In January 1526, with the Treaty of Madrid, Frances I was set free, but forced to concede to the winners all the territories in dispute, starting with Milan. Then, taking advantage of the fears about the growing power of Charles V, the French King promoted an anti-imperial alliance, the League of Cognac, that, in May 1526, united in a cause front France, Rome, Venice and Florence.
The Emperor, informed of these facts, protested to Castiglione, to whom he even wrote numerous autographed letters proclaiming his desire for peace. The apostolic nuncio, because of the repeated and oscillating changes in strategy made by the Pope, felt trapped in a situation he could not easily see his way out of, and indeed he could see the impending doom. Partly he did not know the decisions of the Pope, and partly they contrasted with what he was told and with his own advice. Thus, facing the growing criticisms of the humanists in the Spanish court, filled with the ideas of reform of Erasmus and inclined to be polemical about the customs of the court in Rome, he had no instruments with which to fight back. The tension between Madrid and Rome was such that the good faith that he continued to see in the Emperor bore no fruits. At the end of July 1526, at Granada, the Secretary of State of Clemente VII, Nicolaus Schömberg, confessed that he no longer had room to move: “I have spoken at length to His Majesty, and how satisfied I found him Your Lordship can well imagine. He is greatly worried, and if nothing other than the League had been done, and if it did not appear to have been created to damage him, I think he would not feel it so much. But he tells me that they are constantly writing to him to tell him that the Pope wants to take the Kingdom of Naples from him, excommunicate him and relieve him of his empire. And this upsets His Majesty, feeling that he does not deserve it, and, as far as I can see, he is prepared to loose everything he has, rather than be forced to come to a dishonourable agreement. Here we are doing what we can. May God in his great mercy lend a hand to put out this fire” (B. Castiglione, Lettere, edited by P. Serassi, II, Padova 1771, 60-61).