Biomarker-led adaptive trial blazes a trail in breast cancer


Esserman and Anna Barker.” Esserman, who is one of the I-SPY 2’s principal investigators, is director of the Carol Franc Buck Breast Care Center at the University of California, San Francisco (UCSF), whereas Barker is deputy director of the NCI. The I-SPY 2 TRIAL follows from I-SPY 1 TRIAL, which provided critical data on the utility of multiple molecular biomarkers and MRI in evaluating breast tumors that are treated with chemotherapy before surgery. I-SPY 1 also helped the researchers set up standard methods for collecting core biopsy material for measuring and evaluating gene expression profiles, and for MRI-based tumor evaluation, as well as other processes. In brief, it created the infrastructure to ensure accurate and consistent data collection, capture and sharing to launch the more ambitious trial. The new trial goes much further. Participants must have large aggressive tumors, which are typically extremely hard to treat. The adaptive design, which uses Bayesian statistical methods, will allow the researchers to more quickly determine if a therapy is working or not. All trial participants will receive standard therapy (chemotherapy with or without Herceptin depending on their HER2 status) before surgery. Some of the women will also receive investigative agents at that point. This will allow the researchers to measure the tumor and track its response. Esserman estimates this could shave years off the study’s length. “Typically we start studying these agents in women with metastatic disease,” she says. That requires 2–3 years, followed by another 5–10 years before results come in from studies in the adjuvant setting. It therefore takes a very long time for a good drug to reach the widest range of patients it can benefit. Before entering I-SPY 2, all women will have a core biopsy and a MammaPrint diagnostic test from Amsterdam-based Agendia to determine whether they are at high risk for tumor recurrence (and whether they are eligible for the trial) or not. The MammaPrint test comprises a 70-gene expression profile signature for identifying breast cancer patients at low risk of developing distant metastasis (J. Clin. Oncol. 26, 729–735, 2008). The I-SPY 2 TRIAL (investigation of serial studies to predict your therapeutic response with imaging and molecular analysis 2), coordinated under the auspices of the Foundation for the National Institutes of Health (NIH; Bethesda, MD) Biomarkers Consortium, is adaptive in design—researchers will use information from one set of participants to make informed modifications as the study progresses. “We are learning who is benefiting, and we modify the randomization to go in that direction,” says biostatistician Donald Berry, head of the Division of Quantitative Sciences at MD Anderson Cancer Center, in Houston, and one of the I-SPY 2 TRIAL’s principal investigators. Participants include several academic groups, the National Cancer Institute (NCI; Bethesda, MD), the FDA and drug and diagnostic companies. Although many in industry have been tiptoeing around the biomarker question, I-SPY 2 addresses it head on, using biomarkers to focus on those subjects that will benefit from treatment. The ultimate goal is to quickly pick out the best candidate drugs worthy of testing and ultimately ramp up success rates for potential treatments. The initial five-year phase 2 I-SPY 2 TRIAL will compare five investigational drug candidates from Abbott Labs, of Abbott Park, Illinois; Amgen of Thousand Oaks, California; and Pfizer of New York (Table 1) with conventional therapy. Those that earn a ‘thumbs up’ will pass into the phase 3 study, whereas the others will be dropped and new candidate drugs will be cycled in. In addition, when a drug meets the required “85% chance of succeeding in phase 3 mark,” all the women in that study arm will be able to receive it. I-SPY 2 TRIAL has garnered a great deal of attention, in large part because the design has the potential to shave several years and millions of dollars off the drug development process. If successful, the adaptive trial could recast the currently dreadful state of cancer drug development, where almost three-quarters of drugs in development fail in phase 3 (Box 1). It could also change the way advanced breast cancer trials are conducted in the future. Berry attributes the creation of the I-SPY TRIALs to “two tenacious women: Laura A breast cancer screening study that pairs oncology therapies with biological markers (biomarkers) launched by a consortium of public health agencies, academics and companies is being heralded as a milestone in clinical trials. The I-SPY 2 TRIAL, which involves 20 US cancer centers, will follow an adaptive trial design that promises both time and cost savings. Researchers will use genetic or biological markers from patients to guide decisions about which drug candidates may be most effective for specific types of breast cancer. “The hypothesis here is that one size does not fit all,” says Janet Woodcock of the US Food and Drug Administration (FDA), one of the trial’s many collaborators. Biomarker-led adaptive trial blazes a trail in breast cancer

DOI: 10.1038/nbt0510-383

1 Figure or Table

Cite this paper

@article{Allison2010BiomarkerledAT, title={Biomarker-led adaptive trial blazes a trail in breast cancer}, author={Malorye Allison}, journal={Nature Biotechnology}, year={2010}, volume={28}, pages={383-384} }