Two big mistakes they made, besides the various clauses that serve as gaping loopholes (necessary n proper, general welfare etc) were not designing into the document how constitutional questions would be resolved, and not providing a means for secession.
You can't go back and undo the Civil War, and I daresay youd have a hard time repealing the 14th amendment. We've got all this SCOTUS precedent that won't be overturned. Thats what I mean by not being able to undo history.
You're apparently referring to the "supremacy" and "commerce" clauses. Neither of which on its face necessarily gives the federales any additional powers outside of those listed in article 1, sec 8. They have been "interpreted" and stretched all out of proportion to something I submit our Founders would not recognize or condone for the most part.
For better or for worse the Constitution is clear that the SCOTUS is the final arbiter of things Constitutional. An agent of the feral government deciding issues between the feral government and the States could conceivably be construed as a conflict of interests, but that IS the plan. Secession like most things in life comes down to a power play, or more simply, are you big enough to get away with it. The feral government has been employing this tactic since the beginning.