PHASE II STUDY OF LUTETIUM-177 LABELED CHIMERIC MONOCLONAL ANTIBODY cG250 (177Lu-DOTA-cG250) IN PATIENTS WITH ADVANCED RENAL CANCER

Renal Cell Carcinoma (RCC) is the most common malignancy arising in the kidney.
In the US alone, each year 51,000 people are diagnosed with RCC and 13,000
people die from the disease. Thirty percent of patients with RCC will present
with metastatic disease, whereas of the other 70% treated by nephrectomy,
30-40% will eventually relapse (1). RCC is known as a chemotherapy and
radiation resistant tumor (2;3). Treatment modalities for metastasized disease
include immunotherapy with interferon-α and interleukin-2. Response rates,
however, are low in the range of 5-25% and side-effects are significant (4;5).
Recently, the use of angiogenesis inhibitors Sorafenib and Sunitinib have been
introduced for treatment of this disease. And although response rates are high
(partial responses up to 30%), no patient thus far has been cured using these
new substances and again, side-effects are common and often severe in nature
(6;7). So although advances have been made in the management of metatastic RCC,
there is still a need for a more effective treatment.
Chimeric monoclonal antibody (mAb) G250 (cG250) is a high-affinity (Ka = 4 x
109 M-1) chimeric, IgG1 mAb, reactive with carbonic anhydrase IX (8-10), a
transmembraneous glycoprotein (11-13). Studies showed an almost ubiquitous
expression (>90%) of G250-antigen in clear cell RCC (ccRCC), being the most
prominent histologic type of RCC (80% of cases). Expression in normal tissues
has been evaluated extensively and it has shown to be restricted to the
gastrointestinal mucosa (stomach, ileum, proximal and middle colon) and
gastrointestinal related structures (intra- and extrahepatic biliary system,
pancreas) (10;14).
The chimeric form of the mAb was designed to allow multiple administrations,
since the murine form of G250 induced Human Anti Mouse Antibodies (HAMA) in all
patients even at very low protein doses (<1 mg) (8).
Various clinical studies have been performed with mAb cG250. In a protein
dose-escalation study focal uptake of 131I-labeled cG250 in RCC lesions was
found to be extremely high (up to 0.52 %ID/g) (8;15). In the subsequent
activity dose-escalation study in progressive ccRCC patients with 131I-cG250 a
Maximum Tolerated Dose (MTD) of 2220 MBq/m2 was found. In this study 12
patients with progressive metastatic disease were treated; in one patient
stable disease was achieved and in another a partial response was noted (9).
These findings led to a phase I/II study where patients were treated with
131I-cG250 at the MTD found in the previous study. After 3 months patients were
retreated with 131I-cG250, the MTD of this 2nd injection was found to be 1665
MBq/m2 (=75% of the first dose). Although no objective responses were seen,
stabilisation of previously progressive disease was noted in 4 of 16 (25%)
patients treated at the optimal dose level (16).
In radioimmunotherapy (RIT) experiments in xenografted nude mice, tumor growth
was delayed more effectively with 177Lu-cG250 (185 days) than with 131I-cG250
(25 days) (17). Moreover, an intrapatient comparison revealed higher uptake of
cG250 labeled with the residualizing radionuclide 111In as compared to
131I-cG250 (18), indicating that higher radiation doses could be guided to
tumor lesions when cG250 was labeled with a residualising radionuclide such as
177Lu or 90Y (17).

Primary objective:
- To determine the clinical efficacy of multiple doses of 177Lu-DOTA-cG250 at
MTD in patients with advanced renal cancer using RECIST criteria

Secondary objectives:
- To determine the toxicity of the treatment as defined by NCI Common
Terminology Criteria for Adverse Events (CTCAE v3.0)
- To determine the targeting and dosimetry of 111In-DOTA-cG250 in patients with
advanced renal cancer, as a surrogate for 177Lu-DOTA-cG250
- To determine progression-free survival of study patients

This is a Phase II study using 177Lu-DOTA-cG250 for treatment of patients with
advanced renal cell carcinoma. Patients will be treated at the previously
determined MTD of 2405 MBq/m2 177Lu-DOTA-cG250. If patients respond to therapy
(objective tumor response or stabilization of previously progressive disease)
they are eligible for a maximum of three treatment cycles. The disease status
of patients will be monitored during each cycle for 13 weeks with imaging,
biochemical and hematologic tests. CT scans will be carried out at baseline and
12 weeks after each treatment, for response assessment.
For a detailed description see study protocol pages 5 and 6 or the study flow
chart in the protocol.

not applicable

Burden of the study per cyclus:
- Week 1: screening and injection 111In-cG250 (day 1) and 2 scans (day 2-4 and
5-7)
- Week 2: injection 177Lu-cG250 and subsequent hospital admission for 1 night
only
- Week 3 until 8: Weekly visit UMCN for blood draw and physical examination
- Week 3 until 6: during fulminant hematological toxicity increased checks
laboratory values
- Week 12: CT-scan
- Week 13: evaluation CT-scan and blood draw

Risks:
- First days post-injection 177Lu-cG250: fatigue, nausea and malaise (lasts on
average 1 week and is ubiquitous)
- Week 3 until 6: Hematological toxicity, for which possible extra checks
laboratory values (lasts on average 2 weeks and on this dose level in the phase
I study no patients had to be admitted for transfusions)
- On multiple cycles with cG250 injections possible HACA formation, although no
allergic reactions have been noted