I only know so much about this period, but I daresay weakening the Ottomans is a necessary precondition for this, if only because Venice lost so much in direct confrontations with them. So some sort of POD in the 1400's would work best. Then, if they could be persuaded to hitch their wagon to the Hapsburgs during an ATL-Italian Wars, that could end with them dominating northern Italy, while the Spanish control the south. It's a start.