clinically more convenient subcutaneous route. 
Injections will be alternated in a grid pattern. Equivalent numbers of 
injections of subcutaneous and intradermal doses in the same limb should allow 
local toxicities between the two routes to be compared by parameters described 
in Section 7 using the patient as his or her own control. India Ink or tatoos 
might confound the dermatologic evaluation following vaccination; for this 
trial a custom-made, foam rubber grid will be made for each treated limb to 
ensure injection positioning and evaluation of vaccination sites over time. 
3.6.g. Potential Toxicities 
Potential Toxicity from GM-CSF Secretion 
Toxicities from GM-CSF gene transduced human RCC tumor vaccines are 
difficult to predict. In over 40 separate experiments (>400 mice) escalating 
the cell dosage of B16 melanoma tumor vaccine or RENCA murine RCC with fixed 
secretion of GM-CSF has shown only reversible lymphadenopathy and reversible 
subcutaneous swelling. (Appendix 14. A. 2) No ulcerations in the vaccinated limb 
were observed. Common clinical toxicities predicted from previous phase I and 
phase II studies of recombinant GM-CSF given by subcutaneous injection are 
fever, malaise, and bone pain putatively from proliferation of bone marrow 
precursors. Toxicities from leukocytosis may also be encountered. In the 
human pharmokinetic study of single dose subcutaneous GM-CSF cited above, a 
700 meg subcutaneous injection achieved a serum level of >lng/mL, which 
corresponds to the concentration of rhuGM-CSF supporting near-maximum 
proliferation of human myeloid progenitors in vitro . Less common and case 
reports of toxicities for GM-CSF are listed below and referenced in Table 15. 
TABLE 15 POTENTIAL TOXICITIES OF GM-CSF SECRETION 
-ystemic Toxicity from GM-CSF Administration Reference 
Fever 1 
Transient Leucopenia 2 
Transient Leukocytosis 3 
Diarrhea 4 
Weight Gain/Fluid Retention 4,5 
Malaise 5,6 
Bone Pain 5,6 
Arthralgia 5 , 6 
Liver Transaminase Elevation 6 
Hemolysis 1,7 
Rheumatoid Arthritis 5,6 
Leukoclastic Vasculitis 8 
Renal Failure (after bone marrow transplantation) 5,9 
Severe Hypocalcaemia with Leukocytosis 10 
Eosinophilia , Splenic Hematopoiesis 11,15 
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