Clinical Trials
“Master Protocol” To Rely on Biomarkers
In Testing Multiple Lung Cancer Agents
By Matthew Bin Han Ong
A new kind of clinical trial that will assign patients to therapy based on molecular characteristics of their disease is being launched by a coalition of government agencies, pharmaceutical companies, and a non-government organization.
The effort, called the lung cancer “Master Protocol,” is a phase II and phase III trial that would test five drugs, assigning patients to therapy based on tumor biomarkers.
The master protocol in advanced squamous cell lung cancer (S1400) is one of at least three next-generation trials now in the works at NCI and its clinical trials cooperative groups.
The protocol grew out of discussions between members of the cooperative groups, the NCI Thoracic Malignancy Steering Committee, and a panel put together by Friends of Cancer Research, a Washington, D.C., group.
The trial will be coordinated by the Southwest Oncology Group, in partnership with all the adult cooperative groups in North America, and is expected to open for accrual at all sites that participate in NCI’s new National Clinical Trials Network by spring 2014.
According to sources at the NCI, the trial will be funded by a combination of institute support for cooperative group trials as well as a major contribution by the Foundation for the NIH, and by industry collaborators who have drugs in this trial.
“To my knowledge, there is nothing like this that has ever been attempted before,” said David Gandara, chairman of the SWOG lung cancer committee, and director of the thoracic oncology program at the University of California, Davis. “The governance and organizational structure includes the Friends of Cancer Research, Foundation of the NIH, NCI, FDA, and Foundation Medicine, who will provide the genomic screening, and pharma, who will provide the drugs and funding for this.
“Every one of these groups is directly engaged in this master protocol, and each one will lead one of the arms of the study,” Gandara said, during a D.C. conference co-sponsored by FOCR and the Brookings Institution Nov. 7. “We now have the National Clinical Trials Network going into effect early next year, and these groups are a part of that.”
The master protocol would screen about 1,250 refractory squamous cell lung cancer patients annually, testing multiple lung cancer agents simultaneously, and thereby speeding up the drug development process and reducing costs.
Five agents have been selected for the master protocol: MedImmune’s MED14736, AztraZeneca’s AZD4547, Amgen’s Rilotumumab, Pfizer’s Palbociclib, and a PI3 kinase pathway inhibitor from Genentech. Agreements and company partnerships are being negotiated.
It’s unclear at this point how much the master protocol trial would cost. According to the trial’s organizers, this private-public partnership is estimated to cost less than what drug companies currently pay per patient for a clinical study.
The primary investigator for the trial is Vassiliki Papadimitrakopoulou, a professor at MD Anderson and a SWOG group member.
“This is a phase II-III biomarker driven master protocol for squamous cell lung cancer in the second-line setting, and this is a team effort at the intergroup level with leaders from all the cooperative groups actively participating and leading arms of this study,” Papadimitrakopoulou said. “We’ve taken this challenge, but we want to take it the right way, so no patients should be wasted in this clinical trial.
“All the patients that are potentially screened could be potentially eligible for this, because not only do we offer a wide range of targets, but also because we have an arm for the patients whose targets are not being represented in the protocol.
“This allows for homogeneity in our population and consistency in the eligibility. This is, we hope, a better way to complete the registration and a faster way to safe and effective drugs for patients.”
Hamburg: Trial to Produce Richer Data
Progress in developing new therapies for lung cancer is quite slow, and patients often become resistant to some of the newer targeted therapies, said Roy Herbst, co-chair of the protocol’s executive operations group, translational medicine chair of the SWOG lung cancer committee, and chief of medical oncology at Yale Cancer Center.
“Squamous cell lung cancer is a particular area where there hasn’t been much progress with new FDA approved agents in the last few years,” Herbst said. “Many patients have genetic profiling and some even next generation sequencing but we estimate that very few actually then get a drug that can actually help them. Or often patients receive a drug, perhaps off label (often called n of 1) but that’s equally frustrating because there is currently no national database to follow up on the outcome of these treatments. So how do we come together and do better?”
The current clinical trials methods need to be modified for this new generation of agents, Herbst said.
“For example, if you’re looking for a target that’s comprises only 5 percent of the lung cancer population, you’re unlikely to find enough patients at one center,” Herbst said. “You’re might not even find them at 10 centers.
“Our goal is to help patients, and we developed a phase III trial where we can take drugs based on molecular profile and bring them to testing for clinical benefit.
“Then more agents can become available for patients throughout the country, including both academic and importantly, community sites.”
FDA Commissioner Margaret Hamburg said the approach would produce “a rich amount of data [that] will be collected more quickly and at lower cost. By combining the resources of drug companies to test several therapies specifically targeted to individuals with particular genetic traits and makeup, and to do so in potentially hundreds of clinics throughout the U.S.
