Background: Enhancer of zeste homolog 1 (EZH1) and EZH2 are alternative subunits of polycomb repressive complex 2 (PRC2), and catalyze tri-methylation of the 27th lysine residue of histone H3 (H3K27). This tri-methylated H3K27 (H3K27me3) is epigenetically important for downregulating genes associated with tumor suppression and cell differentiation. DS-3201b is a potent inhibitor with high specificity for EZH1 and EZH2 that has demonstrated anti-tumor activity against various hematological malignancies in preclinical studies (S. Fujita, et al. Blood 2015 126: 457) (D. Honma, et al. Cancer Sci. 2017). This Phase I study explored safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity of DS-3201b in patients with relapsed or refractory non-Hodgkin lymphomas (NHLs), including adult T-cell leukemia-lymphoma (ATL) associated with human T-lymphotropic virus type I.

Methods: This dose escalation study of DS-3201b as an oral single agent started at a dose of 150 mg and escalated through 200 mg and 300 mg dose levels guided by a modified continual reassessment method using a Bayesian logistic regression model with overdose control. The drug was administered orally once daily (QD) over 28-days (1 cycle) continuously until disease progression. Dose limiting toxicity (DLT) was evaluated during the 1st cycle.

Results: Fifteen patients (10 females) with median age of 64 (range 44-75) have been enrolled as of the data cut-off date of 11 July 2017. Histopathologic types of NHLs were follicular lymphoma (FL) (5), diffuse large B-cell lymphoma (DLBCL) (3), and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) (2) for B-cell lymphomas, and ATL (2), angioimmunoblastic T-cell lymphoma (AITL) (2) and peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) (1) for T-cell lymphomas. Four DLTs in three patients at 200 mg QD and 300 mg QD were observed: three grade 4 platelet count decreased and one grade 3 anemia requiring transfusion. Dose de-escalation to 200 mg QD cohort is on-going, and a conclusive MTD has not yet been reached. PK data indicated that the plasma DS-3201a (free form of DS-3201b) concentration increased with dose from 150 mg to 300 mg. Robust inhibition of H3K27me3 in normal granulocytes was detected in all patients in response to DS-3201b, irrespective of the dosage. Drug related adverse events included mainly transit hematological toxicities: platelet count decreased (73%), anemia (47%), lymphocyte count decreased (40%), or neutrophil count decreased (40%). There was one serious adverse event of grade 3 pneumonia leading to discontinuation from this study. The common (≥20%) non-hematological treatment emergent adverse events of any grade regardless of drug-relatedness were dysgeusia (47%), diarrhea (27%), nasopharyngitis (27%), alopecia (27%), rash maculo-papular (20%), decreased appetite (20%), and dry skin (20%). Preliminary efficacy based on international consensus criteria (Cheson BD, et al [JCO 2007] for NHLs or Tsukasaki K, et al [JCO 2009] for ATL) by investigator's assessment were 1 complete response/complete remission (CR), 7 partial response/partial remission (PR), and 5 stable disease (SD) of 15 patients (objective response rate [ORR]=53%) and 8 patients have achieved more than 24 weeks DS-3201b treatment with tumor shrinkage. Focusing on T-cell lymphoma, ORR was 80% (1 CR and 3 PR out of 5 patients).

Conclusions: These preliminary results of the phase I study show that the EZH1/2 dual inhibitor DS-3201b has demonstrated early clinical activity and has the potential to be an orally available, novel therapeutic option for B-cell and T-cell lymphomas, though further evaluation is warranted for optimal dosing regimen.

Clinical trial information: NCT02732275


Maruyama: Chugai, Kyowa Hakko Kirin, Ono, Celgene, Janssen, Eisai, Mundipharma, Takeda: Honoraria; Dai-ichi Sankyo, Chugai, Kyowa Hakko Kirin, Ono, Celgene, Janssen, GSK, Eisai, Mundipharma, Takeda, AbbVie, MSD, Sanofi, Pfizer, Otsuka, Novartis, Solasia, Zenyaku: Research Funding. Tobinai: Servier: Research Funding; GlaxoSmithKline: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; HUYA Bioscience: Honoraria; Daiichi Sankyo Co., Ltd: Consultancy, Honoraria; AbbVie: Research Funding; Mundipharma: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria. Makita: Celgene, Chugai: Honoraria. Ishida: Kyowa Hakko Kirin Co., Ltd. Celgene K.K. Bayer Pharma AG: Honoraria, Research Funding. Kusumoto: Chugai: Honoraria, Other: GALLIUM and GOYA are sponsored by F. Hoffmann-La Roche Ltd. Third-party medical writing support, under the direction of Shigeru Kusumoto, was provided by Cheryl Wright of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd, Research Funding. Ishitsuka: Celgene Kyowa Hakko Kirin Bristol-Myers Squibb Chugai Pharmaceutical Takeda Pharmaceutical mundiharma Taiho Daiichi Sankyo Janssen Novartis Pfizer Astellas sanofi Genzyme Alexion Sumitomo Dainippon Eisai Mochida Shire Otsuka Ono Teijin: Honoraria, Research Funding. Yoshimitsu: Shire Sanofi Celgene Chugai: Speakers Bureau. Utsunomiya: Japan Blood Products Organization, Roche Diagnostics, Daiichi Sankyo, Siemens, Bristol-Myers Squibb, Pfizer, Astellas Pharma, Kyowa Hakko Kirin, Novartis Pharma, HUYA Bioscience International, Nippon Shinyaku, Chugai Pharma, and Celgene,: Honoraria, Research Funding. Tsukasaki: Chugai/Roche: Honoraria; DaiichiSankyo: Consultancy; Kyowa-Kirin: Honoraria; Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Mundypharma: Research Funding; Zenyaku Kogyo: Honoraria; HUYA: Honoraria. Fujitani: DaiichiSankyo: Employment. Araki: Daiichi Sankyo: Employment.

Author notes


Asterisk with author names denotes non-ASH members.

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