Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are potent anticancer agents in preclinical models. Efatutazone is a novel, third-generation thiazolidinedione (TZD) showing higher potency over second-generation TZDs, such as pioglitazone. Now, phase 2 clinical trials of efatutazone in patients with metastatic non-small-cell lung cancer and colorectal cancer at doses of 0.50 mg twice-daily (BID) are ongoing in the USA and Europe.Methods
This phase 1 dose-escalation study using a 3 + 3 design was initiated in Japanese patients with metastatic solid tumors. Patients with preexisting severe fluid retention were excluded. Efatutazone was administered orally BID starting at a dose of 0.25 mg. Pharmacodynamic (PD) and pharmacokinetic (PK) samples were collected on days 1 and 22. Archived tumor specimens were used for immunohistochemistry (IHC). Primary objectives of this study were to assess safety profile and PK. All subjects provided written informed consent.Results
A total of 13 patients were enrolled (eight males and five females; age range 45–73 years), and received treatment at doses 0.25 mg BID (n = 4), 0.50 mg BID (n = 6) and 0.75 mg BID (n = 3). Efatutazone was tolerated. Dose-limiting toxicity (DLT) was not observed, but one grade 3 edema, unresponsive to therapy, occurred after the DLT evaluation period (day 27). The maximum tolerated dose (MTD) was not reached. Observed common adverse events were edema (85%), weight increase (85%), hemoglobin decrease (54%) and creatinine increase (54%). All patients were evaluable for response. One subject with thymic cancer achieved a partial response (treatment duration >365 days as of 19 Janurary 2012). In addition, 3 out of 13 patients showed stable disease. Efatutazone increased plasma adiponectin levels. Plasma concentration of efatutazone and adiponectin had a tendency to be saturated in the 0.50 mg cohort. Results of IHC showed no clear correlation between the immunostaining intensity of PPARγ and the efficacy of efatutazone.Conclusions
Efatutazone is a novel anticancer therapy, which is tolerated and demonstrates evidence of antitumor activity and disease stabilization. Although the MTD was not reached, 0.50 mg BID, corresponding to the global recommended dose, was selected as the recommended phase 2 dose.