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NCI trials overhaul eyes community-based biomarker studies


 

Nearly 3 years after tasking themselves with overhauling the nation’s publicly funded cancer clinical trials system, which had been criticized as sluggish and unwieldy, researchers working for and with the National Cancer Institute are reporting a number of important successes.

The time between concept and activation of phase II trials sponsored by NCI has shrunk by more than a third, the researchers revealed at a 2-day workshop held this month in Washington. Time to activation for phase III trials has been halved since the overhaul process began.

Dr. James Doroshow

Dr. James H. Doroshow of the NCI’s Division of Cancer Treatment and Diagnosis in Bethesda, Md., said that trial opening times would continue to shrink, with an ideal lag of between 6 and 7 months for early phase trials, compared to more than 2 years in the past.

But Dr. Doroshow and other presenters also acknowledged that the overhaul is a work in progress, with serious challenges remaining. Prominent among these, said workshop chair Monica Bertagnolli of the Dana-Farber Cancer Institute in Boston, is "maintaining the integration of the community centers into the research network" as NCI’s scientific emphasis shifts quickly from large phase III trials to smaller, biomarker-driven phase II trials. The trials cannot succeed without broad participation in cutting-edge trials at the community level.

The workshop was sponsored by the American Society for Clinical Oncology and presented by the Institute of Medicine, which had commissioned a 2010 report demanding critical changes to the NCI’s clinical trials cooperative group program. The report described the program as "approaching a state of crisis," and recommended that it streamline its bureaucracy, speed activation and improve completion rates of its trials, emphasize innovative biomarker-driven science, and increase reimbursement per patient for trial participation.

The program has since undergone a restructuring to reduce its 10 cooperative groups to 5, including 1 pediatric group. It has created common enrollment and data management systems to be used by all 3,100 affiliated community and research institutions. It standardized its agreements for industry collaborations, launched a review process for grading the quality of its trials, and is in the process of creating integrated biospecimen banks, among other accomplishments reported by NCI’s Dr. Doroshow.

The conviction that innovative, molecular phase II studies were the key to a more responsive and effective trials system was shared widely at the conference. "We need to rethink clinical trials, not just fund 7,000 patients in toothpaste A vs. toothpaste B," commented Dr. George Sledge of Stanford (Calif.) University. Presenters discussed a number of novel phase II trial designs, including "basket trials," or series of simultaneous single-arm trials matching biomarkers to target agents.

In a presentation on designing cutting-edge trials using genomic profiling for eligibility, Dr. Levi Garraway pointed to both the extraordinary possibilities and challenges of the new, nimble trial ideal.

"This is the first time that we can say for the major cancer signaling pathways, there are multiple drugs targeting multiple alterations in those pathways," said Dr. Garraway, a researcher at Dana Farber Cancer Institute in Boston, noting that in 40%-60% of tumors, there is a genetically-determined actionable target for which there is either an approved agent, an experimental agent, or an agent to avoid. Yet while genomics-driven "precision medicine," is exciting, it is"very hard, daunting even to the most advanced cancer centers," Dr. Garraway said.

Encouraging broad participation in these cutting-edge trials at the community level may prove a daunting task, however.

Dr. Stephen Grubbs

"The No. 1 job is to get these trials done and, without the community programs, they’re not going to get done fast enough," Dr. Steven Grubbs of Christiana Care Health System's Helen F. Graham Cancer Center in Newark, Del., told the conference. Nonacademic community oncology sites, both hospitals and private practices, are responsible for accruing between half and two-thirds of the patients currently taking part in the network’s trials, Dr. Grubbs pointed out, with most cancer patients receiving their first diagnosis outside a research center.

Dr. Robert Comis of Drexel University, Philadelphia, the cooperative groups’ chairman, commented that while the novel phase II trials "are essential to drive the process forward," many community sites hesitate to participate because these trials tend to be small, end quickly, and can be more complicated than are large phase IIIs.

As other participants noted throughout the conference, cancer trials increasingly require tissue submissions to enroll, a financial and logistical burden that falls on hospital pathology departments. Molecular research also means exponentially more data points and requires close collaboration with genetics labs – all at a time in which many of the NCI’s community-based research affiliates are plagued with tightening budgets and looming cuts.

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