At a recent meeting in Washington, DC, Friends of Cancer Research and the Engelberg Center for Health Care Reform at the Brookings Institution officially announced activation of the Lung Cancer Master Protocol, a new research strategy that has the potential to hurdle or bypass known clinical trial roadblocks and barriers.1 This first-of-its-kind clinical trial design has generated considerable anticipation in the cancer research community.
Study Background and Rationale
Cancer clinical trials are time-consuming (requiring up to 15 years), expensive ($50–$100 million each), bogged down in bureaucratic and regulatory red tape, and notoriously difficult to fill. For instance, in 2012, only 1,864 patients with lung cancer out of the 226,000 diagnosed that year were enrolled in a trial.
At the moment, there are 1,320 open trials for lung cancer, costing upwards of $70 billion—and the vast majority will not result in drug approval. In fact, of 20 recent trials for late-stage disease, only two resulted in approval.
These trials face logistical problems as well. If they incorporate biomarkers, which is the best way to focus on patients most likely to respond, then the pool of potential subjects shrinks. For example, the ALK marker appears in fewer than 7% of non–small cell lung cancer (NSCLC) patients. Other biomarkers have even smaller numbers. The Lung Cancer Master Protocol investigators hope to avoid this problem with their new model.
“NSCLC almost always has multiple and often independent mutations—thus many potential therapeutic targets,” said Vali Papadimitrakopoulou, MD, Professor, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston. “Squamous cell carcinoma is really an orphan disease because there have been no substantial therapeutic developments and no approved targeted drug therapies. Therefore, we think that genotype- or phenotype-driven subgroup selection in a clinical trial would improve operational efficiency and provide homogeneous patient populations and consistency in eligibility from arm to arm.”
Genotype and phenotype screening at the outset and grouping similar types in multiple small studies reduces the overall screen failure rate. “Multitarget screening can increase the ‘hit rate’ and provide for uninterrupted accrual. This, in turn, will create a path to approval for safer and more effective drugs, while replacing ineffective ones,” said Dr. Papadimitrakopoulou.
Trial Design
Each drug used in the Master Protocol trial is required to have demonstrated biologic activity in a responsive patient group against a measurable target and to use a validated predictive biomarker assay that then becomes suitable for a pivotal trial.
This master plan for second-line therapy for advanced squamous cell carcinoma is a multiarm, randomized, controlled phase II/III registration protocol. Each arm opens and closes independently of the others and is powered for overall survival. Positive results at varying interim analyses determine whether an arm proceeds to phase III.
The primary objective for phase II is a 40% improvement in progression-free survival and for phase III, a 2.25-month extension in progression-free survival. The trial will be powered to assess overall survival, and secondary objectives are toxicity and response rate for both phase II and phase III Exploratory objectives include additional predictive blood and tumor biomarkers, resistance biomarkers at progression, and creation of a tissue and blood repository from patients with refractory squamous cell carcinoma.
How It Got Started
The Master Protocol project all started 8 months previously at a Friends of Cancer Research workshop, where a group of stakeholders (federal health and regulatory agencies, academic research centers, and patient advocacy organizations) reached consensus about this new idea. The committee was chaired by Roy S. Herbst, MD, PhD, and Ellen V. Sigal, PhD. Because of its unique design, the trial can accelerate the way new biomarker-defined therapies are tested—the master trial will start with five of them.
It also represents an opportunity for patients with rare mutations for whom few clinical trials are available or accessible. About 1,250 patients will be screened annually, and about 500 to 1,000 assigned to trial substudies each year.
Participants at that meeting agreed to overall trial design (endpoints, patient population, biomarker screening, controls, statistical analysis), the most significant of which is the ability to screen for many alterations from the same tissue sample. This maximizes the amount of information available from each tissue sample, as well as the likelihood that any one patient will be successfully matched to a biomarker-defined arm. Equally significant is that it can avoid testing the same patients many times over. Companies participating in the master trial will enroll patients from the large pool of screened candidates in an appropriate trial arm.
