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

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
Phase I/II Study of Increasing Doses of Lutetium-177 Labeled Chimeric Monoclonal Antibody cG250 (177^Lu-DOTA-cG250) in Patients With Advanced Renal Cancer

Conditions
-----------------
Metastatic Renal Cell Carcinoma

Intervention / Treatment
-----------------
* Drug: 111-In-DOTA-cG250
* Drug: 177-Lu-DOTA-cG250


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects with proven advanced and progressive renal cell carcinoma (RCC) of the clear cell type. At least one evaluable lesion < 5 cm. Karnofsky performance status ≥ 70%. 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 Negative pregnancy test for women of childbearing potential (urine or serum). Age over 18 years. Ability to provide written informed consent. Exclusion Criteria: Known metastases to the brain. Untreated hypercalcemia. Metastatic disease limited to the bone. Pre-exposure to murine/chimeric antibody therapy. 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. Cardiac disease with New York Heart Association classification of III or IV. Subjects who were pregnant, nursing or of reproductive potential and were not practicing an effective method of contraception. 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. Life expectancy < 6 months.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1, 30 mCi/m^2 177-Lu-DOTA-cG250<br>Subjects received an initial single dose of 10 mg of cG250 coupled to DOTA and labeled with 30 mCi/m^2 of 177-Lu. | Drug: 111-In-DOTA-cG250<br>* On Day 1, each subject received a single intravenous (IV) infusion of 10 mg of cG250 coupled to DOTA and labeled with 5 mCi of 111-In.<br>* Other names: cG250-In111;Drug: 177-Lu-DOTA-cG250<br>* On Day 8, 9, or 10, each subject received a single IV infusion of 10 mg of cG250 coupled to DOTA and labeled with a dose of 177-Lu at a starting dose of 30 mCi/m^2 in the initial cohort.<br>* Other names: cG200-Lu177;|
| Experimental: Cohort 2, 40 mCi/m^2 177-Lu-DOTA-cG250<br>Subjects received an initial single dose of 10 mg of cG250 coupled to DOTA and labeled with 40 mCi/m^2 of 177-Lu. | Drug: 111-In-DOTA-cG250<br>* On Day 1, each subject received a single intravenous (IV) infusion of 10 mg of cG250 coupled to DOTA and labeled with 5 mCi of 111-In.<br>* Other names: cG250-In111;Drug: 177-Lu-DOTA-cG250<br>* On Day 8, 9, or 10, each subject received a single IV infusion of 10 mg of cG250 coupled to DOTA and labeled with a dose of 177-Lu at a starting dose of 30 mCi/m^2 in the initial cohort.<br>* Other names: cG200-Lu177;|
| Experimental: Cohort 3, 50 mCi/m^2 177-Lu-DOTA-cG250<br>Subjects received an initial single dose of 10 mg of cG250 coupled to DOTA and labeled with 50 mCi/m^2 of 177-Lu. | Drug: 111-In-DOTA-cG250<br>* On Day 1, each subject received a single intravenous (IV) infusion of 10 mg of cG250 coupled to DOTA and labeled with 5 mCi of 111-In.<br>* Other names: cG250-In111;Drug: 177-Lu-DOTA-cG250<br>* On Day 8, 9, or 10, each subject received a single IV infusion of 10 mg of cG250 coupled to DOTA and labeled with a dose of 177-Lu at a starting dose of 30 mCi/m^2 in the initial cohort.<br>* Other names: cG200-Lu177;|
| Experimental: Cohort 4, 60 mCi/m^2 177-Lu-DOTA-cG250<br>Subjects received an initial single dose of 10 mg of cG250 coupled to DOTA and labeled with 60 mCi/m^2 of 177-Lu. | Drug: 111-In-DOTA-cG250<br>* On Day 1, each subject received a single intravenous (IV) infusion of 10 mg of cG250 coupled to DOTA and labeled with 5 mCi of 111-In.<br>* Other names: cG250-In111;Drug: 177-Lu-DOTA-cG250<br>* On Day 8, 9, or 10, each subject received a single IV infusion of 10 mg of cG250 coupled to DOTA and labeled with a dose of 177-Lu at a starting dose of 30 mCi/m^2 in the initial cohort.<br>* Other names: cG200-Lu177;|
