In March, the National Cancer Institute (NCI) transformed its Cooperative Group Program into the National Clinical Trials Network (NCTN). Spurred by recommendations in the Institute of Medicine (IOM) 2010 report, A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program, which called for modernization of the clinical trials system to leverage rapidly evolving scientific innovations, the NCTN endeavors to deliver a more efficient and streamlined approach to developing clinical trials.
While the Cooperative Group clinical trials system, in place since 1950, has produced many advances in oncology care, the IOM and other expert committees reviewing the program concluded that the 10 decentralized organizations (nine adult groups and one pediatric group), each with its own operations and statistical centers, tumor banks, and other scientific support services, needed to be restructured to meet the changes taking place in oncologic science, especially in the improved understanding of tumor biology and the promise of precision medicine.
As a result, the 10 former Cooperative Groups have been consolidated into four adult groups and one pediatric group in the NCTN. The five research groups are SWOG, Alliance, NRG Oncology, ECOG-ACRIN, and the Children’s Oncology Group (COG). The system also includes the Canadian Collaborating Clinical Trials Network. The NCTN centralized functions include a Centralized Institutional Review Board, a Cancer Trials Support Unit, an Imaging and Radiation Oncology Core (IROC) Group, and a Common Data Management System that is hosted centrally.
Recently, the NCI announced four precision medicine initiatives that the NCTN is undertaking. Two of the initiatives, Lung-MAP (a multidrug, multiarm, biomarker-driven clinical trial for patients with advanced squamous cell lung cancer) and ALCHEMIST (a trial investigating whether targeted epidermal growth factor receptor [EGFR] and anaplastic lymphoma kinase [ALK] inhibitors improve survival for adenocarcinoma of the lung in the adjuvant setting), have already launched.
In addition, the Exceptional Responders Initiative (a retrospective study investigating why a minority of patients with solid tumors or lymphoma have either a complete response or a very good partial response to a specific therapy while a majority of similar patients do not) is launching this month, and the NCI Match trial (which will examine whether molecular markers can predict response to targeted therapies in patients with advanced cancer resistant to standard treatment) is launching either at the end of the year or the beginning of 2015.
The ASCO Post talked with Jeffrey S. Abrams, MD, Acting Director for Clinical Research and Associate Director of the Cancer Therapy Evaluation Program (CTEP) in the Division of Cancer Treatment and Diagnosis at the NCI, about the new clinical trials system. He also addressed the concern among some oncology societies, including ASCO1 and members of the NCTN Working Group, that the consolidation of the 10 oncology groups into 5 will result in reduced funding and fewer trials.
Restructuring Rationale
Please talk about why the NCI decided to replace the Cooperative Group clinical trials system with the National Clinical Trials Network.
The main reason the NCI felt it was appropriate to make the change is that the types of trials being done in oncology were changing. The improvement in diagnostics especially occasioned us to look for a smaller number of groups that could screen patients across the country to find those with the molecular alterations in their tumors who would be the best fit for the types of targeted therapies that are currently under development.
In addition, there was sufficient evidence that the prior system was inefficient and that improvement would require us to centralize some of the functions that had been spread among many different groups so we could better use the resources that were available.
From both operational and scientific vantage points, it was felt that only a major restructuring could meet the intended goals.
System Improvements
How will the new system improve the design and results of NCI clinical trials?
Before, we had 10 groups with their own operation centers and tumor banks, and we were duplicating a lot of functions. In coalescing these activities into only four adult groups and one pediatric group, we gain both consistency and streamlining, all of which should result in greater efficiency in getting the trials mounted and conducted.
In addition, we recognized that the financial resources for clinical trials were not likely to increase in the near future. The federal budget committed to clinical trials has been flat for many years, and therefore, we needed a prioritization process whereby only the most important trials—those that we felt would really impact clinical practice and change the standard of care—were the ones conducted with federal support.
