Novel Trial Program Puts Patients First

Novartis Oncology hopes to overcome many challenges with the innovative Signature Clinical Trial program, which “bring[s] the ‘Protocol to the Patient.’”

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

Table. Signature Trial Drugs and Targets⁷

Novel Drug

Targets

BGJ398

FGFR alterations

BKM120 (Buparlisib)

PI3K activation

TKI258 (Dovitinib)

EGFR, PDGFR, VEGF, cKIT, FLTC CSFR1, Trk, RET mutations or translocations

MEK162 (Binimetinib)

RAS, RAF, MEK activation

LGX818 (Encorafenib)

BRAFV600 mutation

LEE011

CDK 4/6 pathway

LDK378 (Ceritinib)

ALK or ROS1 aberrations

LDE225 (Sonidegib)

PTCH1 or SMO mutation

Secukinumab

TNF-IR (psoriasis)

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 rate—the 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.

References

1. Institute of Medicine (US) Forum on Drug Discovery, Development, and Translation. Transforming Clinical Research in the United States: Challenges and Opportunities: Workshop Summary. Washington, DC: National Academies Press (US); 2010.
2. Novartis Oncology. About Signature. https://www.signaturetrial.com/en/hcp/AboutSignature. Published August 2014. Accessed February 16, 2015.
3. Novartis Oncology. Signature trial program — frequently asked questions. https://www.signaturetrial.com/en/hcp/FAQ#HowManyProtocols. Published August 2014. Accessed February 16, 2015.
4. Novartis Oncology. Referring a patient. https://www.signaturetrial.com/en/hcp/Refer. Published August 2014. Accessed February 16, 2015.
5. Slosberg ED, Kang B, Beck JT, et al. The signature program, a series of tissue-agnostic, mutation-specific signal finding trials.J Clin Oncol. 2014;32:5s (suppl; abstract TPS2646).
6. Tufts, CSDD. Survey results of start-up cycle times. http://www.appliedclinicaltrialsonline.com/appliedclinicaltrials/article/articleDetail.jsp?id=796689. Published November 1, 2012. Accessed February 16, 2015.
7. Novartis Oncology. Signature site map. https://www.signaturetrial.com/en/hcp/SiteMap. Published August 2014. Accessed February 16, 2015.
8. New ASCO study aims to learn from patient access to targeted cancer drugs off-label. http://www.asco.org/advocacy/new-asco-study-aims-learn-patient-access-targeted-cancer-drugs-used-label. Published November 21, 2014. Accessed February 16, 2015.
9. Unger JM, Hershman DL, Albain KS, et al. Patient income level and cancer clinical trial participation.J Clin Oncol. 2013;536-542.