RATIONALENapabucasin is an orally administered small molecule that inhibits the phosphorylation of STAT3. Overactivated STAT3 may drive tumor development by helping to maintain the ability of cancer stem cells to renew and differentiate. Previous studies have shown positive results for napabucasin. In a phase Ib/II study, results confirmed that napabucasin can be safely combined with FOLFIRI, with or without bevacizumab, in patients with advanced CRC who have received an average of >2 prior lines of therapy. In a phase III study, napabucasin monotherapy improved overall survival (OS) versus placebo for patients with pretreated advanced CRC whose tumors tested positive for phosphorylated STAT3.
The international CanStem303C trial is seeking to randomize 1250 patients in a 1:1 ratio to twice-daily napabucasin (240 mg) plus FOLFIRI or to FOLFIRI alone. Bevacizumab can be added in both arms at the investigator’s discretion. The trial’s primary endpoint is an improvement in median OS. Secondary endpoints include OS in biomarker-positive patients, defined as positivity for expression of nuclear beta-catenin, another cancer stemness signaling protein, and/ or phosphorylated STAT3.
To date, the most common adverse event (AE) observed with napabucasin therapy has been diarrhea. “We recommend, in the protocol, very aggressive and preemptive management of diarrhea, so that when the patients start the drug, they have been supplied with antidiarrheal agents, and have been educated that they need to hydrate themselves,” explained lead investigator Axel Grothey, MD, a medical oncologist with Mayo Clinic in Rochester, Minnesota. The other main AE investigators expect to see is fatigue, which is linked to the diarrhea. Other AEs are mild and include nausea, anorexia, and loss of appetite, Grothey said, but there is little to no concern of major toxicity in terms of blood counts, fevers, or high risk of infections. “It gets confounded, of course, by the toxicity of the underlying chemotherapy, the FOLFIRI backbone. It’s something we’ll closely monitor.”