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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT00199875
Recruitment Status : Completed
First Posted : September 20, 2005
Results First Posted : November 28, 2018
Last Update Posted : November 28, 2018
Sponsor:
Collaborator:
Memorial Sloan Kettering Cancer Center
Information provided by (Responsible Party):
Ludwig Institute for Cancer Research

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Renal Cell Carcinoma Kidney Neoplasm Renal Cancer Kidney Cancer Drug: Yttrium-90 conjugated chimeric G250 (^90Y-DOTA-cG250) Phase 1

Detailed Description:

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention 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)
Primary Purpose: Treatment
Official Title: Cohort Study of Increasing Doses of Yttrium-90 Conjugated to Chimeric Monoclonal Antibody cG250 (^90Y-DOTA-cG250) in Patients With Advanced Renal Cancer
Actual Study Start Date : July 6, 2005
Actual Primary Completion Date : March 14, 2013
Actual Study Completion Date : March 14, 2013

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Cancer

Arm Intervention/treatment
Experimental: Cohort 1 (0.2 mCi/kg)
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)
Patients received a single infusion of ^90Y-DOTA-cG250, with escalating doses administered to sequentially enrolled cohorts until MTD determination.

Experimental: Cohort 2 (0.3 mCi/kg)
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)
Patients received a single infusion of ^90Y-DOTA-cG250, with escalating doses administered to sequentially enrolled cohorts until MTD determination.

Experimental: Cohort 3 (0.4 mCi/kg)
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)
Patients received a single infusion of ^90Y-DOTA-cG250, with escalating doses administered to sequentially enrolled cohorts until MTD determination.

Experimental: Cohort 4 (0.45 mCi/kg)
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)
Patients received a single infusion of ^90Y-DOTA-cG250, with escalating doses administered to sequentially enrolled cohorts until MTD determination.

Experimental: Cohort 5 (0.55 mCi/kg)
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)
Patients received a single infusion of ^90Y-DOTA-cG250, with escalating doses administered to sequentially enrolled cohorts until MTD determination.




Primary Outcome Measures :
  1. Number of Patients With Treatment-emergent Adverse Events [ Time Frame: Continuously for up to 5 months ]
    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.


Secondary Outcome Measures :
  1. Number of Patients Who Met Protocol-Specified Criteria to Receive ^90-Y-DOTA-cG250 Following ^111In-DOTA-cG250 Administration [ Time Frame: Up to 5 months ]
    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.

  2. Number of Patients With Samples Collected for Evaluation of Human Antichimeric Antibody [ Time Frame: Up to 6 months ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. All patients must have had histologically proven clear cell renal carcinoma.
  2. Age ≥ 18 years. Children were not enrolled because clear cell renal cancer is rarely seen in children.
  3. All patients must have had a clinical presentation consistent with metastatic renal carcinoma.
  4. 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.
  5. 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.
  6. All patients must have been ambulatory with a Karnofsky Performance Status of at least 70.
  7. 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
  8. Able and willing to give valid written informed consent.

Exclusion Criteria:

  1. Significant prior radiotherapy (> 30 Gy) to the entire pelvis and/or lumbosacral spine.
  2. Clinically significant cardiac disease (New York Heart Association Class [III/IV]).
  3. Serious infection requiring treatment with antibiotics, or other serious illness.
  4. Chemotherapy, radiation therapy, or immunotherapy within 4 weeks prior to study agent administration.
  5. Survival expectancy of less than 12 weeks.
  6. 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.
  7. Hypercalcemia > 12.5 mg/100 mL or symptomatic.
  8. Mental impairment that may have compromised the ability to give informed consent and comply with the requirements of the study.
  9. Lack of availability of the patient for clinical and laboratory follow-up assessment.
  10. Patients known to have hepatobiliary disease and/or human immunodeficiency virus/acquired immune deficiency syndrome.
  11. Participation in any other clinical trial involving another investigational agent within 4 weeks prior to enrollment.
  12. Pregnancy or breastfeeding.
  13. Refusal or inability to use effective means of contraception in men or women of childbearing potential.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00199875


Locations
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United States, New York
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10021
Sponsors and Collaborators
Ludwig Institute for Cancer Research
Memorial Sloan Kettering Cancer Center
Investigators
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Principal Investigator: Steven Larson, MD Memorial Sloan Kettering Cancer Center
Principal Investigator: Neeta Pandit-Taskar, MD Memorial Sloan Kettering Cancer Center
Principal Investigator: Joseph O'Donoghue, PhD Memorial Sloan Kettering Cancer Center
Principal Investigator: Robert Motzer, MD Memorial Sloan Kettering Cancer Center

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Responsible Party: Ludwig Institute for Cancer Research
ClinicalTrials.gov Identifier: NCT00199875     History of Changes
Other Study ID Numbers: LUD2002-022
MSKCC IRB #: 05-031 ( Other Identifier: MSKCC IRB )
First Posted: September 20, 2005    Key Record Dates
Results First Posted: November 28, 2018
Last Update Posted: November 28, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Ludwig Institute for Cancer Research:
antibody
renal cell carcinoma
advanced renal cancer
cG250
^90Y

Additional relevant MeSH terms:
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Carcinoma, Renal Cell
Kidney Neoplasms
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Antibodies
Immunoglobulins
Immunologic Factors
Physiological Effects of Drugs