Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center initiative.

PURPOSE: We initiated a personalized medicine program in the context of early clinical trials, using targeted agents matched with tumor molecular aberrations. Herein, we report our observations. PATIENT AND METHODS: Patients with advanced cancer were treated in the Clinical Center for Targeted Therapy. Molecular analysis was conducted in the MD Anderson Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. Patients whose tumors had an aberration were treated with matched targeted therapy, when available. Treatment assignment was not randomized. The clinical outcomes of patients with molecular aberrations treated with matched targeted therapy were compared with those of consecutive patients who were not treated with matched targeted therapy. RESULTS: Of 1,144 patients analyzed, 460 (40.2%) had 1 or more aberration. In patients with 1 molecular aberration, matched therapy (n = 175) compared with treatment without matching (n = 116) was associated with a higher overall response rate (27% vs. 5%; P < 0.0001), longer time-to-treatment failure (TTF; median, 5.2 vs. 2.2 months; P < 0.0001), and longer survival (median, 13.4 vs. 9.0 months; P = 0.017). Matched targeted therapy was associated with longer TTF compared with their prior systemic therapy in patients with 1 mutation (5.2 vs. 3.1 months, respectively; P < 0.0001). In multivariate analysis in patients with 1 molecular aberration, matched therapy was an independent factor predicting response (P = 0.001) and TTF (P = 0.0001). CONCLUSION: Keeping in mind that the study was not randomized and patients had diverse tumor types and a median of 5 prior therapies, our results suggest that identifying specific molecular abnormalities and choosing therapy based on these abnormalities is relevant in phase I clinical trials.

Phase I clinical trial outcomes in 93 patients with brain metastases: the MD anderson cancer center experience.

PURPOSE: Patients with brain metastases are often excluded from clinical trials, but it is unclear whether they pose an enhanced risk. EXPERIMENTAL DESIGN: We reviewed the records of 1,181 consecutive patients, with and without brain metastases, treated in our Phase I Clinical Trials Program. RESULTS: Ninety-three patients had brain metastases at the time of referral. Their median age was 54 years; median follow-up, 8 months. The rates of stable disease ≥ 4 months, partial response, and complete response combined in patients with and without brain metastases were 17% and 27%, respectively (P = 0.03). Although the median survival of patients with brain metastases was shorter than that of patients without brain metastases (7.5 vs. 10.3 months; P = 0.002), in multivariate analysis, the presence of brain metastases was not an independent factor predicting survival. There was no difference in time-to-treatment failure (1.74 vs. 1.84 months, respectively; P = 0.61) or in grade 3 and 4 toxicity rates (including neurologic; 12% vs. 10%, respectively; P = 0.77) between patients with and without brain metastases. CONCLUSIONS: The rates of survival and response of patients with brain metastases were lower than those for other patients in the phase I setting, but the presence of brain metastases was not an independent prognostic factor predicting survival, indicating that other covariates that coexist with brain metastases were more significant. Time-to-treatment failure for patients with brain metastases was not decreased, nor was the incidence of serious adverse effects (including neurologic toxicity) increased, suggesting that these patients should be eligible for early clinical trials.