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RPM Report – Testing A New Model For Personalized Drug Development

RPM Report – Testing A New Model For Personalized Drug Development

A landmark study testing five mechanistically distinct therapies for squamous cell lung carcinoma is on track to start enrolling patients March 1, study organizers announced during the November 7 Friends of Cancer/Brookings conference on cancer clinical research in Washington, D.C.

The so-called “Master Protocol” trial could lead to new therapies for a significant area of unmet medical need. However, the organizers of the trial—which include Center for Drug Evaluation & Research Director Janet Woodcock– hope it does much more than that. They view the trial as a potential new model for studying personalized medicine, one that could revolutionize the clinical development model by creating standing networks for clinical trials, with sponsors plugging in and out of the study as their pipelines mature.

The protocol idea itself grew out of a panel session organized for the annual FOCR/Brookings conference last year. (“FDA Eager For More Master Protocols in Oncology: Approach Means Lower Cost For Sponsors—and Less Control” —The RPM Report,December 2012) The initial proposal evolved into a joint project with the National Cancer Institute last spring. (“Landmark Trial for Personalized Medicine Coming Soon: NGS Approval May Be One Offshoot of Lung Cancer “Master Protocol”” —The RPM Report,April 2013)

The November 7 meeting served as a forum to emphasize progress in launching the trial on two fronts. Operationally, it provided a setting to unveil the final trial protocol, including the identification of the candidate drugs; symbolically, it allowed for the formal embrace of the vision of the “master protocol” model as a part of FDA’s overall approach to accelerate personalized medicine.

FDA Commissioner Margaret Hamburg spoke immediately after the trial was unveiled and stressed its importance as a “tangible and truly revolutionary new structure designed to take advantage of the opportunities in personalized (or precision) medicine, and will help usher us into this exciting new era of research and treatment.”

“Today’s announcement of a lung cancer clinical trial infrastructure that will provide for multi-drug, multi-arm trials in which the same patient sample will be screened for multiple genetic traits at the same time is an exciting development with promising benefits for both the industry and patients,” she said. “As a result of this approach, a rich amount of data 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 makeups — and to do so in potentially hundreds of clinics throughout the United States – the development of this Protocol vastly increases the chance that we will find more effective treatments, and does so in a creative and more cost-effective way,” Hamburg declared.

“But the promise of this Protocol is not confined to the development of specific lung cancer drugs. 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,” she said.

Those comments mirror Woodcock’s perspective as an active participant in the development of the protocol. Woodcock participated in the Friends of Cancer Research/Brookings panel that helped develop the protocol and is serving on the executive committee overseeing the trial. At both the 2012 and 2013 conferences she stressed the importance of the protocol as a model to “turn the clinical trial process on its head.”

“Instead of having a different clinical development program for every drug…we need to set up a standing trial network run by experts,” Woodcock said. Done properly, such a system would both accelerate enrollment for trials of new agents while also reducing doubts about bias (real or imagined) in industry sponsored trials, she said.

Of course, there is a long way to go from the start of an innovative new trial in lung cancer to a new model for clinical trials in oncology. But the enthusiasm of FDA’s top management for that potential makes this protocol one that is important for everyone in the biopharma development sector to monitor.

AZ, Pfizer, Genentech and Amgen Drugs Under Study

The trial will be run by the Southwest Oncology Group and carry the identifier SWOG 1400. However, it is overseen by a steering committee composed of multiple stakeholder organizations (government, academia, industry and patient advocacy) convened under the auspices of the Foundation for the NIH. FNIH is taking the lead on drafting contracts with the manufacturer sponsors. An IND is also being prepared.

Those pending tasks suggest that the March 1 start date is provisional.

The real milestone announced at the conference was the selection of the five drugs to be studied; the overall design had previously been set, as had the choice of diagnostic provider (Foundation Medicine Inc.) to work on the companion diagnostic piece of the protocol.

The study will test four different targeted therapies and one immunotherapy simultaneously, with the goal of maximizing the speed at which each of the agents can move through Phase II and III and into registration. The five interventions include targeted therapies under development byAstraZeneca PLC(AZD-4547),Pfizer Inc.(palbociclib),Amgen Inc.(rilotumumab) andGenentech Inc.(a P13k inhibitor), as well as an immunotherapy also under development by AZ (MED-14736 under theMedImmune LLCumbrella).

The appeal of the “Master Protocol” approach is that it allows investigators to recruit subjects for a single trial, with the promise that all subjects meeting the (fairly broad) inclusion criteria will be enrolled in one of the five arms.

From there, each arm will run as essentially a stand-alone randomized controlled trial. Patients will have their tumors sequenced and be assigned to one of four arms based on potentially promising biomarkers – or the fifth arm for “unmatched” subjects. In each case, the patients will then be randomized to the study drug for their arm of the study or background therapy (with “unmatched” patients randomized to the immunotherapy or background chemo.)


