tulmimetostat (DZR123) / Novartis - LARVOL DELTA

Phase II dose optimization with EZH2/EZH1 inhibitor tulmimetostat in patients (pts) with advanced solid tumors or hematologic malignancies. (ASCO 2024) - P1/2 | "The evolving Phase II data, including early data from lower doses, continue to show signs of antitumor activity/disease stabilization. The safety profile is consistent with EZH2 inhibition. These preliminary findings in heavily pretreated pts with multiple tumor types and evolving dose-optimization data support ongoing investigation of tulmimetostat."

Clinical • Metastases • P2 data • Anemia • Endometrial Cancer • Hematological Disorders • Hematological Malignancies • Oncology • Ovarian Cancer • Solid Tumor • Thrombocytopenia • EZH2

Phase Ib/II Study of Dual EZH2/EZH1 Inhibition With Pembrolizumab in Advanced NSCLC (IASLC-WCLC 2026) - "Tulmimetostat is a potent dual EZH2/EZH1 inhibitor that enables more complete suppression of PRC2 activity and may overcome compensatory EZH1-mediated resistance observed with selective EZH2 inhibition. Secondary endpoints include disease control rate, progression-free survival, duration of response, and safety. Correlative analyses include assessment of H3K27me3 and PD-L1 expression in tumor samples."

IO biomarker • Metastases • P1/2 data • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • EZH2 • PD-L1

CPI-0209 Plus Carboplatin in Patients With Platinum Sensitive Recurrent Ovarian Cancer (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: Lan Coffman | Trial completion date: Dec 2028 ➔ Jul 2029 | Trial primary completion date: Nov 2026 ➔ Jul 2028

Platinum sensitive • Trial completion date • Trial primary completion date • Oncology • Ovarian Cancer • Solid Tumor • BRCA

Combination of tulmimetostat and PD-1 blockade for patients with advanced non–small cell lung cancer who progressed from first or second line of treatments. (ASCO 2026) - P1/2 | "We hypothesize that the addition of tulmimetostat to pembrolizumab may reverse the resistance to pembrolizumab in patients with ICI-refractory NSCLC. Findings from this trial may support the development of a novel therapeutic approach for patients with NSCLC who have progressed after on standard immunotherapy or chemo-immunotherapy. Enrollment was initiated in January 2026."

Clinical • IO biomarker • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EZH2 • PD-L1

The Role of EZH2 ın Malıgnant Pleural Mesothelıoma and Beyond: Current Practıce and Future Perspectıves. (PubMed, Curr Oncol Rep) - "For nearly twenty years, platinum-pemetrexed chemotherapy has persisted as the unchanged standard treatment; although recent progress in immunotherapy has modestly disrupted this therapeutic plateau, survival outcomes remain disappointingly limited...Preclinical and early clinical data demonstrate that EZH2 inhibitors-including tazemetostat, valemetostat, GSK126, EPZ011989, tulmimetostat, and novel PROTAC-based degraders such as MS1943-can suppress tumor progression, modulate the tumor immune microenvironment, and restore therapeutic sensitivity...Further understanding the dual canonical and non-canonical roles of EZH2 in tumor biology will be key to optimizing targeted and combinatorial treatment strategies. Future research should focus on translating EZH2 inhibition into clinical benefit, identifying predictive biomarkers of response, and exploring rational combinations with chemotherapy, targeted drugs, or immunotherapy to improve survival outcomes in mesothelioma..."

IO biomarker • Journal • Review • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor • Targeted Protein Degradation • BAP1 • EZH2

An Open-label Dose Escalation and Expansion, Followed by a Phase II Study of Tulmimetostat (DZR123) and JSB462 (Luxdegalutamide) in Patients With Progressive Metastatic Castrate Resistant Prostate Cancer (mCRPC) (TulmiSTAR-01) (clinicaltrials.gov) - P1/2 | N=188 | Recruiting | Sponsor: Novartis Pharmaceuticals

Trial initiation date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

CDZR123A12107: A clinical trial to learn about the effects of DZR123 and JSB462 given together in men with advanced prostate cancer that has stopped responding to other treatments (clinicaltrialsregister.eu) - P1/2 | N=76 | Recruiting | Sponsor: Novartis Pharma AG | Not yet recruiting ➔ Recruiting

Enrollment open • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

CDZR123A12107: A clinical trial to learn about the effects of DZR123 and JSB462 given together in men with advanced prostate cancer that has stopped responding to other treatments (clinicaltrialsregister.eu) - P1/2 | N=76 | Not yet recruiting | Sponsor: Novartis Pharma AG

New P1/2 trial • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

TulmiSTAR-01: A phase I/II dose optimization study of tulmimetostat in combination with luxdegalutamide versus standard of care (SOC) in patients (pts) with progressive metastatic castrate-resistant prostate cancer (mCRPC). (ASCO-GU 2026) - P1/2 | "Research Funding Novartis Pharma AG. *Choice of ARPI, chemotherapy or lutetium (177Lu) vipivotide tetraxetan. BOR, best overall response; mo, months; DOR, duration of response; QD, once a daily; ORR, objective radiographic response; OS, overall survival; PK, pharmacokinetics, PSA, prostate-specific antigen; RDE, recommended dose for expansion; rPFS, radiographic progression-free survival; R, randomization; RP2D, recommended phase II dose; SOC, standard of care; TTSSE, time to first symptomatic skeletal event."

