Designing a better clinical trial to sort out complex tumors

Esophageal adenocarcinoma - intermed mag" by Nephron - Own work. Licensed under CC BY-SA 3.0 via Wikimedia Commons.

Micrograph showing histopathological appearance of an esophageal adenocarcinoma (dark blue – upper-left of image) and normal squamous epithelium (upper-right of image) Image” by NephronOwn work. Licensed under CC BY-SA 3.0 via Wikimedia Commons.

When oncologist Daniel Catenacci, MD, assistant professor of medicine, designed a clinical trial, he decided to name it PANGEA, for Personalized ANtibodies for Gastro-Esophageal Adenocarcinoma. Not unlike the former “supercontinent” that gave rise to the present continents on Earth, this trial represents an almost unrecognizable assembly of the current clinical trial architecture and biomarker-driven approaches to improve clinical decision-making.

Personalized medicine, or precision oncology, aims to incorporate information about a patient’s and/or their cancer’s genetic make-up into treatment decisions. However, tumors consist of individual cancer cells with distinct molecular features, including DNA mutations, chromosomal abnormalities, and gene expression profiles. This inherent complexity, also referred to as tumor heterogeneity, is a major challenge to refining treatment strategies for cancer patients so that they are as effective as possible. If a tumor is like a jar full of colored marbles, it is impossible to know if it would be better to take out the blue ones, the red ones, both, or some other color, without knowing which ones are the most important.

The PANGEA trial addresses the problem of tumor heterogeneity by gathering as much information about the distinct tumor cell populations, and what drives their behavior, and then use molecularly targeted therapies to eliminate them. The phase I trial has been approved by the United States Food and Drug Administration and University of Chicago Institutional Review Board to enroll patients with newly diagnosed, stage IV gastric, esophageal or esophago-gastric junction cancer. Upon testing the patient’s tumor for its molecular features (biomarkers), the patient will be put on one of five “arms,” or treatment groups, and receive the targeted therapy that is most appropriate for him/her. For example, patients with cancers in which a majority of the tumor cells carry amplification of the HER2 receptor will receive the HER2 inhibitor, trastuzumab. Importantly, all patients will be treated with the most advanced treatment available based on their own cancer’s characteristics.

Daniel Catenacci, MD

What separates this trial from others, however, is that patients may be reassigned to a different arm if they progress on their first therapy and their tumors are revealed to now have a different composition of tumor cell features. Patients could be reassigned as many as three times as a strategy to overcome therapy resistance.

Support for some of the preclinical work necessary for the design and implementation of this innovative clinical trial has come from a Precision Oncology pilot grant funded in 2013 by the University of Chicago Cancer Research Foundation Women’s Board. In the fall of 2014, Catenacci successfully leveraged that funding and work to obtain a five-year K23 Mentored Patient-Oriented Research Career Development Award from the National Cancer Institute.

For Catenacci, among the most exciting elements of the PANGEA trial is its flexibility to incorporate new and highly effective treatment strategies as they are developed. In fact, he is currently adding an arm to the trial using pembrolizumab, a promising immunotherapy recently approved for treatment of melanoma. And because of the potential benefit to patients, he sees this biomarker-driven approach as the future of clinical trials, and ultimately, clinical practice for cancer patients.

“The PANGEA clinical trial design has the potential to test tumor profiling and methods for assigning treatment with the intention to tackle the problem of tumor heterogeneity and improve outcomes for these patients, “ said Catenacci.

This article originally appeared in the University of Chicago Medicine Comprehensive Cancer Center’s “Pathways to Discovery” magazine, Winter 2015 edition.

About Kathleen Goss (30 Articles)
Kathleen Goss, PhD, is the Director for Strategic Partnerships and senior science writer at the University of Chicago Medicine Comprehensive Cancer Center.
%d bloggers like this: