^
    6ms
    Comprehensive Target Engagement by the EZH2 Inhibitor Tulmimetostat Allows for Targeting of ARID1A Mutant Cancers. (PubMed, Cancer Res)
    Tulmimetostat administration achieved efficacy in multiple ARID1A mutant bladder, ovarian, and endometrial tumor models and improved cisplatin response in chemotherapy-resistant models. Importantly, a tulmimetostat controlled gene expression signature identified in whole blood from a cohort of 32 cancer patients correlated with tulmimetostat exposure, representing a pharmacodynamic marker for the assessment of target coverage for PRC2-targeted agents in the clinic. Collectively, this data suggests that tulmimetostat has the potential to achieve clinical benefit in solid tumors as a monotherapy but also in combination with chemotherapeutic agents and may be beneficial in various indications with recurrent ARID1A mutations.
    Journal
    |
    ARID1A (AT-rich interaction domain 1A) • BCL11B (BAF Chromatin Remodeling Complex Subunit BCL11B)
    |
    cisplatin • tulmimetostat (DZR123)
    10ms
    CPI-0209 Plus Carboplatin in Patients With Platinum Sensitive Recurrent Ovarian Cancer (clinicaltrials.gov)
    P1, N=30, Recruiting, Lan Coffman | Not yet recruiting --> Recruiting | Trial primary completion date: Dec 2027 --> Jan 2027
    Enrollment open • Trial primary completion date • Combination therapy
    |
    BRCA (Breast cancer early onset)
    |
    BRCA mutation
    |
    carboplatin • tulmimetostat (DZR123)
    11ms
    Tulmimetostat (CPI-0209) in Patients With Mycosis Fungoides and Sézary Syndrome (clinicaltrials.gov)
    P1, N=30, Recruiting, Washington University School of Medicine | Not yet recruiting --> Recruiting
    Enrollment open
    |
    tulmimetostat (DZR123)
    12ms
    CPI-0209 Plus Carboplatin in Patients With Platinum Sensitive Recurrent Ovarian Cancer (clinicaltrials.gov)
    P1, N=30, Not yet recruiting, Lan Coffman | Trial completion date: Jan 2029 --> Jul 2029 | Initiation date: Sep 2023 --> Dec 2023 | Trial primary completion date: Oct 2025 --> Dec 2027
    Trial completion date • Trial initiation date • Trial primary completion date • Combination therapy
    |
    BRCA (Breast cancer early onset)
    |
    BRCA mutation
    |
    carboplatin • tulmimetostat (DZR123)
    1year
    Tulmimetostat (CPI-0209) in Patients With Mycosis Fungoides and Sézary Syndrome (clinicaltrials.gov)
    P1, N=30, Not yet recruiting, Washington University School of Medicine | Trial completion date: Sep 2029 --> Dec 2029 | Initiation date: Sep 2023 --> Dec 2023 | Trial primary completion date: Oct 2027 --> Jan 2028
    Trial completion date • Trial initiation date • Trial primary completion date
    |
    tulmimetostat (DZR123)
    1year
    FIH: A Study of CPI-0209 in Patients With Advanced Solid Tumors and Lymphomas (clinicaltrials.gov)
    P1/2, N=286, Recruiting, Constellation Pharmaceuticals | N=213 --> 286
    Enrollment change • Metastases
    |
    MSI (Microsatellite instability) • ARID1A (AT-rich interaction domain 1A) • BAP1 (BRCA1 Associated Protein 1) • MUC16 (Mucin 16, Cell Surface Associated)
    |
    MSI-H/dMMR • ARID1A mutation
    |
    tulmimetostat (DZR123)
    1year
    EZH2/EZH1 INHIBITOR TULMIMETOSTAT (CPI-0209): PRELIMINARY PHASE II RESULTS AND FIRST BIOMARKER FINDINGS IN PATIENTS WITH ARID1A-MUTANT OVARIAN CLEAR CELL OR ENDOMETRIAL CARCINOMAS (OCCC/EC) (IGCS 2023)
    24 patients were enrolled (OCCC, n=14; EC, n=10); 50% of each cohort have received ≥3 prior treatment lines. Both cohorts are eligible for Stage 2 expansion, with 1 and 2 confirmed partial responses in patients with OCCC and EC, respectively (Table). The manageable safety profile across all 6 tumor cohorts (n=81) was consistent with known class effects; Grade ≥3 related adverse events (≥10% of patients) included thrombocytopenia, anemia, neutropenia, and diarrhea.