Lung Cancer Master Protocol: Schematic

Click image to enlarge

Source: Vali Papadimitrakopoulou, MD Anderson Cancer Center, November 7 presentation

As a side benefit of the study, it will provide a test of a so-called “Next Generation Sequencing” platform, with Foundation Medicine selected as the partner to develop the companion diagnostic elements of the study arms.

Each arm is designed initially as a Phase II progression-free survival study, with interventions that clear a prespecified threshold of benefit (at least a 41% improvement in PFS after 55 events) moved into a Phase III overall survival study.

The inclusion of an immunotherapy (anti-PDL1 antibody) intervention for the “biomarker” negative group is an important change in the initial design, one that assures that all patients screened will be entering a trial testing a new therapy.

In fact, the immunotherapy arm is expected to accrue most quickly, since investigators estimate that about 30%-40% of subjects will not have one of the four target biomarkers.

The other arms will report data at different time points depending on how common or how rare the particular marker is. As part of the study design, the investigators decided to assign people with two or more of the biomarkers to one of the arms randomly, but to tilt the randomization in favor of assigning patients to the arm with the less common biomarker.

Drug Selection Model a Key Test

The drug selection process will be one of the key elements of making future collaborative protocols work.

One of the reasons squamous cell carcinoma was chosen was because it is a rare disease (38,000 new cases annually), but there are a large number of potentially interesting biomarkers with drugs in development that might offer treatment options. When FOCR and its collaborators were finalizing the protocol, they had identified a list of about two dozen candidate drugs for inclusion.

The study team established a drug selection committee (which did not include the industry partners in the protocol, but did include some consultants with expertise in drug development). The committee requested applications and interviewed about 15 different product development teams, in some cases entering into confidentiality agreements to allow review of proprietary data.

The applicants were scored, and ultimately the panel of five drugs were the “winners.”

Interestingly, several of the selected agents were not on the initial list of two dozen product candidates identified a year ago. In addition, while both Lilly and Merck are represented on the study steering committee and had potential candidates in their pipelines, those companies were not selected as participants in the trial itself.

The funding model includes support from NCI, which should cover about one-quarter of the total trial costs.

In addition, the study organizers are finalizing a budget to set the terms for sponsorship. The model will essentially be a per-patient cost paid by each sponsor (with the total amount reduced due to the NCI support).

That per patient cost should compare favorably to what a sponsor would have expected to spend for a stand-alone trial, given the shared costs for infrastructure. However, the combined Phase II/III design does mean that the per patient cost will be relatively high to assure that data collection meets pivotal trial standards for all subjects – even if the study drug ends up not meeting the threshold to move into Phase III.

Testing An Old Paradigm?

The “Master Protocol” model clearly has a number of attractive features for sponsors, especially for secondary pipeline assets where the loss of control inherent in the collaborative model is less critical. However, it is by no means obvious that the model will be broadly applicable, for both practical and scientific reasons.

From a scientific perspective, there is a danger that FDA and industry are coalescing around an optimal approach to developing companion diagnostic-based targeted therapies just as the cutting edge of research moves onto new phases of development.

The inclusion of an immunotherapy arm is one telling example. As one questioner noted, if the anti-PDL antibodies generate the kind of benefits that advocates hope for, it may make it impossible to continue to recruit patients for targeted therapy study arms – at least, not without offering immunotherapy in combination.

That concern probably won’t derail this trial, assuming the March 1 timeline holds and recruitment is relatively robust, but it may make it all but impossible to use the immunotherapy/non-match arm approach in the future.

More importantly, the cutting edge area of interest is in individualizing therapy based on multiple biomarkers, with patients offered a unique cocktail of ingredients based on the many different targets expressed in their tumor.

That “systems biology” approach, in fact, was the focus of calls for new clinical trial models during the Institute of Medicine’s National Cancer Policy Summit three days before the FOCR/Brookings meeting. While it is clear that no one is ready to affirm that a “systems biology” model is in fact the better model, there was consensus that the idea of one-drug/one-biomarker is not sustainable for long.

As Pfizer SVP-Clinical Development & Medical Affairs Mace Rothenberg put it during the IoM event: “We recognize that the era of one-off diagnostic tests has come and is rapidly leaving us.”

Columbia University’s Andrea Califano was more assertive, declaring that “we are out of the big bullets like HER-2, and are starting to get into more fragmented targets.” The idea, he suggested (and many speakers echoed), is to move from focusing on statistical associations proven by large datasets to a “systems biology approach” where it is possible to predict potential benefits based on a deeper understanding of the interlocking mechanisms driving a specific tumor type.

That evolution in thinking, he argued, “requires fundamental change in policy and focus.”

Several speakers proposed trial designs to test different approaches to therapy, where the “treatment” arm would be a therapeutic approach rather than a specific medicine, and may involve multiple investigational agents in many different combinations.

