First-in-Human Study of the EZH1/2 Dual Inhibitor DS-3201b in Patients with Relapsed or Refractory Non-Hodgkin Lymphomas — Preliminary Results

Dai Maruyama, Kensei Tobinai, Shinichi Makita, Takashi Ishida, Shigeru Kusumoto, Kenji Ishitsuka, Makoto Yoshimitsu, Yoshitaka Imaizumi, Yasushi Sawayama, Shogo Takeuchi, Atae Utsunomiya, Kunihiro Tsukasaki, Sumiaki Fujitani and Kazushi Araki


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

Disclosures 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.

  • * Asterisk with author names denotes non-ASH members.