Phase I/II Dose-escalation Study of Lutetium-177-labeled cG250 in Patients With Advanced Renal Cancer

This was a Phase I/II, single-center, dose-escalation study. 177-Lutetium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-cG250 (177-Lu-DOTA-cG250) was administered at a starting dose of 30 mCi/m\^2 of 177-Lu (fixed dose of 10 mg cG250) and escalated in increments of 10 mCi/m\^2 of 177-Lu in sequentially enrolled cohorts according to a standard 3 + 3 design until determination of the maximum tolerated dose (MTD). The primary objectives were to determine the safety, targeting, and dosimetry of 177-Lu-DOTA-cG250 in subjects with advanced renal cell carcinoma. The secondary objective was measurement of tumor response according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0.

Prior to administration of 177-Lu-DOTA-cG250, subjects received 5 mCi/10 mg of the 111-Indium-DOTA-cG250 (111-In-DOTA-cG250) antibody (an imaging dose). Whole body and blood measurements of radioactivity were obtained on at least 3 occasions for 1 week to determine targeting and dosimetry. If at least one known and evaluable metastatic lesion was visualized with 111-In-DOTA-cG250, a single dose of therapeutic 177-Lu-DOTA-cG250 was administered the following week. In the absence of disease progression and after recovery from toxicity, subjects may have been retreated no sooner than 12 weeks after the previous treatment with a dose of no more than 75% of the previous dose, for a total of not more than 3 treatments. Only subjects with normal pharmacokinetics on the diagnostic 111-In-DOTA-cG250 study (indicative of human anti-chimeric antibody \[HACA\] negativity) were eligible for re-treatment.

Subjects in the initial cohort were enrolled sequentially to receive 30 mCi/m\^2 of 177-Lu-DOTA-cG250 (fixed dose of 10 mg cG250). In the absence of a dose-limiting toxicity, the dose was escalated in each subsequent cohort in 10 mCi/m\^2 increments of 177-Lu. At least 3 subjects per dose level were followed for up to 12 weeks with imaging, biochemical, and hematologic tests. Safety was monitored continuously throughout the study.

Eligibility Criteria:
Inclusion Criteria:

1. Subjects with proven advanced and progressive renal cell carcinoma (RCC) of the clear cell type.
2. At least one evaluable lesion \< 5 cm.
3. Karnofsky performance status ≥ 70%.
4. Laboratory values obtained \< 14 days prior to registration:

   * White blood cells (WBC) ≥ 3.5 × 10\^9/L
   * Platelet count ≥ 100 × 10\^9/L
   * Hemoglobin ≥ 6 mmol/L
   * Total bilirubin ≤ 2 × upper limit of normal (ULN)
   * Aspartate aminotransferase and alanine aminotransferase ≤ 3 × ULN (\< 5 × ULN if liver metastases present)
   * Serum creatinine ≤ 2 × ULN
5. Negative pregnancy test for women of childbearing potential (urine or serum).
6. Age over 18 years.
7. Ability to provide written informed consent.

Exclusion Criteria:

1. Known metastases to the brain.
2. Untreated hypercalcemia.
3. Metastatic disease limited to the bone.
4. Pre-exposure to murine/chimeric antibody therapy.
5. Chemotherapy, external beam radiation or immunotherapy within 4 weeks prior to study. Limited field external beam radiotherapy to prevent pathological fractures was allowed, when unirradiated, evaluable lesions were present elsewhere.
6. Cardiac disease with New York Heart Association classification of III or IV.
7. Subjects who were pregnant, nursing or of reproductive potential and were not practicing an effective method of contraception.
8. Any unrelated illness, e.g., active infection, inflammation, medical condition or laboratory abnormality, that in the judgement of the investigator would have significantly affected the subject's clinical status.
9. Life expectancy \< 6 months.