Clinical • Combination therapy • Metastases • P1/2 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • EZH2

CDZR123C12101: TulmiSTAR-02: Phase I/II open-label study of tulmimetostat in combination with darolutamide vs. darolutamide, and tulmimetostat with abiraterone in patients with metastatic hormone-sensitive prostate cancer (mHSPC) (clinicaltrialsregister.eu) - P1/2 | N=54 | Recruiting | Sponsor: Novartis Pharma AG

New P1/2 trial • Genito-urinary Cancer • Hormone Sensitive Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

TulmiSTAR-02: A phase I/II open-label study of dose escalation and expansion of tulmimetostat in combination with darolutamide versus darolutamide, and tulmimetostat with abiraterone in patients with metastatic hormone-sensitive prostate cancer (mHSPC). (ASCO-GU 2026) - P1/2 | "The time-to-event efficacy endpoints will be estimated by Kaplan–Meier method. BCR, biochemical response rate; BID, Twice a day; BOR, best overall response; CRPC, castration–resistant prostate cancer; DOR, duration of response; QD, once a daily; OR, objective response; OS, overall survival; PK, pharmacokinetics, PSA, prostate-specific antigen; PO, oral; RDE, recommended dose for expansion; rPFS, radiographic progression-free survival; TTSSE, time to first symptomatic skeletal event."

Clinical • Combination therapy • Metastases • P1/2 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Hormone Sensitive Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor • EZH2

Tulmimetostat (DZR123) in Patients With Mycosis Fungoides and Sézary Syndrome (clinicaltrials.gov) - P1 | N=24 | Active, not recruiting | Sponsor: Washington University School of Medicine | Recruiting ➔ Active, not recruiting | N=36 ➔ 24 | Trial completion date: Jan 2030 ➔ Jan 2029 | Trial primary completion date: Feb 2028 ➔ Feb 2027

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Cutaneous T-cell Lymphoma • Dermatology • Lymphoma • Mycosis Fungoides • Non-Hodgkin’s Lymphoma • Oncology • Sezary Syndrome

EZH2 Inhibitor, Tulmimetostat, and PD-1 Blockade for Treatment of Advanced Non-small Cell Lung Cancer (clinicaltrials.gov) - P1/2 | N=66 | Recruiting | Sponsor: VA Office of Research and Development | Not yet recruiting ➔ Recruiting

Enrollment open • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

TulmiSTAR-02: A Phase I/II Open-label Study of Tulmimetostat in Combination With Darolutamide vs. Darolutamide, and Tulmimetostat With Abiraterone in Patients With Metastatic Hormone-sensitive Prostate Cancer (mHSPC) (clinicaltrials.gov) - P1/2 | N=203 | Recruiting | Sponsor: Novartis Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • Genito-urinary Cancer • Hormone Sensitive Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

An Open-label Dose Escalation and Expansion, Followed by a Phase II Study of Tulmimetostat (DZR123) and JSB462 (Luxdegalutamide) in Patients With Progressive Metastatic Castrate Resistant Prostate Cancer (mCRPC) (TulmiSTAR-01) (clinicaltrials.gov) - P1/2 | N=188 | Recruiting | Sponsor: Novartis Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

An Open-label Dose Escalation and Expansion, Followed by a Phase II Study of Tulmimetostat (DZR123) and JSB462 (Luxdegalutamide) in Patients With Progressive Metastatic Castrate Resistant Prostate Cancer (mCRPC) (TulmiSTAR-01) (clinicaltrials.gov) - P1/2 | N=188 | Not yet recruiting | Sponsor: Novartis Pharmaceuticals

New P1/2 trial • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

TulmiSTAR-02: A Phase I/II Open-label Study of Tulmimetostat in Combination With Darolutamide vs. Darolutamide, and Tulmimetostat With Abiraterone in Patients With Metastatic Hormone-sensitive Prostate Cancer (mHSPC) (clinicaltrials.gov) - P1/2 | N=203 | Not yet recruiting | Sponsor: Novartis Pharmaceuticals

New P1/2 trial • Genito-urinary Cancer • Hormone Sensitive Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

CPI-0209 Plus Carboplatin in Patients With Platinum Sensitive Recurrent Ovarian Cancer (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: Lan Coffman | Trial primary completion date: Jul 2026 ➔ Nov 2026

