Novartis Oncology hopes to overcome many of these challenges with the innovative Signature Clinical Trial program, which â€œbring[s] the â€˜Protocol to the Patient.â€™â€
The standard clinical trial model for a new drug presents many challenges. Trials are expensive, costing anywhere from $300-600 million.1Busy practitioners are sometimes reluctant to refer their patients to off-site clinical trials because of cumbersome requirements and lost revenue. Patients may be unaware of available trials, live too far from a study site to consider participating, or live just far enough away that travel and time costs would impose significant burdens, especially for someone dealing with an illness like cancer.1Also, some patients are unwilling to exchange their regular provider for someone new.
Novartis Oncology hopes to overcome many of these challenges with the innovative Signature Clinical Trial program, which “bring[s] the ‘Protocol to the Patient.’”2Signature is a series of phase II proof-of-concept trials, each with a specific molecular target.3The program was designed to provide patients with faster, more convenient access to novel targeted oncology drugs, thus providing researchers with data on a drug’s safety and effectiveness much sooner than a conventional trial.2
Under the Signature program, instead of opening a fixed number of sites at specified locations, Novartis will establish a trial site wherever an eligible patient is identified.2Once a physician determines that a patient’s cancer has a one of the qualifying mutations, he or she calls a Novartis Signature trial administrator to discuss opening a site.4Any “research-experienced site in the United States accepting [the Novartis] study model” is able to participate.5Normally, it takes around 8 months to get a trial site operational6; Novartis expects it to take no more than 3 weeks to open a Signature site.2Whereas a traditional trial site must enroll multiple patients, a Signature site has no requirement to enroll anyone beyond the initial patient.
Another unconventional aspect of Signature is its tissue-agnostic approach. Frequently in oncology, a clinical trial for a targeted drug enrolls patients who share the same cancer type. For example, trastuzumab (Herceptin) was first evaluated in and approved for patients with breast cancer. Later, it was studied in and approved for patients with gastric cancer. The Signature trials will include patients with any type of cancer who test positive for a specific mutation.2,5Because the patient was already pre-identified as eligible, no further screening is required.2
EGFR, PDGFR, VEGF, cKIT, FLTC CSFR1, Trk, RET mutations or translocations
RAS, RAF, MEK activation
CDK 4/6 pathway
ALK or ROS1 aberrations
PTCH1 or SMO mutation
Novartis currently has 9 Signature trials under way (8 in oncology;Table).7
As with conventional trials, the Signature trials require informed consent. These trials include a centralized Institutional Review Board. Each compound being evaluated is covered under a separate protocol.3To ensure the safety of the doses being tested, phase I dose-finding trials were conducted for each compound. Patients enrolled in Signature receive the test drug for 16 weeks. The primary endpoint is clinical benefit ratethe percentage of patients who achieve a response or have stable disease at the end of the study. At a presentation at the 2014 American Society of Clinical Oncology (ASCO) annual meeting, an abstract reported that “73 patients have been consented at 46 network, academic, and community sites.”5
ASCO is launching a similar program called the Targeted Agent and Profiling Utilization Registry (TAPUR) study.8TAPUR, which is the first clinical trial ASCO has ever initiated, will allow physicians to enroll patients who they have identified as having one of the qualifying molecular targets. During the trial, patients will receive an approved drug off label. ASCO plans to release a list of eligible drugs matched to specific targets. The primary endpoint in TAPUR is response rate, but other safety and efficacy data will be collected.
As companies and institutions implement new approaches to clinical trial design in the United States, it is unclear how the US Food and Drug Administration will respond to data obtained through these nonstandard trials. However, less than half of oncology patients discuss clinical trials with their physician, and less than 10% enroll in a clinical trial.9Signature, TAPUR, and similar programs aim to improve these numbers and allow more patients to reap the benefits of precision medicine.