In an interim analysis of a first-in-human clinical trial, researchers evaluating the safety and efficacy of CYT-0851 found that the first-in-class small molecule inhibitor of RAD51-mediated DNA repair is well-tolerated by patients and has promising anti-tumor clinical activity in both hematological and solid cancers.
The RAD51 gene contains the instructions for making a protein that is essential in activation homologous recombination, which is a high-fidelity mechanism in the repair of DNA double-strand breaks (DSBs).
When the DNA repair was inhibited with CYT-0851, it caused an accumulation of unrepairable DSBs and tumor cell death in patients with advanced solid tumors and non-Hodgkin lymphoma, according to the researchers, who recently detailed the early findings from the Phase I/II study at the ASCO 2021 meeting.
The results of an interim analysis of the study data, which was updated at ASCO, were published in the May issue of the Journal of Clinical Oncology (2021; doi: 10.1200/JCO.2021.39.15_suppl.3006).
"At this time, we have not found any dose-limiting toxicities, and as such, have not yet identified the maximum tolerated dose. Despite that, we've seen clinical activity in three different histologies: follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), and soft tissue sarcoma," said Ryan C. Lynch, MD, Assistant Professor at the University of Washington School of Medicine and Fred Hutchison Cancer Research Center, and a physician on staff at the Seattle Cancer Care Alliance who presented the initial findings of the study.
"As more patients in the study undergo dose escalation, and as we are learning more about the safety and activity of CYT-0851, we would hope to soon have a Phase II dose selected so we can expand our enrollment into disease-specific cohorts in the next phase of the study," added Lynch, who is also a board-certified hematologist-oncologist specializing in treating lymphomas.
CYT-0851 was discovered in a phenotypic screen that evaluated compounds for a synthetically lethal relationship with overexpression of cytidine deaminase, a DNA damaging enzyme present in many cancers but absent in most normal cells. This allowed for the identification of compounds that would selectively target abnormal cancer cells that are more sensitive to inhibition of DNA repair, while having minimal impact on normal cells, Lynch noted.
"This particular mechanism of action was predicted to work on a variety of different lymphomas, as well as solid tumors, based on the tumor biology. As a lymphoma specialist, I thought it was very intriguing and something that had the possibility of helping our patients, in a way that could minimize toxicity," Lynch told Oncology Times.
The study data so far "validates the type of screen done by the sponsor in trying to select a compound that minimizes the off-target effect on the normal cells while targeting the malignant cells that are sensitive to the inhibition of the DNA repair," he said. "Hopefully, we will learn more as we treat increasing numbers of patients at higher doses."
First Impressions
As of the April 2021 cutoff date for the data included in the interim analysis presented at the ASCO 2021 meeting, 35 patients with advanced cancers and lymphomas were treated and received continuous 28-day cycles of the increasing doses of CYT-0851. The patients were enrolled in eight cohorts who received doses of 15 mg, 20 mg, 30 mg, and 45 mg BID; 90 mg, 130 mg, 200 mg, and 300 mg QD in continuous 28-day cycles.
No patients experienced dose-limiting toxicity and so escalation continues. Three patients had mild cases of nausea and two patients experienced mild constipation, but there was no treatment-related, clinically significant myelosuppression; serious adverse events; study discontinuation; or deaths. Pharmacodynamic effects were observed with increases in H2AX in circulating tumor cells at exposures associated with preclinical anti-tumor activity.
Twenty-one patients were response-evaluable. Partial responses were seen in patients with DLBCL, follicular lymphoma, and myxofibrosarcoma at 45 mg BID, and treatment continued for more than 10, 8, and 6 months, respectively.
"These are very early results on a limited number of patients with a wide variety of diseases, many of whom have been treated at a level lower than we would expect to have clinical activity, so looking at raw overall response rate is probably not appropriate until we have a larger disease-specific population treated at the recommended Phase II dose," Lynch said. "But to have at least demonstrated disease stability, as well as several objective responses, even in a handful of pathologies, is not very common this early in a Phase I study."
Future Implications
Preclinical models identified both hematological and solid tumors that might be sensitive to DNA repair inhibition, Lynch said.
"Looking at gene expression profiling over various solid tumors and cell lines, there was a prediction made of which histologies would work best. And some of them we are currently testing include ovarian cancer, pancreatic cancer, sarcomas, as well as lymphomas," he said.
"Tumor tissue is being collected from all of the patients enrolled in the study as well, so that we can look on an individual basis at how various expressions of genes that might predict sensitivity to a double-strand DNA inhibitor like this one would work. That data is not available at this time, but it should be available as the study proceeds."
"While it is too soon to predict the clinical implications of the research, the early study data is very promising and may lead to further development of CYT-0851 for both hematological and solid tumors," he noted.
Chuck Holt is a contributing writer.
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