There should only be a few games that give you a file size that large, SMBB, Metroid Prime Trilogy, Metroid: Other M, and Samurai Warriors 3 are the only ones I know of. If other games are going that, you may have another issue to address first. Either way, I see that you did not post which USB Loader you are using. Try to use CFG USB Loader v60, see if that fixes your issue. I also recommend using a FAT32 setup, and in that guide it will show you how to make your ISO files into wbfs files, which act like scrubbed ISOs, in that they take up less HDD space.
Edit: Post a syscheck if possible.