Platinum sensitive • Trial primary completion date • Oncology • Ovarian Cancer • Solid Tumor • BRCA

Phase II dose optimization update with EZH2/EZH1 inhibitor tulmimetostat in patients with ARID1A-mutated ovarian clear cell carcinoma or endometrial carcinoma. (ASCO 2025) - P1/2 | "Tulmimetostat showed an improved and acceptable safety profile in OCCC and EC at 200 mg and 300 mg doses (versus 350 mg) with promising antitumor activity, supporting further clinical investigation. Best confirmed responses and most common Grade ≥3 related TEAEs.Data cut off: October 15, 2024. *Patients who received ≥1 dose, had ≥1 post-baseline response assessment, or discontinued treatment prior to first post-baseline assessment for any reason."

Clinical • P2 data • Clear Cell Carcinoma • Endometrial Cancer • Oncology • Oral Cancer • Ovarian Cancer • Solid Tumor • ARID1A • EZH2 • STAT3

FIH: A Study of Tulmimetostat DZR123 (CPI-0209) in Patients With Advanced Solid Tumors and Lymphomas (clinicaltrials.gov) - P1/2 | N=275 | Recruiting | Sponsor: Novartis Pharmaceuticals | N=210 ➔ 275 | Trial completion date: Mar 2026 ➔ Feb 2030 | Trial primary completion date: Dec 2025 ➔ Feb 2030

Enrollment change • Trial completion date • Trial primary completion date • B Cell Lymphoma • Castration-Resistant Prostate Cancer • Clear Cell Carcinoma • Diffuse Large B Cell Lymphoma • Genito-urinary Cancer • Hematological Malignancies • Lymphoma • Mesothelioma • Non-Hodgkin’s Lymphoma • Oncology • Ovarian Cancer • Peripheral T-cell Lymphoma • Prostate Cancer • Solid Tumor • T Cell Non-Hodgkin Lymphoma • Urothelial Cancer • ARID1A • BAP1 • MSI

CPI-0209 Plus Carboplatin in Patients With Platinum Sensitive Recurrent Ovarian Cancer (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: Lan Coffman | Trial completion date: Aug 2028 ➔ Dec 2028 | Trial primary completion date: May 2025 ➔ Jul 2026

Platinum sensitive • Trial completion date • Trial primary completion date • Oncology • Ovarian Cancer • Solid Tumor • BRCA

Polycomb repressive complex 2 (PRC2) pathway's role in cancer cell plasticity and drug resistance. (PubMed, Funct Integr Genomics) - "Inhibitors like MAK683 and EED226 disrupt EED's ability to maintain PRC2 activity, thereby reducing H3K27me3 levels and reactivating tumor suppressor genes. Valemetostat, a dual inhibitor of both EZH2 and EED, has shown promising results in aggressive cancers like diffuse large B-cell lymphoma and small-cell lung cancer, underlining the therapeutic potential of targeting multiple PRC2 components...Tazemetostat, a selective EZH2 inhibitor, has demonstrated significant clinical efficacy in EZH2-mutant cancers, such as non-Hodgkin lymphomas and epithelioid sarcoma. However, the compensatory function of enhancer of zeste homolog 1 (EZH1) in some cancers requires dual inhibition strategies, as seen with agents like UNC1999 and Tulmimetostat, which target both EZH1 and EZH2. Given PRC2's multifaceted role in cancer biology, its inhibition represents a promising avenue for therapeutic intervention. The continued development of PRC2 inhibitors and exploration of their..."

IO biomarker • Journal • Review • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Genito-urinary Cancer • Hematological Malignancies • Lung Cancer • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Prostate Cancer • Sarcoma • Small Cell Lung Cancer • Soft Tissue Sarcoma • Solid Tumor • EZH2

CPI-0209 Plus Carboplatin in Patients With Platinum Sensitive Recurrent Ovarian Cancer (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: Lan Coffman | Trial completion date: Aug 2029 ➔ Aug 2028 | Trial primary completion date: Jan 2027 ➔ May 2025

Trial completion date • Trial primary completion date • Oncology • Ovarian Cancer • Solid Tumor • BRCA

Phase II dose optimization with EZH2/EZH1 inhibitor tulmimetostat in patients with ARID1A-mutated ovarian clear cell carcinoma (ESMO 2024) - P1/2 | "This ongoing Phase II data in patients with heavily pretreated ARID1A-mutated OCCC show signs of antitumor activity across dose levels. Response requirements to open Stage 2b have been met in this fast enrolling disease cohort. The safety profile across doses is consistent with EZH2 inhibition."

Clinical • P2 data • Oncology • Ovarian Cancer • ARID1A • EZH2 • STAT3

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 • Bladder Cancer • Endometrial Cancer • Genito-urinary Cancer • Oncology • Ovarian Cancer • Solid Tumor • Urothelial Cancer • ARID1A • BCL11B