Signature Trial Program Aims for Rapid Delivery of Novel Therapies

August Salvado, MD

The objective of the Signature trial program is to deliver the protocol directly to the patient, expediting site initiation. If any physician in an academic or community setting determines that a patient has an actionable mutation through genetic testing, the physician can contact Novartis to receive a Signature protocol package, which includes an institutional review board-approved consent and approval.

Traditional clinical research usually takes place in large, academic centers, where patients may have difficulty enrolling because of travel restrictions and other factors. In addition, multiple academic settings may enroll patients, but if the disease is rare, many sites will not accrue patients for the trial.

“We are trying to make physicians broadly aware that we have a number of protocols available for the patient who may have a target or an abnormality in a particular pathway,” said Salvado.

About 80 to 100 patients have been accrued for each trial, Salvado said. The studies are phase II trials typically open to patients with both solid and hematologic malignancies with the matching mutations; the primary endpoint is the clinical benefit rate, which consists of complete and partial responses.

Salvado said the program has engaged 394 sites; most are community settings but about 20% have been academic settings. “You can only have so many open protocols in an academic setting,” said Salvado. “If an academic site has a patient who doesn’t fit into one of those protocols, which happens quite often, the Signature program is a way to offer a potential benefit to a broad group of patients.”

The program is also cost effective because “physicians can contact Novartis with patients who are candidates for the trial,” said Salvado. The protocol does not limit recruitment to a specific number of sites, so the reach of the program could encompass the entire United States, he added.

As of mid-July, the Signature program featured 5 ongoing clinical trials, including 3 studies recruiting participants, according to Novartis and the ClinicalTrials.gov website (Table). One of the drugs under study, ceritinib (Zykadia) has been approved for the treatment of patients with ALK-positive metastatic non—small cell lung cancer (NSCLC).

Clinical Trial Innovation

Three additional studies have either been completed or closed due to low enrollment, according to the ClinicalTrials.gov website.Signature is not the only program that follows this innovative protocol. The National Cancer Institute Molecular Analysis for Therapy Choice (NCIMATCH) and the first ASCO-led trial, Targeted Agent and Profiling Utilization Registry (TAPUR), have similar rationales as Signature.

NCI-MATCH seeks to determine whether treating patients with cancers according to their molecular abnormalities will show evidence of effectiveness. NCI-MATCH can add or drop new treatments over time. Each treatment is used in a unique arm, or substudy, of the trial.

The trial opened for enrollment in August 2015 with 10 treatment arms and was expected to have a total of 24 treatment arms by June 2016. Each arm is expected to enroll a maximum of 35 patients.

TAPUR is a nonrandomized clinical trial that aims to describe the safety and efficacy of commercially available, targeted anticancer drugs prescribed for treatment of patients with advanced cancer that have a potentially actionable genomic variant.

Researchers will provide approved targeted therapies that are contributed to the program by collaborating pharmaceutical companies, catalog the choice of genomic profiling test by clinical oncologists, and learn about the utility of registry data to develop hypotheses for additional clinical trials.

Colorectal and NSCLC adenocarcinoma are the most common tumor types that Signature focuses on, although Novartis said patients with some rare cancers, such as gallbladder and anal, have enrolled. Tumor types were excluded if key studies were planned or ongoing, or there were data showing no benefit. The most common genetic alterations are RAS (17%) and PIK3CA (16%), although less frequent alterations (<1%) have been detected.

In a status report on the Signature trial last year,1 researchers said that the average time from a new site approaching Novartis with a potential patient, through site start-up activities, to patient consent and screening, was 4.9 weeks (range, 1.0-34.4 weeks). “The median startup time across all of the sites was 4.9 weeks. When you compare this to an industry standard of about 41.0 weeks [to open a trial], this is pretty impressive,” said Sarina A. Piha-Paul, MD, of The University of Texas MD Anderson Cancer Center.¹

It is estimated that only about 2% to 3% of adults enroll in clinical trials, despite the belief that sometimes the best care can be delivered through trial participation. It is a significant unmet need.

“It’s an exciting time in oncology because the science has progressed so rapidly over the last few years,” said Salvado. “Whether it’s an academic setting or a community setting, we have to change the way we perform clinical trials so that we provide drugs to patients in the most effective way.”

Reference

1. Peguero JA, Knost JA, Bauer TM, et al. Successful implementation of a novel trial model: The Signature program. Presented at: 2015 ASCO Annual Meeting. Abstract 106.

A collection of clinical trials that uses a target-specific and tissue-agnostic algorithm to rapidly match patients to investigational therapies aimed at the tumor’s molecular makeup takes the approach that “one trial really does not fit all,” according to August Salvado, MD, vice president of Early Stage and Innovation at Novartis Pharmaceuticals Corp.