Data presented in a poster presentation during the 59th Annual Meeting of the American Society of Hematology (ASH) held in Atlanta, Georgia (USA), December 9-12, 2017, confirms preliminary exploratory efficacy results from an ongoing Phase I dose escalation study with single agent DS-3201, an investigational and potential first-in-class EZH1/2 dual inhibitor being developed by Daiichi Sankyo, in patients with relapsed or refractory non-Hodgkin lymphomas.
The data confirmed an overall response rate of 58.8% (10 of 17 patients).
Targeting epigenetic regulation is an approach to treating cancer that aims to reverse aberrant epigenetic changes that contribute to cancer cell growth and to maintain normal gene expression.
These patients, participating in a?multicenter, non-randomized, open-label Phase I dose escalation trial, were relapsed from or refractory to standard treatment or included patients for whom no standard treatment was available. Among the 10 patients with response, there were one complete remission and nine partial remissions. Additionally, four patients experienced stable disease and three patients experienced progressive disease.
DS-3201 is a novel, orally bioavailable, investigational agents targeting epigenetic regulation by inhibiting both the EZH1 (enhancer of zeste homolog 1) and EZH2 (enhancer of zeste homolog 2) enzymes, which may reactivate various genes that have been silenced by the protein H3K27me3. Reactivation of the silenced genes has been shown to result in decreased proliferation of EZH2-expressing cancer cells. Preclinical research has shown that DS-3201 suppressed trimethylation of H3K27 in cells (IC50: 0.55 nM) more potently than EZH2 selective inhibitors.
In a number of preclinical and clinical studies some EZH2 selective inhibitors have demonstrated anti-cancer potential. However, in spite of this promise, there is concern that the efficacy anticipated with EZH2 selective inhibitors may be compromised as a result of EZH1 activity.
The investigational drug is in Phase I clinical development for hematologic cancers including acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL) and non-Hodgkin lymphoma (NHL).
Non-Hodgkin lymphoma is a form of cancer that originates in lymphocytes, a type of white blood cell. The two main types of NHL are B-cell lymphomas and T-cell lymphomas, which are classified into subtypes based on the origin and stage of the cancer. There were an estimated 386,000 new cases and about 200,000 deaths globally from NHL in 2012.
In Japan, there were nearly 21,000 new cases of NHL in 2012, accounting for around five percent of cases worldwide. While recent treatment advances have led to improved outcomes for patients with certain types of NHL, patients with aggressive NHL subtypes or relapsed or refractory disease still face a poor prognosis.
Although a number of? novel treatment options have led to dramatic improvements in the prognosis of non-Hodgkin’s lymphoma, relapsed and refractory disease still represents a major treatment challenge. At the same time, there is no standard of care for salvage regimens for both aggressive and indolent subtypes of non-Hodgkin’s lymphoma.
In subgroup analyses, an overall response rate of 45.5% with DS-3201 was observed in patients with B-cell lymphomas and 83.3% in patients with T-cell lymphomas.
An overall response rate of 45.5% (5 of 11 patients) was observed with DS-3201 in 11 evaluable patients with B-cell lymphomas, including follicular lymphoma (5 patients), diffuse large B-cell lymphoma (3 patients), extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (2 patients) and lymphoplasmacytic lymphoma (1 patient).
An overall response rate of 83.3% (5 of 6 patients) was observed with DS-3201 in six evaluable patients with T-cell lymphomas, including peripheral T-cell lymphoma not otherwise specified (2 patients), angioimmunoblastic T-cell lymphoma (2 patients) and adult T-cell leukemia-lymphoma (2 patients).
?Based on these preliminary safety and efficacy data on DS-3201 in a clinical setting, further evaluation of DS-3201 is warranted,? said Dai Maruyama, MD, PhD, Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.
?As the first dual inhibitor of EZH1 and EZH2 in clinical development, DS-3201 may represent a new epigenetic approach to treating blood cancers. We look forward to reviewing additional data as it becomes available to evaluate the potential of this approach,? Maruyama added
Following observation of dose-limiting toxicities (DLTs) in three of 18 evaluable patients, dose expansion is ongoing to determine a conclusive recommended Phase II dose. Four DLTs were observed in three patients who received either the 200 mg or 300 mg dose: there were three cases of temporary grade 4 platelet count decreases (one patient in the 200 mg cohort and two patients in the 300 mg cohort) and one case of grade 3 anemia requiring transfusion in a patient in the 300 mg cohort.
Preliminary safety data from 18 evaluable patients in the study also were reported.
The most common treatment emergent hematologic adverse events of any grade seen in all patients included decreased platelet count (77.8%), anemia (55.6%), decreased lymphocyte count (50.0%) and decreased neutrophil count (44.4%). The most common treatment emergent non-hematologic adverse events were dysgeusia (50.0%), alopecia (33.3%), diarrhea (22.2%), decreased appetite (22.2%), nasopharyngitis (22.2%), alanine aminotransferase increased (22.2%), rash (16.7%), aspartate aminotransferase increased (16.7%) and dry skin (16.7%).
One serious adverse event of grade 3 pneumocystis jirovecii pneumonia (PJP) led to discontinuation from the study. There was one additional non-serious case of PJP observed, leading to the institution of prophylactic treatment for all subsequent patients enrolled into the study.
Reversing aberrant epigenetic changes
?Targeting epigenetic regulation is an approach to treating cancer that aims to reverse aberrant epigenetic changes that contribute to cancer cell growth and to maintain normal gene expression. The dual inhibition of EZH1/2 is theoretically able to provide a different spectrum of activity compared to EZH2-specific inhibitors already in the clinic. Our Phase I program is designed to address the question of the potential benefit for this dual mode of action,? noted Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo.
?In addition to the Phase I study in non-Hodgkin lymphomas, we also are evaluating targeting epigenetic regulation with DS-3201 in patients with acute myeloid leukemia and acute lymphocytic leukemia,? Yver added.
A separate study of DS-3201 is also underway in U.S. in patients with acute myeloid leukemia and acute lymphocytic leukemia.
Last Editorial Review: December 11, 2017
Featured Image: General views during Saturday sessions at the American Society of Hematology 59th Annual Meeting at the Georgia World Congress Center, Saturday December 9, 2017. The Annual Meeting is the premier hematology event of the year for basic, translational, clinical and population science, in the United States, with more than 20,000 hematology experts from around the world attending the meeting. Courtesy: ? 2017 Todd Buchanan/American Society of Hematology | Used with permission. Photo 1 and 2: Japanese calligraphy (?? shod?) also called sh?ji (??) is a form of calligraphy, or artistic writing, of the Japanese language. Artist at Daiichi Sankyo exhibition booth during the 59th Annual Meeting of the American Society of Hematology (ASH) held in Atlanta, Georgia (USA), December 9-12, 2017. Courtesy: ? 2017 Evan Wendt/Sunvalley Communication | Used with permission.
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