So on top of this infrastructure change, we also instituted a series of steering committees in all major cancer types, such as gastrointestinal, gynecologic, urologic, and childhood cancers, that oversee the trials conceived by the five different groups. The groups themselves generate the ideas for these trials, but then each steering committee reviews the trial concepts and evaluates them to see if they are high enough priority to be done in the NCTN.
Another important new feature of the revised system is a change in incentives. Previously, groups were rewarded for leading their own trials and having a full portfolio of trials in every disease. Now, the emphasis is changed. All trials that get through the prioritization process are put on a common menu that is available online via our Cancer Trials Support Unit. These trials are then open to all the groups in the network, not just the group that originated the idea. Groups are rewarded for participation in each other’s trials and no longer have to maintain an open trial in every cancer type.
Our hope is that this change will mean that all the groups will contribute to the accrual process and that important questions will be answered more quickly.
Complementary Systems
How will the NCTN trials differ from industry-sponsored trials?
NCTN trials are not primarily focused on getting a specific drug to market. They tend to study what is the best treatment approach for a specific cancer. Sometimes that focus does involve new drugs, but it also often involves how to combine drugs with radiation therapy and surgery or how to move new diagnostic techniques into the field. Those are the types of trials that this network will conduct. Although there clearly is some overlap with areas that industry is interested in, and we often partner with industry, the difference in emphasis tends to make the private and public systems very complementary.
In addition, we frequently collect a lot of blood and tumor specimens on NCTN trials so we can understand how to select for the best therapy, appreciate what causes resistance to treatment, and learn about toxicity, all of which will help us prepare for the next trial. That isn’t to say that industry doesn’t do this as well, but the big difference is that in the public system, all the information that is gained in clinical studies is made available to researchers around the world, whereas in industry-sponsored trials the information that is made public is more limited.
Precision Medicine Trials
How will the NCTN system produce greater efficiency than the prior system to advance knowledge about cancer and more effective therapies?
Perhaps the best example of how we hope to accomplish those goals is with the four precision medicine trials we have planned: Lung-MAP, ALCHEMIST, Exceptional Responders, and NCI MATCH.
The Lung-MAP trial is taking advantage of the fact that we now have a network that can screen a large number of patients looking for a subset of lung cancer. We will then send their tumor tissue to be sequenced using next-generation sequencing of their tumor DNA, find those with the relevant genetic abnormalities, and in one single trial be able to enroll them to the appropriate treatment arm. This approach is much more efficient compared to having five separate trials.
NCTN gives the clinical trials system much more flexibility to work in an integrated way, to find patients who have specific genetic abnormalities and efficiently move them into what we believe will be the best trial for them.
The ALCHEMIST trial is also novel because it is investigating patients with early-stage adenocarcinoma of the lung with uncommon EGFR or ALK gene alterations to determine if treating them with targeted drugs can cure some of those patients. These gene alterations only represent 10% to 15% of this subset of patients with adenocarcinoma of the lung, and we have to screen a lot of patients to find those who have the genetic changes for this trial. Having this streamlined network will not only allow us to do that, but it will also allow us to capture important genetic information on the 85% or so of patients who do not have these gene mutations, as all patients in the trial will undergo genome sequencing.
We intend to follow these patients for up to 5 years. Over time, we will see what happens to them in terms of who has a cancer recurrence and who doesn’t. At the time of relapse, we will again sequence their tumors to learn about changes in the genetic makeup, which should provide clues regarding how best to treat them.
The Exceptional Responders Initiative is an exciting retrospective study. We are looking for at least 100 people whose tumors responded very well to a particular therapy, while the majority of patients with that tumor type did not. By sequencing the genes in the tumors of these exceptional responders, we hope to learn why patients had this exceptional response to a specific drug. This trial should provide new leads that can be further investigated in new clinical trials.
