Cardiovascular side effects of Ibrutinib
By Michael Choi, MD
The holy grail of cancer therapy research is to make a treatment that can distinguish between cancer cells and normal tissues. Cirmtuzumab was designed with this in mind.
Cirmtuzumab inhibits a target called ROR1 (receptor tyrosine kinase like orphan receptor 1). This is a protein that is important for fetal development, but is usually turned off in normal adult tissues. However, interestingly, ROR1 is expressed again and turned back on in many cancers, including 95% of cases of chronic lymphocytic leukemia. We have found that ROR1 plays a role in pro-survival signaling and in the migration of leukemic cells to lymph nodes or tissues. And importantly, in those cases, ROR1 is found on the cancer cells, but not in the normal tissue equivalents. In other words, we see ROR1 on CLL B-cells, but not normal B-cells.
Based on that rationale, scientists at UC San Diego, in collaboration with Oncternal Therapeutics, have developed Cirmtuzumab as a first-in-class monoclonal antibody that inhibits ROR1. In comprehensive preclinical tests, cirmtuzumab killed CLL cells in the laboratory and in mouse models, without any perceivable toxicity. After the Food and Drug Administration determined that there is sufficient safety and rationale to proceed with a first-in-human clinical trial, patients started to receive the drug in 2014. To date, 26 patients with relapsed or refractory CLL have received Cirmtuzumab as a single-agent. Full analysis is ongoing, but the highlights are that Cirmtuzumab was extremely safe and well-tolerated There have not been any dose-limiting toxicities, and no patients needed to stop due to side effects. We have also confirmed that ROR1 signaling is successfully blocked by Cirmtuzumab, and that this correlates with most cases stabilizing without further CLL progression after starting the drug.
What’s next? Based on its excellent safety profile, we think Cirmtuzumab can be safely combined with other drugs. Specifically, we have found that Cirmtuzumab may have synergistic activity with ibrutinib. Blocking both ROR1 and BTK (the target of ibrutinib) may be akin to taking 2 legs out from under a stool and leave little for the leukemia cells to stand on for survival.
A phase 1/2 clinical trial will therefore open very soon (estimate October-November 2017) to evaluate this combination. The main inclusion criteria are a diagnosis of CLL or Mantle Cell Lymphoma (a closely related disease, also known to have high ROR1 expression). The trial will enroll patients with previously treated disease, but not prior ibrutinib treatment. The trial will open first in San Diego, but is planned to open broadly in the United States during 2018.
We think this trial may lead to yet another step forward for patients with CLL. Ibrutinib and other inhibitors have been successful and effective, but perhaps the addition of Cirmtuzumab can improve outcomes even more.
Michael Choi, MD is a Clinical Instructor at Moores UCSD Cancer Center and Professor of Medicine at the University of California San Diego UC San Diego, School of Medicine in San Diego, CA.
Originally published in The CLL Tribune Q3 2017.
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