Newer trial designs may help to personalize cancer treatments based on DNA alterations in tumors, rather than on primary tumor site or stage of disease. The result could be more effective treatments. A summary of three of these novel trial designs is published in Annals of Internal Medicine.
Traditional trial designs in oncology have proceeded along three phases of research. Phase 1 oncology trials seek to find the maximum dose tolerated by the patient’s normal tissues among patients with metastatic disease of various primary tumor sites that were resistant to known treatments; phase 2 trials are used to evaluate antitumor drug activity in patients with advanced disease of a given primary tumor site in which other treatments have failed; and phase 3 trials are randomized controlled trials (RCTs) comparing a new treatment to a standard-of-care control in patients who are representative of the general population of patients with a specified primary site and stage of cancer. However, developments in tumor biology and genomics have indicated that tumors of a primary site represent a heterogeneous collection of diseases that differ with regard to DNA drivers. This means that conventional approaches to clinical trial design and analysis may no longer be appropriate as clinicians look to base treatments on molecular phenotypes. This movement is known as precision medicine.
The author describes new clinical trial designs in oncology that may help to advance precision medicine. In phase 2 basket trials, which can be randomized or nonrandomized and include a single drug or multiple individual drugs, patient eligibility is based on a defined genomic alteration rather than on primary tumor site. For example, eligibility may require that the tumor contains a V600E mutation in the BRAF gene in a patient with any type of solid tumor. Phase 3 enrichment designs conducted for regulatory approval have eligibility limited to patients with a single primary site of disease and genomic alteration. Approval of a drug is accompanied by an approval of a companion diagnostic for identifying the patients who have tumors for which the drug is effective. For example, trastuzumab was approved for breast cancer with an assay for amplification of the HER2 gene overexpression of the HER2 protein as the companion diagnostic test. And finally, phase 3 umbrella designs involve several molecularly targeted test drugs and a population of patients with a single primary site of disease. Phase 3 umbrella trials consist of a combination of several enrichment designs conducted with a common genomic alteration testing infrastructure. For example, in the Lung-MAP (Lung Master Protocol-phase II/III Biomarker Driven Master Protocol for Second Line Therapy of Squamous Cell Lung Cancer) study, patients with advanced squamous cell lung cancer who have undergone one previous treatment are screened for genomic alterations in more than 200 genes using a sequencing platform that has been analytically validated for accuracy. As a result of this tumor characterization, patients are recommended for 1 of 5 subtrials with the umbrella framework.
These new trial designs are promising in oncology precision medicine and have may indications in other disease areas, as well, according to the author.