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FDA Pipeline: Designations in Triple-Negative Breast Cancer, ctDNA Detection

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This week, the U.S. Food and Drug Administration (FDA) granted a Fast Track designation to a treatment for CCR5-positive metastatic triple-negative breast cancer; granted Breakthrough Device designation to a test for the postsurgical detection and quantification of circulating tumor DNA (ctDNA); and approved an investigational device exemption for the diagnostic assay that will be used to determine molecular eligibility for enrollment into the phase II portion of the global TRIDENT-1 clinical study studying repotrectinib in advanced solid tumors.

Fast Track Designation for Leronlimab in Metastatic Triple-Negative Breast Cancer

The FDA granted Fast Track designation to leronlimab (PRO140) for use in combination with carboplatin for the treatment of patients with CCR5-positive metastatic triple-negative breast cancer. Clinical trial sites include Quest Clinical Research in San Francisco, along with four additional trial sites, which are in the process of initiating patient enrollment, including: Northwestern University Medical School, Methodist Houston, Vanderbilt University, and Sidney Kimmel Cancer Center.
Leronlimab is an investigational humanized IgG4 mAb that blocks CCR5, a cellular receptor that appears to play multiple roles with implications in HIV infection, tumor metastases, and immune signaling. Leronlimab has successfully completed 9 phase I/II/III clinical trials in over 700 people, including a successful pivotal phase III trial in combination with standard antiretroviral therapies in human immunodeficiency virus (HIV)-infected, treatment-experienced patients.

In the setting of cancer, research has shown that CCR5 likely plays a central role in tumor invasion and metastasis, and that increased CCR5 expression is an indicator of disease status in several cancers. Moreover, research has shown that drugs that block CCR5 can block tumor metastases in laboratory and animal models of aggressive breast and prostate cancer.

The CCR5 receptor also appears to play a central role in modulating immune cell trafficking to sites of inflammation and may be crucial for the development of acute graft-vs-host disease and other inflammatory conditions. Clinical studies by others further support the concept that blocking CCR5 using a chemical inhibitor can reduce the clinical impact of acute graft-vs-host disease without significantly affecting the engraftment of transplanted bone marrow stem cells. The FDA has granted Orphan Drug designation to leronlimab for the prevention of graft-vs-host disease.

Breakthrough Device Designation for Signatera Test for ctDNA Detection

The FDA granted Breakthrough Device designation for the Signatera test for use in the postsurgical detection and quantification of circulating tumor DNA (ctDNA) in the blood of patients previously diagnosed with certain types of cancer and in combination with certain drugs. The designation will help accelerate FDA assessment and review of Signatera as an in vitro diagnostic for use in pharmaceutical trials.

Signatera is the first ctDNA test custom-built for each patient based on the unique mutations in an individual patient's tumor. Signatera has been shown in numerous clinical studies—across non–small cell lung, bladder, breast, and colorectal cancers—to identify molecular residual disease significantly earlier (up to 2 years earlier) than standard imaging.Studies have also shown that Signatera test status is the most significant predictor of long-term patient outcomes after surgery and treatment, relative to all other clinical and pathological factors.

Investigational Device Exemption for the Companion Diagnostic Assay to the TRIDENT-1 Clinical Study in Solid Tumors

The FDA approved an investigational device exemption for the diagnostic assay that will be used to determine molecular eligibility for enrollment into the phase II portion of the global TRIDENT-1 clinical study studying repotrectinib in advanced solid tumors. The next-generation sequencing (NGS) assay is intended for use in identifying patients with ROS1NTRK1-3, and ALK gene fusions in advanced solid tumors.

Repotrectinib is an investigational, next-generation tyrosine kinase inhibitor developed for the treatment of patients with advanced solid tumors harboring ROS1, NTRK1-3, or ALK molecular rearrangements. Repotrectinib is a rationally designed, low–molecular weight, macrocyclic tyrosine kinase inhibitor that is much smaller than current ROS1, TRK family, and ALK inhibitors with the objective to systematically overcome the clinically acquired resistance mutations of ROS1, TRK family, and ALK kinases, especially the gatekeeper and solvent front mutations.

The phase II TRIDENT-1 open-label, multicohort study is planned for initiation in the second half of 2019.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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