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4-18-2013 – RPM Report – Landmark Trial for Personalized Medicine Coming Soon: NGS Approval May Be One Offshoot of Lung Cancer “Master Protocol”

4-18-2013 – RPM Report – Landmark Trial for Personalized Medicine Coming Soon: NGS Approval May Be One Offshoot of Lung Cancer “Master Protocol”


The primary goal of a proposed new trial for targeted therapies intended to treat squamous cell carcinoma of the lung is straightforward enough: to test several different therapies against a very hard to treat cancer population in hopes that one or more therapies will show substantial effects in different subpopulations and gain FDA approval.

In a patient population with an expected survival of just eight months, that makes the proposed trial important. Even one highly effective new agent would be a major advance.

But this study has much broader ambitions than that. It is intended as a test of a very different model of pivotal trials for lung cancer and oncology in general. If the proposed “master protocol” approach is successful, it could dramatically accelerate the targeted therapy revolution, by reducing the costs for developing individual agents, accelerating the screening and enrollment process for trials – and making clinical trial participation much more common among US cancer patients.

And it could provide another milestone: serving as the basis for FDA approval of the rapid, genome-wide analysis technology known as “Next Generation Sequencing.”

The “master protocol” registrational trial concept was proposed in November as part of a Friends of Cancer/Brookings cancer development conference. (“FDA Eager For More Master Protocols in Oncology: Approach Means Lower Cost For Sponsors—and Less Control” — The RPM Report, December 2012)

Since that time, the idea has advanced considerably, helped by a February event hosted by the National Cancer Institute’s Thoracic Malignancy Steering Committee and a March 12 workshop hosted by FOCR. The latter event included a large FDA contingent and participation by about a dozen different companies.

The groups have reached agreement on a number of key issues, including the basic outline of the proposed protocol, the initial disease condition, the primary sponsor, the trial network, and the sequencing technology to be used.

There is still plenty of work to be done: “The immediate next steps for this project include writing the protocol, working with companies to select drug candidates, developing the governance, developing a template of data set expectations, and determining the overall cost estimates and staffing needs,” FOCR says in a summary of the March workshop. In addition to establishing a budget, the group still needs to settle on an appropriate funding model, including industry participation.

However, based on strong support from NCI on the funding side as well as the enthusiasm and engagement from FDA and industry participants, FOCR is confident the trial will move forward quickly.

Plenty of biopharma sponsors will have a direct interest in the trial since squamous cell lung carcinoma is an active area of research across the industry. But even sponsors with no interest in the specific disease area have a strong interest in understanding whether the “master protocol” model can work as well as its advocates hope.

Almost Two Dozen Potential Drug Candidates

The first key decision in advancing the trial is the selection of squamous cell carcinoma of the lung as the initial indication.

That choice combines two desirable qualities:

A high degree of unmet medical need. Squamous cell carcinoma represents about a quarter of all lung cancer diagnoses, but there are few good treatment options beyond surgery for the disease.

A full pipeline of potential candidates against many different targets. The trial organizers have identified nearly two dozen compounds in development against no fewer than 16 different molecular targets.

That combination is key to the “master protocol” idea. The unmet need assures a relatively broad pool of subjects will likely be interested in trials and screening. The broad number of differently-targeted investigational agents assures that the trial can offer many different options to match different biomarker profiles.

The Candidates List: Targets and Possible Therapies for Squamous Cell Carcinoma of the Lung

Friends of Cancer Research notes, in fact, that its initial list of drug targets is not comprehensive; it was generated by workshop participants and a quick check of public sources. The initial list of six potential targets expanded quickly to 16 based on industry input. There are likely more sponsors and potentially more targets who may have interest in the trial as word spreads.

The exact indication selected will be second-line squamous cell carcinoma of the lung (advanced, incurable stage IIIB or Stage IV), with multiple study arms randomizing patients to a targeted therapy or standard of care.

The trial sponsors expect to select four agents to start the study, each of which will be targeted at a different marker. The actual selection of the agents will be made by an independent committee, which has yet to be established as the governance structure is developed.

However, it is expected that manufacturers will “apply” to participate – and that the number of study drugs will expand over time as the trial gets up and running.

In theory, the trial design would allow multiple agents targeted against the same biomarker to be tested using a shared control group. That feature would further reduce the cost of studying individual agents—but would also invite explicit or implicit head-to-head comparisons. The trial sponsors have decided to avoid opening up those issues by limiting the trial (at least initially) to agents with different targets.

FNIH to Sponsor, Oncology Groups to Launch Study

There has been considerable progress in organizing the study team and assigning overall responsibilities.

As expected, the official study sponsor will be the Foundation for the NIH – the same group that holds the IND for the I-SPY breast cancer screening trial.

As a starting point, there will be a Global Trial Oversight committee, whose members will include FDA, NIH, FNIH, patient foundations and industry.

The study organizers have agreed that the NCI cooperative oncology groups will serve as the initial infrastructure to set up the study, with the Southwest Oncology Group (SWOG) taking the lead role on writing the trial protocol and standing-up the study.

