Resumen:
Background: Metastatic urothelial carcinoma (mUC) is an aggressive disease associated with poor outcomes. Despite the recent incorporation of several immunotherapy agents targeting the PD-1 pathway, most patients will ultimately experience progressive disease. Moreover, there are no available predictive biomarkers to these novel agents. Clinical studies testing new anticancer drugs embedded with biomarkers analysis are still urgently needed for mUC. Mammalian target of rapamycin (mTOR) is a key intracellular target involved in several cellular signaling pathways, promoting cell proliferation and tumor angiogenesis. TAK-228 is a new investigational mTOR inhibitor of both TORC1 and TORC2. TAK-228 is currently being investigated in several phase II studies as treatment for advanced cancers. Paclitaxel, a taxane chemotherapy that stabilizes microtubules interfering with normal cell division, is a valid treatment option in mUC progressing to platinum-based chemotherapy. The combination of TAK-228 and paclitaxel has shown synergistic activity in bladder cancer cell lines, xenograft models and a phase I trial in advanced solid tumors.
Trial design: This is a single-arm open-label phase II study evaluating the efficacy and safety of TAK-228 (given orally on days 2¿¿¿4, 9¿¿¿11, 16¿¿¿18 and 23¿¿¿25 of 28-day cycles) in combination with paclitaxel (given on days 1, 8 and 15). Eligibility criteria include patients with mUC, performance status 0¿¿¿1, prior platinum-based chemotherapy with no limit in number of lines, adequate organ function and measurable disease. The primary endpoint of the study is objective response rate (ORR). Secondary endpoints include safety, tolerability, progression-free survival and overall survival. As an exploratory endpoint, PI3K/AKT/mTOR pathway mutations will be characterized and correlated with clinical outcomes. A maximum of 52 patients will be enrolled in order to obtain 40 evaluable patients. The combination will be considered for further testing should the ORR increase from a historical 10% to¿¿¿26%. A sample size of 40 patients will have a 90% power to detect this change with a 10% alpha risk. The trial is open, and enrollment is ongoing.
