March 2014 Edition Vol.11, Issue 3
Biomarker status trials’ unique aspect is that they use patient biomarker status across multiple tumor types to randomize patients to treatment arms of a trial.
Basket/Bucket Trials: NCI-MATCH
Researchers hope that basket studies will also help accelerate the drug approval process for treatments targeting rare cancer types for which large randomized trials are logistically impossible. If a drug were shown to be active in in one of these types of cancer, the basket trial would allow for the enrichment of that particular cohort (Willyard, 2013).
Various studies are underway to test the efficacy of this type of approach. Two examples are Roche’s Phase 2 study of vemurafenib in patients with BRAF V600-mutant cancers (NCT01524978) and the Italian Sarcoma Group’s Phase 2 study of imatinib in patients whose tumors express the platelet-derived growth factor receptor (PDGFR) (NCT00928525). An additional study now within the planning stage is NCI-MATCH, which proposes to match 1,000 patients to various therapies based on biomarker status. So far, over 40 drugs have been pledged from companies such as Clovis, Genentech and Pfizer, and 20 separate arms have been established for tumors with genetic alterations in known tumor drivers such as EGFR, HER2, BRAF, and ALK.
Novartis SIGNATURE Trial
The design will provide for “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,” Dr. Steven Stein, SVP of U.S. Clinical Development and Medical Affairs at Novartis, said in a statement to Cancer Commons.
Aptiv Solutions
On February 19, 2014, these companies partnered to develop the ADDPLAN® DF Consortium, the purpose of which is to improve upon current standard of practice procedures for designing and analyzing Phase 2 dose-selection trials. The consortium identifies poor dose selection as one of the leading causes of Phase 3 trial failures, and plans to develop new adaptive statistical methodologies in order to reduce selection error and uncertainty (Aptiv Solutions, 02/19/2014).
Additional new strategies are being launched, such as The Master Protocol initially for squamous cell lung cancer. The trial is unique as it is a collaboration between lung cancer researchers, the National Cancer Institute, the Foundation of the National Institutes of Health, the Food and Drug Administration, Friends of Cancer Research, and industry (ASCO Post, 2013).
The Master Protocol investigates multiple new therapies simultaneously for one tumor type. Unlike I-SPY 2 and BATTLE in which markers and drugs are analyzed for association, each biomarker included is associated with a targeted therapy and assignment to that treatment is based on results of a validated diagnostic test. It is designed as a Phase 2/3 trial powered to demonstrate efficacy, with the goal of expediting FDA approval (FOCR, 2013).
Through advances in Next Generation Sequencing technologies, it is becoming increasingly feasible to quickly and efficiently generate a molecular profile of each patient’s tumor. With this information, patients can now select to participate in clinical trials that test therapeutic response not only in the context of their specific disease but also in the context of their tumor’s molecular characteristics. Under this paradigm, data from clinical trials can be used more expeditiously to adjust participation and improve clinical trial metrics.
___________________________________________________________________________________________New Clinical Trials Designed to Better Leverage Precision Medicine
New Clinical Trials Designed to Better Leverage Precision Medicine (cont.)
The Biomarker Status Trial
The basket or bucket-trial method recruits patients via biomarker status instead of cancer type. After biomarker identification, the patients are divided into multiple study arms (baskets) by cancer type, and the drug’s impact is assessed within the separate arms as well as within the study as a whole (AACR, 2013).
To date, oncology drugs are approved for an indication based on cancer type, but MATCH hopes to deliver positive results that could support future approvals based on molecular targets as well.
Another example of this approach is Novartis’ Phase 2 non-randomized, open-label SIGNATURE trial, which will assign patients with solid tumors to one of five different trial arms with different targeted therapy regimens. Patients will first have their tumors tested for the pertinent genetic alterations or biomarkers of pathway activation at a CLIA certified laboratory, and then will be assigned to a trial arm via the recommendation of a board of experts who have reviewed the data.
Important to the success of these novel trial designs is the need for cooperation and collaboration between different pharmaceutical companies. Companies have begun to acknowledge this requirement as demonstrated by the recent collaboration of global CRO Aptiv Solutions with Novartis, Janssen Pharmaceuticals Inc., and Eli Lilly.
Designing the Future
About the Contributor
Chief Medical Officer and Founder, N-of-One, Jennifer Carter, MD has been an early driver in shaping and delivering personalized medicine for oncologists at the point of care. Today, N-of-One is the leading provider of molecular interpretation and therapeutic strategies for oncology.
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