FDA Office of Hematology & Oncology Products Director Richard Pazdur and Personalized Medicine Staff Director Elizabeth Mansfield both stressed their willingness to consider new models during the IoM event. Mansfield acknowledged the move towards ever more fragmented definitions of cancer. “We are using a sledgehammer where we would probably prefer to be using something smaller and finer to get at cancer,” she said. “The idea of having one test per drug probably doesn’t make a lot of sense going forward.”

Pazdur followed in the same vein, underscoring FDA’s willingness to break-the-mold on approval paradigms – but also a healthy dose of skepticism about whether the proposed “systems biology” model will in fact pan out.

Next Test in Colorectal; Also Potential Model For Post-Marketing Studies

Regardless, even if the personalized medicine era is poised to jump beyond the single-target drug/diagnostic model, the Master Protocol model could be immensely valuable if it can be applied more broadly.

The fact is that the pipeline is full of targeted therapies that use the one drug/one biomarker model. There are already indications of interest in trying to adapt the Master Protocol for another setting: colorectal cancer. That area looks like the most likely “fast follower” on the model developed by the FOCR/Brookings group.

However, the broader idea of collaborative study designs with multiple industry partners could also be applied by FDA in other settings, Pazdur suggested during the IoM cancer policy summit November 4.

Pazdur was one of several speakers to highlight the master protocol model during the National Cancer Policy forum’s priority-setting conference.

FDA’s top oncology review manager also suggested that a similar concept may be necessary to allow for appropriate post-marketing trials of targeted agents when there are several almost simultaneous entrants into a similar category.

He noted that there are currently several products in development targeting the ALK lung cancer mutation. In each case, the sponsor is hoping for accelerated approval based on a single-arm study in patients resistant to Pfizer’s ALK-inhibitorXalkori(crizotinib). Each would then propose to do a randomized trial head-to-head with crizotinib as a confirmatory study.

Pazdur wondered aloud at the feasibility of doing multiple clinical trials in a population that is already a small subset of lung cancer, using two approved therapies as the treatment arms. The only viable approach, he suggested, would be a single “master protocol” trial, where all of the new therapies use a common control arm.

FDA does not (and will not) require comparative efficacy to support approval, Pazdur stressed. However, he noted, a shared control-arm approach will inevitably drive comparisons—by providers and payors.

The idea of a shared control arm was considered in drafting the lung cancer master protocol, but organizers agreed that moving forward on what amounts to five parallel controlled trials would be a more viable starting point. While less efficient from a cost and patient resource perspective, the multiple control-arm approach is probably easier from the perspective of bringing multiple sponsors together – precisely because it avoids the question of direct comparison between the agents.

Measuring Success: Can it be Replicated?

Launching the trial, of course, is only the first step in building a new model. To the degree that the Master Protocol” model is a test of a trial design, the standard rules of scientific experimentation apply: the key step will be in whether it can be replicated.

From a pragmatic standpoint, the lung cancer trial has moved quickly from white paper stage to proposed launch date (although the March 1 target date could slip further, given that the IND has yet to be submitted and the contracts with the five sponsor teams are not yet finalized).

Still, all nine panelists sharing the stage for the announcement of the study launch agreed that the effort in putting together the collaboration was immense, and all credited FOCR in particular with pushing them to keep moving as quickly as possible.

It is very much an open question whether similar collaborations can be built in other cancers (or other diseases) without that high-level of engagement from a relative handful of key figures in FDA and the advocacy community. It is also extremely unlikely that future trials will be able to count on the degree of funding support NCI is offering for this study.

Panelists at the FOCR/Brookings event all stressed the importance that the trial be “successful” in order to assure that the master protocol model itself succeeds.

That, of course, only begs the question of what counts as “success” for the study. Obviously, there are no guarantees that any of the study drugs will actually prove to be safe and effective treatments for squamous cell lung carcinoma. However, it is only natural to suppose that it will be much easier to declare success if at least some of the initial treatments under study turn out to be breakthroughs for the disease.

The trial does offer some potential secondary measures of “success.” For example, the design assumes about a 4% rate of clinical trial participation among patients diagnosed with SCLC. That reflects the national average for trial participation in oncology. In theory, at least, the master protocol model could raise that participation rate significantly—which by itself could be a reason for industry to support expanding the model.

More importantly, higher than expected recruitment rates would dramatically accelerate the reporting of initial results – particularly if one or more of the agents shows “breakthrough”-type efficacy in the Phase II portion. That could generate considerable buzz around the trial and encourage acceleration of plans to run similar studies in other cancers.

It will be an emotionally tougher but still logical argument if the only outcome turns out to be a faster, cheaper failure of the study drugs. For industry, at least, the value of reducing the cost of failure should be clear. That “success” could be defined early, as sponsors analyze the per patient cost of participating in this trial vs. the cost of a stand-alone study.

Translating that “success” into excitement to design future studies will be difficult, but still feasible – if the advocates remain committed.

For now, the enthusiasm for the approach is at a high. “The world is looking at this group,” UC Davis Thoracic Oncology Program Director David Gandara declared. If the study is successful, “we will have changed the entire paradigm for drug development.”