10 mg of cG250 on Day 1. Whole body and blood measurements of radioactivity were obtained on at least 3 occasions for 1 week to determine targeting and dosimetry. Provided that protocol-specified criteria were met, including targeting to lesions > 2 cm detected on computed tomography (CT) scan, a single dose of therapeutic ^90Y-DOTA-cG250 was administered on Day 8, 9, or 10. The starting dose of ^90Y-DOTA-cG250 was 0.2 mCi/kg of ^90Y + 10 mg of cG250 administered as an intravenous (IV) infusion, with escalation of the ^90Y dose in subsequent cohorts in 0.05 to 0.1 mCi/kg increments. Patients were treated in an outpatient setting and were observed for at least 2 hours following each infusion, at which point vital signs and blood samples were obtained. Patients were followed for 6 to 8 weeks post-treatment (or after recovery from toxicity) with imaging, biochemical, serological, and hematologic tests to determine the safety of ^90Y-DOTA-cG250 and to inform dose-escalation decisions. Extent of disease evaluations, preferably by positron emission tomography (PET)/CT or standard CT, were performed at baseline and 6 to 8 weeks post-treatment (or after recovery from toxicity). Long-term follow-up was performed, when possible, every 12 weeks thereafter for up to 2 years.

Official Title
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Cohort Study of Increasing Doses of Yttrium-90 Conjugated to Chimeric Monoclonal Antibody cG250 (^90Y-DOTA-cG250) in Patients With Advanced Renal Cancer

Conditions
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Renal Cell Carcinoma, Kidney Neoplasm, Renal Cancer, Kidney Cancer