The main purpose of the screening is to achieve rapid accrual. The master protocol is flexible enough to accommodate amendment of individual study arms, which avoids the need to initiate separate new trials.
For the initial trial, five compounds have been selected:
- Rilotumumab (Amgen), a human monoclonal antibody against human hepatocyte growth factor/scatter factor.
- A fibroblast growth factor receptor tyrosine kinase inhibitor (AstraZeneca).
- MED14736 (Medimmune), a human IgG1 monoclonal antibody targeting programmed cell death 1 ligand.
- Palbociclib (Pfizer), a cyclin-dependent kinase 4 and CDK6 inhibitor.
- An inhibitor of phosphoinositide 3-kinase (Genentech).
Participants, Challenges, and Hesitations
A number of groups are involved in the Master Protocol:
- The National Cancer Institute (NCI) Thoracic Malignancy Steering Committee provides initial approval of the master Investigational New Drug (IND).
- Foundation for the National Institutes of Health (FNIH), a public-private biomedical research partnership, will hold the master IND, as well as contracts with trial sites, labs, and pharmaceutical companies.
- A drug selection committee of independent experts will determine which biomarkers and drugs will be studied.
- Pharmaceutical companies will be represented.
- A Global Trial Oversight committee, including members of the Food and Drug Administration (FDA), NCI, FNIH, patient foundations, and industry) will evaluate site management and data collection.
- SWOG will be responsible for operational monitoring, quality control, and tissue and data flow.
Next steps for the project include writing the protocol, developing the governance structure, establishing a data set expectations, and determining overall cost and staffing. This should be done within 2 to 3 months, and enrollment is slated to begin in March 2014, according to David Gandara, MD, Director, Thoracic Oncology Program, University of California Davis.
“In NSCLC, ‘all-comer’ clinical trial designs are rarely successful, so we need early codevelopment of drugs and their associated biomarkers. Through master protocols for both early-stage adjuvant therapy and advanced disease, we can account for the tumor heterogeneity and genomic complexity of NSCLC. However, we believe that this approach will transcend lung cancer and this particular group of patients. By using a Master Protocol, ‘the future is now’,” he said.”
Industry Concerns
There remain concerns about the workability of such a large endeavor: competition among pharmaceutical companies, their need to protect proprietary information, and the logistics of such a large and complex trial. However, Roy S. Herbst, MD, PhD, Ensign Professor of Medicine, Chief of Medical Oncology, Yale University Cancer Center, and Co-Chair of the Master Protocol Steering Committee (see sidebar), said that it is much easier to get a pharmaceutical company into a group plan for a small, early trial than it is to persuade them to provide drugs and proprietary information for a large late-stage one. However, we are entering a new world of genomic profiling, and this type of intercompany cooperation will be essential.
Dr. Herbst added a caveat: “Many companies often think they can do these kinds of studies alone, and they worry about losing autonomy, so the idea of a master trial is a challenge for them,” he said. “We hope to show this design will be a ‘win-win,’ adding efficacy and speed to the process.”
“We tried to address industry concerns early,” said Ellen V. Sigal, PhD, Founder and Chair, Friends of Cancer Research. “At the March [2013] planning meeting, we assured the original 20 companies that expressed interest that FDA supports the idea and has put its statisticians at our disposal so it can make approval decisions based on trial data. We also will have a neutral third party monitoring the trial to assure that drugs from the participating companies will not be compared directly with one another.”
Drug companies also can be enticed to participate by means of access to NCI’s network of comprehensive cancer centers that have much experience conducting trials. ■
For more on the Lung Cancer Master Protocol, see The ASCO Post, November 1, 2013 article here.
Disclosure: Drs. Papadimitrakopoulou, Gandara, Herbst, and Sigal reported no potential conflicts of interest.
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