“The development of this protocol vastly increases the chance that we will find more and better treatments and does so in a creative and more cost-effective way.
“But the promise of this protocol is not confined to the development of specific lung cancer therapies,” Hamburg said. “Its significance also derives from the model it establishes for other clinical research as well as for future collaborations between FDA, industry and academic researchers.”
Next-Generation NCI Trials in Development
The master protocol in advanced squamous cell lung cancer is one of several new initiatives that NCI plans to launch in 2014.
“The others include a study of ‘exceptional responders’ to drugs that seemingly have not worked well for most patients in a given disease but for which a small number (usually less than 10 percent) have a major durable response,” according to sources at the NCI. “Another study is called ‘Alchemist’ and this study will test an ALK inhibitor and an EGFR inhibitor in patients with selected mutations who have early stage, resectable lung cancer.
“To have ample patients with these uncommon mutations, this trial will screen over 7,000 patients nationwide over the next five years. Those who don’t have the select mutations will be followed and their genomes studied
“The final study, NCI ‘MATCH,’ will sequence tumors in 3,000 patients with advanced cancer whose disease has progressed on standard therapy to determine in they have a select molecular change for which a targeted agent might be beneficial. NCI will work with a large number of company partners to have as many agents available to cover the majority of actionable mutations.”
Fulfilling An Unmet Need
The idea for the lung cancer master protocol first emerged from a Friends/Brookings white paper and a concurrent February 2012 meeting involving the NCI Thoracic Malignancy Steering Committee, FDA, the European Medicines Agency, and several pharmaceutical companies.
Patients need a better clinical trial structure, because it takes 7.5 years on average for drugs to reach approval status and many fail along the way, Gandara said.
“The topic [of the meeting] was: how do we incorporate new biomarkers into clinical development and new therapies for lung cancer?” Gandara said. “Among the topics that we discussed was the fact that unselected patients in randomized trials in lung cancer—the track record for those studies is very poor.
“Secondly, the need to develop biomarkers very early on in the context of drug development. Out of the last 22 randomized clinical trials for non-small cell lung cancer, only two trials were positive for overall survival. Only one of these incorporated a biomarker although all of these therapies were presumed to be targeted.
“The product of this meeting was the creation of the ‘master protocol’ task force in the thoracic malignancies steering committee to develop a series of master protocols for drug development and lung cancer.”
“Not only did we conclude that this needs to be sped up, but that we could also consider phases of development of a companion diagnostic, and that it should be in sync, step-by-step, with the development of the drug,” Gandara said. “So, at the end of the day, the FDA would approve a new drug and a companion diagnostic identifying those patients most likely to benefit from the drug.
“We also discussed the fact that these changes, if they were implemented, need to be taken into context with the current understanding that non-small cell lung cancer is not one disease, or even a few histologic subtypes, but a multitude of genomic subsets. So the issues to be addressed by the master protocol are: ‘How do we develop drugs for uncommon or rare genotypes?’
“Pharma by itself has great difficulty in doing a registration trial for a targeted drug for the population that is a fraction of 1 percent of patients,” Gandara said. “How do we incorporate broad-based screenings such as next-generation sequencing? How do we, in a clinical sense, have an acceptable turnaround time of less than two weeks to get the information to the investigators, to the patients, so that they can be randomized? And how do we expedite the entire drug approval process?
“There were parallel efforts between the thoracic steering committee, one of those early-stage trials in development is called Alchemist, and we focus, with the Friends of Cancer Research and this public-private partnership on advanced-stage squamous cell lung cancer, to be coordinated through the Southwest Oncology Group.
“So this represents, perhaps, the greatest unmet need—advanced-stage squamous cell lung cancer—almost all the new targeted therapies have really been in adenocarcinoma, but we now know there are molecular targets which are druggable in squamous cell lung cancer and we have drugs for these targets,” Gandara said.
Herbst said the trial’s organizers wanted to work with NCI and the cooperative groups.
“We decided to do it through SWOG,” he said. “I think that’s great, because what better time to do a trial through the cooperative groups following the IOM report recommending how to revise the clinical trials infrastructure. When you do a trial within SWOG now, it’s not only with SWOG, it’s with all the North American cooperative groups because it’s part of the NCTN.”
This trial, along with other parallel NCI initiatives, will benefit cancer patients nationwide, said Jeff Abrams, director of clinical research at the Division of Cancer Treatment and Diagnosis at NCI.
“These precision medicine initiatives will begin to deliver therapy for cancer nationwide via research trials in a way that truly individualizes treatment according to our desire to learn how best to predict what drug is indicated for which molecular change in any tumor type,” Abrams said.