Among the many larger implications of the trial will be as potential trigger to evolution in the NCI oncology group model, a subject of considerable attention in the oncology community in recent years. The decision to rely on the COGs to start the trial was debated during the November FOCR/Brookings meeting, but the choice likely makes the budget process easier. NCI is expected to contribute well over half the cost of launching the study in part out of a desire to demonstrate that the COGs can play an important role in advancing the clinical trial enterprise in oncology.

The plan, however, will be to expand study site participation over time.

MD Anderson’s Vassiliki Papadimitrakopoulou will serve as study chair. She is already the principle investigator on a multi-arm Phase II study of targeted therapy in non-small cell lung cancer, the BATTLE-2 trial. Sponsors of that trial include AstraZeneca PLC, Bayer AG, Merck & Co. Inc., and Astellas Pharma Inc.

Registration is Goal…

The major difference between the new study and I-SPY or BATTLE-2 is that the explicit goal of the squamous cell trial will be registrational—not simply identifying promising targets and therapeutics in Phase II.

“The trial would be designed with the ultimate goal of FDA approval for those drugs that meet pre-specified criteria,” the Friends of Cancer Research summary notes. Office of Hematology & Oncology Products medical officer Shakun Malik is serving as the FDA co-chair on the trial committee.

The protocol, in fact, applies a separate concept developed from the Friends of Cancer Research/Brookings cancer project: the idea of performing an interim analysis after a relatively modest number of patients are treated that would be sufficient to demonstrate a large treatment effect, and then continuing the study to enroll a larger patient population sufficient to demonstrate a smaller effect. (“Expedited Approval Pathway Concept Draws Strong Support But Different Proposals” — “The Pink Sheet,” Dec. 5, 2011)

The proposal, crafted by a working group that included University of Washington statistician Thomas Fleming among others, was presented at the November 2011 FOCR/Brookings event.

The specific proposal outlined was a “screening study,” which calls for early randomization to a sample size with enough patients (c. 150) to demonstrate statistical significance if the effect size proves to be large (say a 50-60% increase in response rates). In that case, it could be a registrational study. If the effect size is moderate (say 25%) it is still a “positive” trial—but a Phase II study that leads to a larger Phase III.

The design is intended as much to screen out drugs where the early signal is exaggerated and the real effect size is minimal, Fleming explained. The trial would be randomized with the goal of identifying therapies that are worth advancing to registrational trials—but offering a realistic chance of achieving statistical significance if the effect size is very large.

Fleming estimated that the study design would dramatically reduce the Phase III failure rate by screening out about 6 out of 7 agents where the early sign of efficacy was a false one.

The proposed trial design for the SCCL master protocol adopts a similar model, which proposes a “Phase II/III” design, with a Phase II analysis providing a “go/no-go decision” for proceeding to Phase III. As in Fleming’s proposal, the emphasis is on stopping an arm where there is little potential of showing benefit even in a larger sample size; however, FOCR notes, the design would allow for the potential of halting the study at that point due to clear efficacy and proceeding to filing.

Still, in designing the master protocol, the expectation is that most sponsors will be unlikely to offer up agents whose efficacy appears to be so significant that they would likely not require full Phase III development.

…For the Sequencing Process as Well

The study is not only intended to provide registrational data for the therapeutics.

The study planners will be working with Foundation Medicine Inc. to perform the genomic analysis for the trial, and, FOCR says, Foundation has agreed to apply for FDA approval of its “Next-Generation Sequencing” platform based on the data developed from the protocol.

The regulatory status of NextGen Sequencing is one of the key issues for the evolution of the pharmacogenomic era, and FDA has lately missed no opportunity to emphasize is interest in approving the technology.

During a recent Institute of Medicine workshop, for example, FDA Personalized Medicine Staff Director Elizabeth Mansfield, stressed the agency’s excitement about NGS—and the agency’s desire to review an application.(“The Companion Diagnostics Dilemma” — The RPM Report, March 2013)

FDA diagnostics review staff were among the participants in the FOCR workshop on SCCL. The trial design itself posits screening using Foundation Medicine’s NGS platform operated through a central, CLIA-certified lab. The most likely scenario is that FDA will approve individual diagnostic tests one at a time in the early phases of the study – but may ultimately grant a platform approval or otherwise set a new paradigm for NGS.

That could make the SCCL trial a significant landmark in the personalized medicine era.

But the trial planners hope it doesn’t stop there: the study “has the potential to revolutionize and accelerate the way new biomarker-defined therapies are tested for lung cancer,” the FOCR workshop summary notes.

Moreover “the trial also aims to serve as a model that can be used for other diseases.” There already appears to be considerable interest in testing the model in metastatic colon cancer. But in theory, it could also apply to non-oncology indications – any setting where multiple different mutations create subsets within a traditional disease.

“It also represents a new opportunity for patients in a setting where few clinical trials may be available or accessible, especially for those patients with very rare mutations,” the workshop summary states.

That potential may be many years in the future—or may never materialize at all. But still, the SCCL “master protocol” looks like a study that every biopharma sponsor should follow as a potential milestone in the personalized medicine era.