Trial aims to shave years off cancer drug development

ABSTRACT: The I-SPY 2 breast cancer trial features a novel design of uninterrupted enrollment and patient stratification using biomarkers in order to target therapy.

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.

“This trial is a model for innovation in drug development.” - Janet Woodcock, MD

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.

Gauging response

Early response will be gauged by tumor response as seen in MR images. Preliminary research has shown that MRI is highly predictive of pathologic response and the cancer burden left behind after chemotherapy prior to surgery.

Contrast-enhanced MRI will play a key role in quantifying the effect of experimental cancer therapies on the tumors of breast cancer patients participating in I-SPY 2, Dr. Woodcock said. "By measuring tumor volume with imaging and validating that with pathologic response, we will learn more about the use of images as a marker for drug effects," she said.

Pharmacodynamic markers will be correlated with molecular markers in hopes that these markers will serve as in vitro indicators of early response to therapy.

Ultimately some of the information uncovered as part of the I-SPY 2 research may lead to the identification of biomarkers that predict response to therapy in its early stages and throughout the treatment regimen. After research has proven the value of certain drugs, in vitro tests for these biomarkers will be used to identify patients in routine oncologic practice who will be most likely to benefit from them. Similarly, these biomarkers, along with pharmacodynamic markers employed in the research, will be used to monitor patient response throughout the regimen.

Other information obtained during the trial may provide the basis for more accurate prognoses for breast cancer patients. This information will come from the clinical and genomic signatures of individual patients' tumors, signatures that might ultimately be detected before clinical signs of the disease appear, allowing preventive measures to be applied.

Addressing the bottleneck

The I-SPY 2 initiative sprang from early research that examined how clinical, gene expression, and comparative genomic hybridization data could best be captured and integrated. The research, part of the initial part of the I-SPY program, included the development of data query and reporting tools. These were designed to support the analysis of biomarkers, angiogenesis, apoptosis, hormone receptors, and gene expression arrays, as well as contrast-enhanced breast MRI.

The investigators said they are shooting for an 85% success rate in the development of new treatments for women with high-risk, fast-growing breast cancers. Promising drugs are expected to reach their last stage of testing in record time and at substantially lower cost than ever before.

“The current drug development pathway is a serious bottleneck to bringing new innovations to patients.” - Donald A. Berry, PhD

The key will be doing more with fewer patients. Rather than lumbering through a preset course of development, as is currently the case in clinical research, experimental drugs and their combinations will be given to more patients as soon as results demonstrate their therapeutic promise.

"Knowing up front, at an early stage of drug development, who responds to a specific drug is probably the single most important factor in completing a cancer drug development program," Dr. Woodcock said. "It is something we do not have now."

Drug companies can spend more than $1 billion over 12 to 15 years in the development of a single drug, testing it on thousands of patient volunteers to find statistical effectiveness across a broad swath of patients.

"The current drug development pathway is a serious bottleneck to bringing new innovations to patients," Dr. Berry said. "Thousands of discoveries arise in the laboratories only to languish because of the risk, cost, time, and effort needed to evaluate the performance of even a single candidate in the clinic."

Doing more with fewer patients

If the I-SPY 2 design works, it will dramatically reduce the number of subjects needed to prove the value of prospective cancer agents while shaving years and hundreds of millions of dollars off the testing process.

Using this new research paradigm, only a few dozen, or at most a few hundred, patients will be tested in phase II trials. These tests should be enough for researchers to home in on the specific type of patient who will respond to a given type of treatment.

"We are targeting phase III trial sizes of 300 patients," Dr. Berry said. "That is an order of magnitude less than what we are doing now [in current trials]."

“What [experimental drugs] need to do is fail or succeed early.” - Laura J. Esserman, MD, MBA

If the drug proves ineffective, developers can move on to other candidates in their pipeline, conserving effort and funds, and speeding the most promising drugs to phase III tests and, hopefully, into commercial production. "Most companies have many drugs in the pipeline," Dr. Esserman said. "They want to know which ones to move forward on."

Drugs that fail early in the testing process are easy to give up on, she said, whereas spending hundreds of millions of dollars on a drug makes giving up difficult. "What [experimental drugs] need to do is fail or succeed early," she said.

If I-SPY 2 can do this for breast cancer drugs, it will serve as a model for research studies in and outside of oncology, Dr. Esserman said. In the process, medical imaging will have been established as a core technology in the early assessment of experimental cancer drugs and an integral part of patient assessment and monitoring, when those drugs enter routine clinical use, she added.

"This is not just an important trial for breast cancer," Dr. Woodcock said. "It is a model for innovation in drug development, something that is seriously needed."