Randomized phase II adjuvant factorial study of dose-dense temozolomide
Despite optimal therapy with radiation and concurrent and ad-juvant temozolomide (TMZ),1 survival is poor for most patients with glioblastoma (GBM), and effective second-line therapies are scarce.2,3 Even in the context of clinical trials, 3-year survival is only 16%, and 5-year survival is 10%.4 There is an urgent need for more effective ﬁrst-line therapies. The implementation of novel clinical trial designs is an important step for increasing efﬁciency when testing new treatments.
Molecular studies have uncovered many potential targets for treatment of malignant gliomas.5 However, despite promis-ing preclinical testing, the results of trials evaluating single-agent targeted therapies have been generally disappointing and have shown very low response rates and no improvement in progression-free survival (PFS) or overall survival (OS).6,7 Com-binatorial strategies targeting more than one critical pathway have been developed with the goal of overcoming resistance to single agents.8 – 10 However, the increasing number of prom-ising treatments exponentially increases the potential combi-nations to be tested. Novel clinical trial designs are needed to test combinations of targeted agents more efﬁciently.
One of the novel designs that can address this challenge is the factorial design,11 which can be planned as a randomized, mul-tiple arm study involving different combinations of the agents to be tested. For instance, a 2×2×2 factorial design can accom-modate 3 investigational agents to be tested with a standard cy-totoxic agent. The cytotoxic agent can be tested alone, combined with each of the 3 agents (doublets), added to each of 3 pairs of agents (triplets), and, ﬁnally, given together with all 3 (quadruplet combination), for a total of 8 treatment arms.
There has been interest in examining the utility of combining TMZ with various cytostatic agents that have non-overlapping toxicity proﬁles and overall better tolerance than cytotoxic drugs. Several combinations of TMZ and cytostatics have been evaluated in recurrent malignant gliomas with promising preliminary results. Reported 6-month PFS rates were 24% for TMZ plus thalidomide, a putative antiangiogenic agent, and 35% for TMZ plus isotretinoin, a differentiation- and growth-inhibitory agent.12 – 16 COX-2 enzyme is upregulated in high-grade gliomas, and high expression in tumor cells is a strong predictor of poor survival.17 Preclinical studies have shown that celecoxib exerts both cytostatic and potentially cy-totoxic effects in vitro,18 and a study using a C6 rat glioma orthotopic model suggested synergy between TMZ and cele-coxib.19 At the time our trial was designed, dose-dense temozolomide (ddTMZ) at 150 mg/m2/day, week-on/week-off, was felt to be a promising schema due to rapid, marked, and sustained inactivation of MGMT and preliminary evidence of ac-tivity in recurrent malignant gliomas.20,21
The results of the phase I component of the study evaluat-ing the different combinations of ddTMZ with isotretinoin, cele-coxib, and thalidomide have been previously published.22 Overall, all combinations were well tolerated. Herein we present the results of the ﬁrst phase II factorial randomized trial in par-ticipants with newly diagnosed GBM. This study was designed to evaluate efﬁcacy measured by PFS and gauge the feasibility of the factorial design.