| Experimental: Cohort 5, 70 mCi/m^2 177-Lu-DOTA-cG250<br>Subjects received an initial single dose of 10 mg of cG250 coupled to DOTA and labeled with 70 mCi/m^2 of 177-Lu. | Drug: 111-In-DOTA-cG250<br>* On Day 1, each subject received a single intravenous (IV) infusion of 10 mg of cG250 coupled to DOTA and labeled with 5 mCi of 111-In.<br>* Other names: cG250-In111;Drug: 177-Lu-DOTA-cG250<br>* On Day 8, 9, or 10, each subject received a single IV infusion of 10 mg of cG250 coupled to DOTA and labeled with a dose of 177-Lu at a starting dose of 30 mCi/m^2 in the initial cohort.<br>* Other names: cG200-Lu177;|
| Experimental: Cohort 6, 65 mCi/m^2 177-Lu-DOTA-cG250<br>Subjects received an initial single dose of 10 mg of cG250 coupled to DOTA and labeled with 65 mCi/m^2 of 177-Lu. | Drug: 111-In-DOTA-cG250<br>* On Day 1, each subject received a single intravenous (IV) infusion of 10 mg of cG250 coupled to DOTA and labeled with 5 mCi of 111-In.<br>* Other names: cG250-In111;Drug: 177-Lu-DOTA-cG250<br>* On Day 8, 9, or 10, each subject received a single IV infusion of 10 mg of cG250 coupled to DOTA and labeled with a dose of 177-Lu at a starting dose of 30 mCi/m^2 in the initial cohort.<br>* Other names: cG200-Lu177;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Treatment-emergent Adverse Events | Toxicity was graded in accordance with the NCI CTCAE version 3.0. Treatment-emergent adverse events (TEAEs) were reported based on clinical laboratory tests, physical examinations, and vital signs from pre-treatment through 4 weeks after the last dose of study treatment. | Up to 1 year | 
| Number of Subjects With Dose-limiting Toxicity (DLT) During Cycle 1 | Subjects were monitored for AEs for ≥ 8 weeks after the last infusion of 177-Lu-DOTA-cG250 before dose escalation could be implemented. Toxicity was graded in accordance with the NCI CTCAE version 3.0. DLT was defined as the following treatment-related events: ≥ Grade 3 non-hematologic toxicity; ≥ Grade 4 hematologic toxicity (platelets < 25 × 10^9/L or leukocytes < 1.0 × 10^9/L) that persisted for > 4 weeks except anemia; thrombocytopenia < 10 × 10^9/L; clinically relevant myelotoxicity that required hospitalization and/or blood product transfusion (e.g., uncontrolled bleeding, infections that had to be treated clinically). | 12 weeks | 
| Radiation Absorbed Doses by Organ for 177-Lu-cG250 | After each 177-Lu-cG250 administration, 3 whole-body scintigrams were acquired (directly after injection and 2-4 days and 5-7 days post-injection) and blood samples were drawn at 5, 30, 60, and 120 min, 2-4 days, and 5-7 days post-infusion. Estimated radiation absorbed doses were calculated according to the Medical Internal Radiation Dose scheme, which permits estimation of the factors required to calculate dose to one organ attributable to a source in another organ. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Best Overall Tumor Response | Tumor responses were evaluated using computed tomography and categorized according to RECIST v1.0 at baseline and at the end of every cycle (every 12 weeks) or after recovery from toxicity. Per RECIST v1.0 for target lesions and assessed by MRI: Complete Response (CR): Disappearance of all target lesions [no evidence of disease]; 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. | Up to 9 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Monoclonal Antibody, Advanced Renal Cell Carcinoma, Clear Cell Renal Cell Carcinoma (CCRCC), Lutetium-177, 177-Lu, cG250, DOTA-cG250