Phase I trial of exisulind (sulindac sulfone, FGN-1) as a chemopreventive agent in patients with familial adenomatous polyposis

Exisulind (sulindac sulfone; FGN-1), a metabolite of sulindac without known effects on prostaglandin synthesis, can promote apoptosis and inhibit tumo rigenesis in preclinical systems. We performed a Phase I trial of this comp ound in patients with familial adenomatous polyposis (FAP) to examine the t olerability and safety of this drug in the cancer chemoprevention setting. Six patients each were treated with exisulind at doses of 200, 300, and 400 mg p.o. twice a day. Reversible hepatic dysfunction was noted in four of s ix patients treated at the 400-mg p.o., twice-a-day dose level, but in only one to two of six patients treated at each of the lower dose levels. The s erum half-life of exisulind was 6-9 h; little drug accumulation was noted o ver time. A nonsignificant trend toward increased apoptosis in polyps was n oted at the maximum tolerated dose, but no decrease in polyp numbers or sig nificant effects on cellular proliferation was noted. After treatment, poly ps tended to display a "halo" appearance grossly and mucinous differentiati on histologically, The maximum safe dose of exisulind is 300 mg p.o. twice a day in patients with subtotal colectomies. Reversible hepatic dysfunction limits further dose escalation. A decrease in polyp numbers could not be d emonstrated, but the trend toward increased apoptosis at the MTD and the ob servation of mucinous change histologically suggest that further investigat ion of drugs of this class might be warranted.