The last of the first wave of precision medicine trials to open is NCI MATCH. This trial is unique in that NCI is working with over 15 pharmaceutical companies to bring their new, targeted agents into a multiarm, single phase II trial. Adult patients with advanced solid tumors or lymphoma who have progression of their cancer on standard therapy are eligible. They will have a fresh biopsy of their tumor that will undergo DNA sequencing for a panel of selected genetic alterations. Genetic changes in the tumors, irrespective of histology, will be matched to specific agents that target the abnormality. NCI MATCH is a discovery trial in that we hope to find new leads that can then be followed up in larger, phase II trials.
Funding Gap
One of the concerns expressed by the NCTN Working Group and ASCO is a 3-month gap in funding for community oncology clinics engaged in institute-funded research through the Community Clinical Oncology Program. Has the issue been resolved?
Yes. That problem was brought to the attention of Harold E. Varmus, MD [Director of the National Cancer Institute] and to others who run that program in the Division of Cancer Prevention. They realized that although it was never intended to have a 3-month gap in funding, the issuance of the new program application deadline resulted in that possibility. Once the problem was brought to our attention, we rapidly contacted all the sites involved and assured them that there would be funding to cover the gap period.
Budget Reduction
Another concern is that NCTN faces a 40% reduction in its operating budget. How will that funding decrease affect trials currently underway or new trials being planned? Are there plans to make up the funding deficit through private partnerships?
In 2013, the prior Cooperative Group system had a budget of $151 million from NCI resources, and the new NCTN has exactly the same amount—$151 million. As we went through the reorganization process, it was determined that the NCTN would benefit from several new components that the prior Cooperative Group system did not have. For example, the NCTN now has lead academic participating site grants, which include 30 grants to major cancer centers that provide a lot of intellectual leadership for the NCTN groups.
We also developed an integrated translational science award that we hadn’t had before, and those grants went to seven cancer centers that are going to work on biomarkers for NCTN trials. In addition, we included a new imaging and radiation oncology center for quality control of NCTN trials, and we had not had that component funded at the current level before.
To fund these new components of the NCTN program, the group operation and statistical centers received a reduction in the proportion of the money that went to them. Because they have received somewhat lower funding in order to enable the existence of these new components, the Groups may have to do fewer trials and enroll fewer patients. However, it will not be anything like 40%.
For instance, in 2014 we are targeting the enrollment of about 19,000 patients, whereas in 2013 we had about 21,000 patients. We will have to have some decrease in our patient enrollment to compensate for the new activities, but I expect that we will continue to do many important trials with the available funding. Moreover, by selecting our patients for treatment more appropriately using better diagnostic tools, it is likely that our trials will not need as many patients to prove the effectiveness of a new intervention.
It remains to be seen if the NCI budget situation will allow us to enroll more patients or at least get back to enrolling the same number of patients in future years.
Private Partners
Is there a plan to partner with private groups for additional funding?
Most definitely. The Lung-MAP trial, for example, is a partnership trial with the Friends of Cancer Research and Foundation Medicine, along with several major pharmaceutical partners. We have partnered with industry and philanthropic groups on many of our trials, not just recently, but in past years as well.
Moving forward, we intend to increase our collaborations with both industry and the advocacy community, as well as any philanthropic group that wants to help support cancer research.
Positive Signs
What has been the reaction by the various stakeholders to the NCTN so far?
It’s a little too early to say how all this is going to work out. Sometimes people are very eager to get results, but the NCTN is brand new and only just received funding in March of this year.
So far we have been very pleased with the collaboration among the investigators. When you attend Cooperative Group meetings now, the researchers seem quite enthusiastic and collaborative, with many innovative trials coming forward, so those are all positive signs. ■
Disclosure: Dr. Abrams reported no potential conflicts of interest.
Reference
1. Hudis CA: Cancer clinical trials, patients’ access to care threatened by NCI budget decisions: ASCO statement. Posted April 4, 2014. Available at www.asco.org.
