Novartis Revolutionizes Clinical Trials for Targeted Cancer Drugs

Someone had to do it; now it looks like Novartis may be the first. The pharma company’s new series of clinical trials, SIGNATURE (also known as, ‘bring the protocol to the patient,’ or  ‘P2P’), is recruiting patients with different cancers to receive investigational targeted drugs selected to match the distinct genetic changes found in each patient’s tumor.

The design of clinical trials put in place decades ago for testing chemotherapy drugs has become outdated with the advent of targeted therapies. People with the same type of cancer are recruited into clinical trials to receive an investigational drug, chemotherapeutic or targeted. If a new drug shows promise, it is advanced to a larger clinical trial, frequently randomized; that is, some patients receive the investigational drug, while others receive an older drug already approved for their type of cancer. If the new drug works better, it might be eventually approved by the U.S. Food and Drug Administration (FDA) and might eventually used by oncologists. The results of large, phase III randomized trials essentially shape the drug choices of oncologists.

This traditional trial design is not suitable for targeted drugs for several reasons. First, the ‘same type of cancer’ is poor grounds for choosing a particular targeted drug. Only a small percent of patients with a given type of cancer might have a mutation in the gene targeted by this drug. For example, enrolling all patients with lung cancer in a clinical trial to test an inhibitor of ALK would be a terrible mistake, because only about 4% of them would have the particular ALK genetic mutation required to respond to the drug. Unfortunately, all too frequently, patients enrolled in studies of targeted drugs are not tested for relevant genetic alterations in their tumors.

Second, large genomic cancer studies conducted in the past few years have made it clear that very different types of tumors might share the same genetic alterations. For example, mutations in the BRAF gene are found in about 50% of melanomas, but are also present in lung and colon cancer, albeit at a low frequency, and even in a certain type of leukemia. Most importantly, the BRAF inhibitor drugs developed for melanoma work in these other cancers as well. Similar findings are true for a number of different cancer-causing mutations that are shared across cancer types.

Enter, the clever design that Novartis has now put into action; the company has initiated SIGNATURE with drugs aimed at the following molecular targets:

PI3K pathway (targeted by the drug BKM120)

FGFR (targeted by TKI258)

MEK (MEK162)

RAF (LGX818)

SMO (LDE225)

Some of the drugs actually target an entire chain or ‘pathway’ of chemical reactions used by a cancer cell, and not just one mutant protein, so they could be used for more than one mutation. For example, the drug BKM120 could be used for patients whose tumors have mutations in the genes PIK3CA or PIK3R, or who have the mutation known as deletion of PTEN.

Here’s how SIGNATURE works: first, cancer patient must get tested for the presence of the relevant genetic changes in their tumor. Once the results of this molecular testing are received and verified, they will be advanced to Novartis’ board of experts who will rule on their eligibility to be treated with a relevant drug, based on the molecular ‘blueprint’ of the tumor. Experts are already lined up for this task and are facilitating recruitment of patients. From here on, it is a fast train to start treatment in one of the many clinics that has signed up with Novartis to participate. The treatment protocols have been approved, the agreements with clinical entities involved have been signed, and the time to get the investigational treatments to patients has literally shrunk under this scheme.

Dr. Steven Stein, SVP of U.S. Clinical Development and Medical Affairs at Novartis says: “The major advantages for patients are obvious: precise matching of the genetic abnormalities found in their tumors to relevant drugs; rapid enrollment; little if any geographical constraints on participation; and, of course, access to promising new therapies that have already undergone safety testing.”

The benefits for Novartis are also clear: drugs that have been developed at great expense to the company will now move through clinical testing much faster; they are precisely matched to a selected and relevant patient population; and this design speeds up the realization of the full clinical potential of the drugs by not limiting their testing to a single cancer type.

Even better, Novartis already has an expanded list of drugs from its pipeline to be tested in future SIGNATURE trials and intends to test drug combinations as well. It is very likely now that other drug companies will adopt the SIGNATURE trial design to speed up their own drug development.

To explore SIGNATURE, visit