Personalized Medicine in a Phase I Clinical Trials Program: The MD Anderson Cancer Center Initiative

Abstract

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.

Precision Oncology: The UC San Diego Moores Cancer Center PREDICT Experience

“…In addition, the availability of targeted drugs has dramatically increased since Von Hoff's study in 2010 (22). Similarly, Tsimberidou and colleagues (31) showed that matched therapy (n ¼ 175) compared with treatment without matching (n ¼ 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), longer survival (median, 13.4 vs. 9.0 months; P ¼ 0.017), and longer TTF compared with their prior systemic therapy (5.2 vs. 3.1 months, respectively; P < 0.0001); in multivariate analysis, matched therapy was an independent factor predicting response (P ¼ 0.001) and TTF (P ¼ 0.0001).…”

On the Road to Precision Cancer Medicine: Analysis of Genomic Biomarker Actionability in 439 Patients

“…Beyond logistics, a fundamental question relates to the amount and quality of data needed to qualify a patient for a drug, or inversely to determine that withholding that drug might be detrimental. Because many molecular abnormalities do not appear to segregate well by histology, and because many mutations and amplifications can be found in a subset of patients with almost any cancer (14), it appears unlikely that classical methods of approval that require high-level scientific evidence (usually randomized phase III trials) will be feasible for the subset of patients with a particular molecular anomaly in each histology. On the other hand, new classifications based on molecular diagnosis or the use of genomically driven bucket trials that cross canonical disease boundaries may be able to provide adequate scientific evidence to determinate actionability.…”

“…For instance, treatment of chronic myelogenous leukemia, a disease driven by an aberrant BCR-ABL kinase, with imatinib (a BCR-ABL kinase inhibitor) has dramatically increased median survival (11)(12)(13). In the phase I setting, molecular matching was associated with improved outcomes in multivariate analysis (14). Further, a systematic review of phase II clinical trials in advanced/metastatic non-small cell lung cancer showed that molecular matching of patients' tumors to drugs was independently associated with better outcomes, including higher median response rate (48.8% vs. 9.7%; P ¼ 0.005), longer median progression-free survival (6 vs. 2.8 months; P ¼ 0.005), and overall survival (11.3 vs. 7.5 months; P ¼ 0.05), as compared with those of unselected patients (15).…”

Novel Oncology Drug Development Strategies in the Era of Personalised Medicine

“…Understanding of the 'driving' pathway, receptor or network before treatment initiation, especially with new molecularly targeted agents, will become standard of care for several new treatments and guide us in the decision making algorithm even in advanced stages of disease. This can be further evidenced by a recent study in a cohort of heavily pre-treated phase-I patients who were tested for aberrations in the MAPK and PI3K-AKT-mTOR pathways and then treated with drugs targeting these pathways (Tsimberidou et al, 2011). Impressively, those patients with molecular alterations treated with targeted therapy had a response rate of 29% (complete response or partial response) compared to 8% in the group without alterations.…”