Trial example
toxicity, TNBC, Toxicity, thyroid cancer
TRIPLE-NEGATIVE BREAST CANCER, SOLID TUMOR, T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA, REGRESSION, TUMOR GROWTH, THYROID CANCER
To further evaluate the proposed strategy, we applied the proposed design to a clinical trial of PF03084014 combined with doxorubicin for the treatment of advanced triple-negative breast cancer (TNBC). PF-03084014 is a reversible, noncompetitive, and selective secretase inhibitor that blocks the NOTCH signaling pathway. In preclinical studies, this combination has demonstrated anticancer efficacy in solid tumor models, such as advanced thyroid cancer and sclerofibrosarcoma, and in T-cell acute lymphoblastic leukemia. In TNBC patient-derived and cell lineage xenograft models, the combination of PF-03084014 with doxorubicin greatly improved the inhibition of tumor growth [In this phase I study (A8641016), patients with advanced TNBC were evaluated for safety, tolerability, pharmacokinetics, and antitumor efficacy. The goal of the study was to determine the MTDC of the drug PF03084014 when combined with the chemotherapy drug doxorubicin. The dose exploration component used a modified probability interval technique based on a 2 × 3 matrix design to evaluate toxicity. On day 1 of each 21-day cycle, oral PF-03084014 was coadministered with intravenous doxorubicin twice a day.To redesign the trial, we fitted logistic regression models to the data observed in this PF03084014 with doxorubicin combination trial. Table Toxicity scenarios for PF03084014 in combination with doxorubicinThe target toxicity probability was set to 0.33, the maximum sample size was 30 patients, the cohort size was 3, and the first group of patients was treated with the lowest dose combination (1, 1). After the parameter set simulation, the optimal parameters Example of PF03084014 in combination with doxorubicinAs shown in Fig. Example results of the PF03084014 and doxorubicin combination trial“-” represents a dose combination that was not administered in the trial. The dose combination (2, 2) is selected as the MTDC. As shown in Figs. 