Factorial clinical trials: a new approach to phase II neuro-oncology studies.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Standard initial treatment consists of maximal surgical resection followed by concurrent radiotherapy and temozolomide chemotherapy and then at least six months of adjuvant temozolomide (in the absence of disease progression or unacceptable toxicity). However, nearly all tumors eventually recur, ultimately leading to death within 1– 2 years from diagnosis. Innumerable clinical trials have tested new agents, each with promising pre-clinical data. Some demonstrated encouraging phase II efficacy results, but nearly all failed when tested in a randomized phase III context. Recent examples include the vascular endothelial growth factor inhibitor bevacizumab and the integrin inhibitor cilengitide for newly diagnosed GBM. New approaches to screen drugs for efficacy rapidly in the phase II setting are needed. Simultaneously, the need to combine agents is pressing because the number and types of anticancer therapies, including signal transduction inhibitors, antiangiogenic agents, and more recently immunotherapies, has exploded in recent years. Many have proven activity in and FDA approval for other cancers. However, obvious, validated, and drugable driver mutations in GBM are elusive, and it is also possible, if not likely, that many GBMs are driven by multiple molecular abnormalities requiring multiple simultaneous approaches. A factorial approach is one method to test multiple drugs simultaneously and efficiently. Dr. Penas-Prado and her team are to be congratulated on their diligence for designing such a phase II study. They enrolled patients with “newly diagnosed” GBM (although after concurrent chemoradiotherapy but without disease progression, rather than treatment naı̈ve patients) and treated them with three experimental therapies, isotretinoin (a pro-differentiating agent), celecoxib (a COX-2 inhibitor), and thalidomide (a purported antiangiogenic), along with dose-dense temozolomide. These agents were tested in 8 different arms under one IRB-approved randomized clinical trial: arm 1, dose-dense temozolomide alone; arms 2–4, doublets of dose-dense temozolomide with each of the other agents; arms 5–7, triplets of dose-dense temozolomide plus two of the three other agents; arm 8, the quadruplet of all four agents. The primary endpoint was to determine the benefit, measured by progression-free survival (PFS) from each of the experimental drugs. For example, to determine efficacy of isotertinoin, PFS of patients treated with istotretinoin (pooling all isotretinoin containing arms) was compared against PFS of patients not treated with istretinoin (pooling all nonisotretinoin containing arms). The same analyses were conducted for the other agents. By design, the study was not powered for arm-to-arm comparisons, as each arm was to accrue only 20 evaluable patients. Factorial design studies were developed in the late 1800s and early 1900s and have been widely used in other contexts, typically those using highly controlled conditions with low variability, such as agriculture or machinery. Attributed mainly to the statistician Sir Ronald Aylmer Fisher, they allow multiple questions to be asked and answered simultaneously as part of the same experiment. Fisher objected to the notion that multiple experiments were impossible to conduct simultaneously, expressing his view that “no aphorism is more frequently repeated in connection with field trials, than that we must ask Nature . . . one question, at a time. The writer is convinced that this view is wholly mistaken.” In clinical research, factorial designs have been successfully employed in prevention studies such as the 2×2 factorial design Physician’s Health Study (aspirin, beta-carotene, both, or none) for reducing cardiovascular or cancer incidence and the 2×2 factorial design of alpha-tocopherol, beta-carotene, both or none for lung cancer prevention. The track record of factorial design in therapeutic trials in oncology is mixed. A major advantage of the factorial design is symmetry; i.e. each individual experimental drug is given to 50% the subjects, so each research subject’s data contributes to many treatment comparisons. For example, although there were only 20 patients per arm, approximately 80 patients received isotretinoin and 80 did not in the trial under discussion. More importantly, the ability of the factorial design to simultaneously assess 3 different experimental drugs in one clinical trial certainly allows fewer subjects to be enrolled when compared to 3 conventional trials of 1-experimental-drug-a-time. This potential gain in efficiency and reduced sample size for phase II trials in neurooncology is welcomed, where the main goal is screening of drugs with potential activity for larger confirmatory phase III trials.