I-SPY2: Breast Cancer Trial Aims to Speed Drugs to the Clinic
On March 17, the Foundation for the National Institutes of Health and its Biomarkers Consortium announced the launch of the I-SPY2 breast cancer clinical trial, a novel, adaptive clinical study designed to move promising new drugs into phase III clinical trials more quickly and cost effectively than traditional phase II studies.
I-SPY2 (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2) will use biomarkers to identify women who might benefit from investigational new drugs given along with standard neoadjuvant chemotherapy (chemotherapy given before surgery) with paclitaxel, doxorubicin, and cyclophosphamide. The trial will enroll women who have early-stage breast cancer and a high risk of recurrence, as determined by estrogen receptor status, HER2 status, and the MammaPrint test.
“It takes 15 to 20 years to develop a new drug for cancer, at an enormous cost—$700 million to $1 billion—depending on the drug and the complexity of the disease being targeted. This cannot continue,” commented NCI Deputy Director Dr. Anna Barker. “It’s unsustainable, and it contributes significantly to rising health-care costs.”
The neoadjuvant setting of the trial is particularly important, explained Dr. Laura Esserman, professor and director of the Carol Franc Buck Breast Care Center at the University of California, San Francisco, and a co-principal investigator of the trial. “In trials enrolling patients with metastatic disease, it can take 2 to 5 years to find out if a new drug extends survival. In the adjuvant setting, we have to wait 5, maybe 10 years to learn whether or not our drugs are saving lives. But in the neoadjuvant setting, we learn at the time of surgery—in less than a year—whether or not a drug has been effective” in those patients, she explained.
Investigational Drugs to be Tested
I-SPY2 will test up to 12 investigational new drugs, each from a different class of therapeutic agent. Information on the results from all drugs will be shared among participating pharmaceutical companies to help guide future work on drugs in the development pipeline. The first five drugs for I-SPY2 have already been selected by an outside advisory committee:
- ABT-888 (veliparib), a PARP inhibitor developed by Abbot Laboratories
- AMG 655 (conatumumab), an APO-TRAIL inhibitor developed by Amgen
- AMG 386, an angiogenesis inhibitor developed by Amgen
- CP-751,871 (figitumumab), an IGFR inhibitor developed by Pfizer, Inc.
- HKI-272 (neratinib), a pan-ERbB inhibitor developed by Pfizer, Inc.
This rapid knowledge gain will allow I-SPY2 investigators to test as many as 12 new investigational drugs (see sidebar) from many different pharmaceutical companies that have agreed to cooperate and share data from the trial. If a drug fails to show efficacy in any subgroup of patients, that drug will be dropped from the trial and replaced with another investigational drug in the I-SPY2 queue.
“Most companies have many drugs in their pipeline. What they need to do is fail or succeed early” to minimize the cost and time devoted to testing, said Dr. Esserman.
The patient subgroups in the I-SPY trial will be classified by biomarkers, which are genetic or biologic properties of a tumor that can be measured accurately and reproducibly. The biomarkers to be used in I-SPY2 fall into three categories: standard biomarkers, such as the estrogen receptor and HER2, which are known to correlate with breast cancer prognosis; qualifying biomarkers, which are thought to be related to the drugs being tested but have not yet been validated in clinical trials; and exploratory biomarkers, which will be taken from genome-wide sequencing studies performed during the trial.
Any drug that demonstrates an 85 percent chance of being successful in a phase III trial in one or more biomarker-defined subgroups of patients, as determined by statistical methods developed for the I-SPY2 trial, will be “graduated” from I-SPY2 and replaced with another drug awaiting testing, explained Dr. Donald Berry, a co-principal investigator of I-SPY2. The promising drug will be sent for phase III testing in women whose tumors have the biomarker signature that helps predict the drug’s success.
“Oncology drug development has been hampered in the past by inefficient design in the early clinical trial stages,” commented Dr. Berry, who is also professor and chair of the Department of Biostatistics at the University of Texas M. D. Anderson Cancer Center. Instead of testing a new drug in all patients with a particular type of cancer, he explained, I-SPY2 will use Bayesian updating (a statistical method) to adaptively focus on subgroups of breast cancer patients who might need to be treated differently from others.
All participants in I-SPY2 will have blood and tumor tissue samples tested for the three categories of biomarkers and will undergo MRI scans before and during treatment. Biomarker analysis will be aided by a broad, collaborative information infrastructure that was set up during the proof-of-concept I-SPY1 trial and includes tools developed by caBIG. One such tool, caIntegrator, allows molecular information, imaging data, and clinical observations to be combined for prediction of a drug’s effect on disease progression and survival.
As the trial progresses, patterns of biomarkers from women whose tumors have responded to a particular drug will be used to select additional participants who are more likely than other women to benefit from that drug. The investigators also hope that the biomarker signatures will allow for the development of smaller, more focused phase III trials.
“The phase III trial size that we’re aiming for is 300 patients—that’s an order of magnitude less than the thousands we need for a traditional phase III trial,” explained Dr. Berry. “We can do that because we’ll be looking at a subset of patients in which we already think a drug will be effective.”
The I-SPY2 trial will cost approximately $26 million over 5 years. The trial funding has been coordinated through the Foundation for the National Institutes of Health and includes diverse private sources such as the Safeway Foundation, Johnson & Johnson, Genentech, and Lilly. Additional funding is being sought from corporate partners, nonprofit cancer organizations, philanthropic foundations, and individuals.