The regimented and inflexible protocols that have long served as the hallmarks of clinical trials are giving way to a personalized research design that could dramatically reduce the time and expense of developing cancer drugs. A new trial dubbed I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis) has set an ambitious goal: To change the way clinical trials are conducted.
"We are not testing, stopping, waiting two or three years, and then writing another protocol. Those days are over," said Laura J. Esserman, MD, MBA, I-SPY 2 co-principal investigator and director of the Carol Franc Buck Breast Care Center at the University of California, San Francisco.
Specifically, I-SPY 2 will run continuously, with stages II and III breast cancer patients first being stratified into subgroups based on biomarkers and genetic testing. Then, rather than blasting all patients with a single experimental drug, patients will be randomized to receive standard neoadjuvant chemotherapy alone or paired with an experimental agent, selected according to the molecular signature of the patient's tumor, said Donald A. Berry, PhD, co-principal investigator and head of the division of quantitative sciences at Houston's M.D. Anderson Cancer Center.
When a drug combination proves effective against a certain subtype of cancer, that experimental arm will "graduate" into a larger trial. If the combination continues to be successful, it will proceed into a relatively small, focused phase III trial and, ultimately, routine medical practice.
Just as the I-SPY 2 design is novel so is the underlying collaboration. The FDA, National Institutes of Health, and several major pharmaceutical companies have come together to form a public-private partnership, the Foundation for the National Institutes of Health Biomarkers Consortium.
Eventually the research will include some 20 top-flight cancer centers in the U.S., where drugs will be tested on patients grouped according to genetic and biologic markers. Patients will be tested for estrogen/progesterone receptor and HER2 status, along with MammaPrint risk score to judge risk of recurrence.
"By correlating genetic signature with tumor response, I-SPY 2 will teach us how to effectively use biomarkers to enable targeted therapy," said Janet Woodcock, MD, director of the FDA Center for Drug Evaluation and Research.
An unprecedented opportunity
Initially, investigators will test five experimental drugs, all of which will be covered under a master investigational new drug (IND) application constructed in collaboration with the FDA (see Table). More will be added over time while others will be dropped if results do not pan out in any of the subtypes.
In the trial, chemotherapy and the experimental drugs will be administered prior to surgery. "As a surgeon, I know that it is not the local therapy that matters; it is whether you get the systemic therapy right," Dr. Esserman said. "If you get it right at the beginning, patients survive. If you don't, very often they do not."
The effectiveness of a drug may be apparent between six and 12 months of the start of drug testing, she said. If so, this will provide an unprecedented opportunity to learn sooner rather than later if the drug will actually save the patient's life, Dr. Esserman said.
Furthermore, in this adaptive randomization trial design, early data from one set of patients will be used to guide treatment assignments of later patients. When a drug proves effective in a particular subset, newly enrolled patients with similar tumors will have a greater chance of being randomized to that treatment.