Novartis widens tulmimetostat trial to 300 as EZH2 field stays thin
The Phase 1/2 basket study bumped its enrollment target for the eighth time since 2020, tracking to a 2030 primary completion after Novartis pushed the date out more than four years.
Executive Summary
- Novartis increased the enrollment target for its Phase 1/2 tulmimetostat basket trial, the latest in a string of enrollment revisions stretching back to the study's 2019 start.
- The trial has added disease-specific cohorts and a prostate cancer combination arm over its life, so a larger target tracks with that expansion rather than signaling a struggle to fill existing arms.
- The more consequential registry change landed in 2025, when the primary completion date moved out by more than four years, extending the timeline for when any cohort's results become gradable.
- EZH2 inhibition in tumors remains a field with few active comparators, and only one other prior trial in this pairing has resolved, so the drug's cohort-by-cohort performance across the study's ten arms will be one of the few data points defining whether the mechanism holds beyond blood cancers.
The update
Novartis Pharmaceuticals increased the anticipated enrollment ceiling for NCT04104776 to 300 patients, up from 275, according to the trial's ClinicalTrials.gov record. The study tests tulmimetostat, an oral EZH2/EZH1 inhibitor also known as DZR123 or CPI-0209, as monotherapy across ten disease-specific and dose-optimization cohorts spanning tumors, lymphomas, and a prostate cancer combination arm with enzalutamide. The trial has logged enrollment target changes seven times since 2020, moving from 252 up to 284, down to 268, down again to 213, up to 286, down to 210, up to 275, and now up to 300. NCT04104776A Study of Tulmimetostat DZR123 (CPI-0209) in Patients With Advanced Solid Tumors and LymphomasNCT04104776
Cohort expansion, not a shortfall
The trial's design has grown substantially since it opened: what started as a single dose-escalation and expansion study now runs ten arms, including Cohort M7 testing a food effect in ARID1A wild-type endometrial carcinoma and Cohort M8 evaluating tulmimetostat plus enzalutamide in metastatic castration-resistant prostate cancer. Cohort M8's Part 2 expansion was itself widened from roughly 15 to roughly 40 participants under a later amendment, with the primary efficacy read there shifted to focus on prostate-specific antigen response. Enrollment growth of this kind, layered onto an early-phase basket study that keeps adding cohorts, tracks with scope expansion rather than a failure to fill existing arms. NCT04104776A Study of Tulmimetostat DZR123 (CPI-0209) in Patients With Advanced Solid Tumors and LymphomasNCT04104776
The timeline that moved
The more material registry change came in May 2025, when the trial's primary completion date shifted from December 31, 2025 to February 27, 2030, a delay of more than four years recorded in the same update that also reset enrollment from 210 to 275. That single amendment extended the entire study's operational window by roughly four and a half years, pushing any read on the drug's later-added cohorts, including the enzalutamide combination in prostate cancer, well into the next decade. NCT04104776A Study of Tulmimetostat DZR123 (CPI-0209) in Patients With Advanced Solid Tumors and LymphomasNCT04104776
What has already been disclosed
Preliminary Phase 1/2 data presented in October 2022 described responses or disease stabilization across five evaluable cohorts, with a safety profile characterized as consistent with EZH2 inhibition, though no numeric response rates or formal primary-endpoint results were disclosed at that time. No results have since been posted to the trial's ClinicalTrials.gov record. The eight primary endpoints tracked across the study's cohorts are a mix of dose-limiting toxicity assessments in the escalation cohorts and objective response or PSA50 rates in the later-stage disease-specific cohorts, so what counts as a readout differs by arm. NCT04104776A Study of Tulmimetostat DZR123 (CPI-0209) in Patients With Advanced Solid Tumors and LymphomasNCT04104776
The competitive frame
EZH2 inhibition in tumors is a narrow field: four active trials study the target in this tumor class, and one of two prior Phase 1 EZH2 x tumor programs on record has terminated. The closest same-mechanism, same-indication comparator is Bayer's darolutamide trial in prostate cancer, alongside Novartis's own second tulmimetostat program combining the drug with darolutamide and abiraterone in hormone-sensitive prostate cancer. Tazemetostat, the only EZH2 inhibitor approved so far, holds that approval in epithelioid sarcoma and EZH2-mutant follicular lymphoma, not in the -tumor cohorts this trial is testing, so no approved EZH2 inhibitor yet covers this trial's focal indications. Given that gap, a result from any single cohort here, particularly the ARID1A-mutant or BAP1-loss populations where a genetic rationale for EZH2 dependency exists, would carry weight for whether the mechanism extends past the lymphoma setting where it has already succeeded.
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