    Clinical • P2 data
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    ARID1A (AT-rich interaction domain 1A) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • STAT3 (Signal Transducer And Activator Of Transcription 3)
    |
    ARID1A mutation
    |
    tulmimetostat (DZR123)
    over1year
    Tulmimetostat (CPI-0209) in Patients With Mycosis Fungoides and Sézary Syndrome (clinicaltrials.gov)
    P1, N=30, Not yet recruiting, Washington University School of Medicine
    New P1 trial
    |
    tulmimetostat (DZR123)
    over1year
    CPI-0209 Plus Carboplatin in Patients With Platinum Sensitive Recurrent Ovarian Cancer (clinicaltrials.gov)
    P1, N=30, Not yet recruiting, Lan Coffman
    New P1 trial • Combination therapy
    |
    BRCA (Breast cancer early onset)
    |
    BRCA mutation
    |
    carboplatin • tulmimetostat (DZR123)
    over1year
    EZH2/EZH1 inhibitor tulmimetostat (CPI-0209) in patients with advanced solid tumors or hematologic malignancies: Preliminary phase II results. (ASCO 2023)
    Based on response criteria of ORR ≥1/10 pts, the ovarian (M2), endometrial (M3), and mesothelioma (M5) cohorts achieved eligibility for stage 2 expansion (not relevant in M4). The safety profile of tulmimetostat is consistent with EZH2 inhibition and previous data. These preliminary findings in heavily pretreated pts with multiple tumor types, including tumors with ARID1A alterations or BAP1 loss, support ongoing investigation of tulmimetostat.
    Clinical • P2 data • Metastases
    |
    ARID1A (AT-rich interaction domain 1A) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • BAP1 (BRCA1 Associated Protein 1) • STAT3 (Signal Transducer And Activator Of Transcription 3)
    |
    ARID1A mutation • BAP1 mutation • EZH2 mutation
    |
    tulmimetostat (DZR123)
    over2years
    Ex vivo treatment in high grade serous ovarian cancer demonstrates the benefit of EZH2 inhibition in combination with standard therapy (AACR 2022)
    Xenograft-derived organotypic tumor spheroids (xDOTS3) were loaded into 3D devices (AIM Biotech), treated with either CPI-0209, carboplatin, or olaparib alone, or with CPI-0209 for 7 days prior to adding carboplatin or olaparib for an additional 5-11 days. Increased SLFN11 protein level supported the importance of EZH2-SLFN11 axis. Further exploration of CPI-0209 combination in ovarian cancer in known genomic contexts is warranted.
    Preclinical • Combination therapy • BRCA Biomarker • PARP Biomarker
    |
    SLFN11 (Schlafen Family Member 11) • BRCA (Breast cancer early onset) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1)
    |
    BRCA mutation
    |
    Lynparza (olaparib) • carboplatin • tulmimetostat (DZR123)
    over3years
    A Study of CPI-0209 in Patients With Advanced Tumors Ensayo de CPI-0209 en pacientes con tumores avanzados (clinicaltrialsregister.eu)
    P1/2, N=284, Ongoing, Constellation Pharmaceuticals, Inc.
    Clinical • New P1/2 trial • Combination therapy
    |
    ARID1A (AT-rich interaction domain 1A)
    |
    ARID1A mutation
    |
    tulmimetostat (DZR123)