Intervention / Treatment
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* Drug: Yttrium-90 conjugated chimeric G250 (^90Y-DOTA-cG250)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients must have had histologically proven clear cell renal carcinoma. Age ≥ 18 years. Children were not enrolled because clear cell renal cancer is rarely seen in children. All patients must have had a clinical presentation consistent with metastatic renal carcinoma. Patients must have had bidimensionally measurable disease by conventional imaging methods including radiography, ultrasound, CT, or other anatomic imaging modalities. Lesions seen on skeletal scintigraphy alone were not considered measurable. Female patients of childbearing age were required to have a negative pregnancy test carried out the day of and prior to receiving therapy, and were asked to use effective contraception during the study. All patients must have been ambulatory with a Karnofsky Performance Status of at least 70. The following laboratory results within the last 2 weeks prior to study Day 1: serum creatinine ≤ 2.0 mg/dL serum bilirubin (total) ≤ 2.0 mg/dL aspartate aminotransferase (AST) ≤ 2.5 × the upper limit of normal (ULN) alanine aminotransferase (ALT) ≤ 2.5 × ULN white blood cell (WBC) count ≥ 3500/mm^3 platelet count ≥ 100,000/mm^3 prothrombin time ≤ 1.3 × control Able and willing to give valid written informed consent. Exclusion Criteria: Significant prior radiotherapy (> 30 Gy) to the entire pelvis and/or lumbosacral spine. Clinically significant cardiac disease (New York Heart Association Class [III/IV]). Serious infection requiring treatment with antibiotics, or other serious illness. Chemotherapy, radiation therapy, or immunotherapy within 4 weeks prior to study agent administration. Survival expectancy of less than 12 weeks. Patients with central nervous system (CNS) involvement were excluded under the following criteria: Brain metastasis, except for stable disease over 3 months. Untreated brain metastasis. Evidence of progression of neurologic CNS involvement within 3 months prior to entering the protocol. Hypercalcemia > 12.5 mg/100 mL or symptomatic. Mental impairment that may have compromised 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. Patients known to have hepatobiliary disease and/or human immunodeficiency virus/acquired immune deficiency syndrome. Participation in any other clinical trial involving another investigational agent within 4 weeks prior to enrollment. Pregnancy or breastfeeding. Refusal or inability to use effective means of contraception in men or women of childbearing potential.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Patients were enrolled sequentially in cohorts of 3 to 6 patients to receive escalating doses of study treatment until determination of the MTD.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 (0.2 mCi/kg)<br>Patients initially received a nontherapeutic injection of ^111In-DOTA-cG250 (5 mCi ^111In + 10 mg cG250) on Day 1. Pending satisfaction of protocol-specified lesion targeting criteria, a single dose of therapeutic ^90Y-DOTA-cG250 (0.2 mCi/kg ^90Y + 10 mg cG250) was administered on Day 8, 9, or 10 as a continuous IV infusion over approximately 5 to 15 minutes. | Drug: Yttrium-90 conjugated chimeric G250 (^90Y-DOTA-cG250)<br>* Patients received a single infusion of ^90Y-DOTA-cG250, with escalating doses administered to sequentially enrolled cohorts until MTD determination.<br>|
| Experimental: Cohort 2 (0.3 mCi/kg)<br>Patients initially received a nontherapeutic injection of ^111In-DOTA-cG250 (5 mCi ^111In + 10 mg cG250) on Day 1. Pending satisfaction of protocol-specified lesion targeting criteria, a single dose of therapeutic ^90Y-DOTA-cG250 (0.3 mCi/kg ^90Y + 10 mg cG250) was administered on Day 8, 9, or 10 as a continuous IV infusion over approximately 5 to 15 minutes. | Drug: Yttrium-90 conjugated chimeric G250 (^90Y-DOTA-cG250)<br>* Patients received a single infusion of ^90Y-DOTA-cG250, with escalating doses administered to sequentially enrolled cohorts until MTD determination.<br>|
| Experimental: Cohort 3 (0.4 mCi/kg)<br>Patients initially received a nontherapeutic injection of ^111In-DOTA-cG250 (5 mCi ^111In + 10 mg cG250) on Day 1. Pending satisfaction of protocol-specified lesion targeting criteria, a single dose of therapeutic ^90Y-DOTA-cG250 (0.4 mCi/kg ^90Y + 10 mg cG250) was administered on Day 8, 9, or 10 as a continuous IV infusion over approximately 5 to 15 minutes. | Drug: Yttrium-90 conjugated chimeric G250 (^90Y-DOTA-cG250)<br>* Patients received a single infusion of ^90Y-DOTA-cG250, with escalating doses administered to sequentially enrolled cohorts until MTD determination.<br>|
| Experimental: Cohort 4 (0.45 mCi/kg)<br>Patients initially received a nontherapeutic injection of ^111In-DOTA-cG250 (5 mCi ^111In + 10 mg cG250) on Day 1. Pending satisfaction of protocol-specified lesion targeting criteria, a single dose of therapeutic ^90Y-DOTA-cG250 (0.45 mCi/kg ^90Y + 10 mg cG250) was administered on Day 8, 9, or 10 as a continuous IV infusion over approximately 5 to 15 minutes. | Drug: Yttrium-90 conjugated chimeric G250 (^90Y-DOTA-cG250)<br>* Patients received a single infusion of ^90Y-DOTA-cG250, with escalating doses administered to sequentially enrolled cohorts until MTD determination.<br>|
| Experimental: Cohort 5 (0.55 mCi/kg)<br>Patients initially received a nontherapeutic injection of ^111In-DOTA-cG250 (5 mCi ^111In + 10 mg cG250) on Day 1. Pending satisfaction of protocol-specified lesion targeting criteria, a single dose of therapeutic ^90Y-DOTA-cG250 (0.55 mCi/kg ^90Y + 10 mg cG250) was administered on Day 8, 9, or 10 as a continuous IV infusion over approximately 5 to 15 minutes. | Drug: Yttrium-90 conjugated chimeric G250 (^90Y-DOTA-cG250)<br>* Patients received a single infusion of ^90Y-DOTA-cG250, with escalating doses administered to sequentially enrolled cohorts until MTD determination.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Treatment-emergent Adverse Events | Toxicity was graded in accordance with the National Cancer Institute (NCI) Common Toxicity Criteria (CTC), version 3.0. Treatment-emergent adverse events (TEAEs) were reported based on clinical laboratory tests, physical examinations, and vital signs from pre-treatment through the study period. Dose-limiting toxicity (DLT) was defined as follows for the purposes of dose escalation: Grade 4 hematopoietic toxicity in excess of 5 days or Grade 3 or greater nonhematopoietic toxicity. | Continuously for up to 5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Who Met Protocol-Specified Criteria to Receive ^90-Y-DOTA-cG250 Following ^111In-DOTA-cG250 Administration | In order to receive the therapeutic ^90Y-DOTA-cG250 injection on Day 8, 9, or 10, patients must have demonstrated tumor targeting to lesions > 2 cm detected by CT scan and must not have exhibited the following characteristics following the nontherapeutic injection of ^111In-DOTA-cG250: excessive liver and/or spleen uptake; excessive uptake in the normal kidney; non-visualization of the cardiac blood pool in the first imaging set; whole body clearance half-life (t1/2) < 1.5 days; serum t1/2 < 2 days; rapid clearance of the radiopharmaceutical from the blood pool with prominent marrow uptake on the first image. | Up to 5 months | 
| Number of Patients With Samples Collected for Evaluation of Human Antichimeric Antibody | Blood samples were drawn for evaluation of the human antichimeric antibody (HACA) at screening, between Days 22 and 28, between Days 36 and 42, between Days 43 and 57 or at the end of study, and during long-term follow-up (approximately 12 weeks later). Serial dilutions were tested by the enzyme-linked immunosorbent assay (ELISA) using the double antibody sandwich technique and pretreatment serum as negative control. | Up to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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antibody, renal cell carcinoma, advanced renal cancer, cG250, ^90Y