A Phase I/II Study of CPI-0209 in Patients With Advanced Solid Tumors and Lymphomas
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Study Summary
The purpose of this open-label, first-in-human (FIH) trial is to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of DZR123 (Tulmimetostat, CPI-0209), both as monotherapy and in combination with enzalutamide, in patients with advanced solid tumors and lymphomas.
To evaluate next-generation EZH2 inhibitors in cancer patients Samples were analyzed via next-generation sequencing (NGS) and immunohistochemistry (IHC) for molecular features including mutational and copy number status, and gene expression profile (genes of interest included ARID1A and BAP1) to determine correlation with efficacy or novel biomarkers. To study the efficacy, safety, and biomarker findings from OCCC and EC cohorts receiving tulmimetosta To evaluate tulmimetostat 350 mg once daily in 6 disease-based cohorts, including ARID1Amut OCCC/EC. Per Simon 2-stage design, expansion of enrolment (plus n=19 patients per cohort in Stage 2) requires objective response rate (ORR) ≥1/10 in Stage 1. Evaluation of two additional dose levels was implemented for both cohorts, per FDA recommendation of Project Optimus, to inform on optimal tulmimetostat dose to evaluate safety and tolerability and antitumor activity of CPI-0209 in six disease-specific cohorts (M1 to M6) In Phase 2, two additional doses are planned to be evaluated in cohorts M2 and M3 in 2 stages: Stage 2a and Stage 2b. Phase 1 (CPI-0209 Monotherapy Dose Escalation): Determine maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of CPI-0209 as monotherapy in patients with advanced tumors Phase 2 (CPI-0209 Monotherapy Dose Expansion and Dose Optimization): Evaluate the antitumor activity of CPI-0209 as monotherapy in patients with selected advanced solid tumors and lymphomas Cohort M8 Part 1 (CPI-0209 and Enzalutamide Combination Dose Escalation in Patients with mCRPC): Determine the RP2D of CPI-0209 in combination with enzalutamide Cohort M8 Part 2 (CPI-0209 and Enzalutamide Combination Dose Expansion in Patients with mCRPC): Evaluate the antitumor activity of CPI-0209 in combination with enzalutamide
- All Patients:
- Adults aged ≥18 years with life expectancy ≥12 weeks
- ECOG performance status 0-1
- Adequate recovery from prior therapy-related toxicities (Grade ≤1, with exceptions)
- Adequate bone marrow, renal, and hepatic function per protocol-defined thresholds
- Willingness to provide tumor tissue and blood samples for biomarker analyses
- Agreement to protocol-specified contraception requirements
- Signed informed consent prior to study procedures
- Disease-Specific Inclusion Criteria:
- Phase 1 (Dose Escalation):
- Histologically or cytologically confirmed locally advanced or metastatic solid tumors or lymphoma
- Disease refractory to standard therapy or with no available effective standard treatment
- For prostate cancer: castrate testosterone levels maintained throughout the study
- Phase 2 (Disease-Specific Cohorts):
- M1: ARID1A mutant urothelial carcinoma or other ARID1A mutant solid tumors (with cohort specific prior therapy and RECIST 1.1 measurable disease requirements)
- M2: ARID1A mutant ovarian clear cell carcinoma after prior platinum-based therapy (and bevacizumab unless contraindicated)
- M3: ARID1A mutant recurrent/metastatic endometrial carcinoma after platinum therapy and appropriate immunotherapy
- M4: Relapsed/refractory peripheral T cell lymphoma or diffuse large B cell lymphoma, transplant-ineligible, with measurable disease
- M5: Relapsed/refractory pleural or peritoneal mesothelioma with documented BAP1 loss
- M6: Metastatic castration-resistant prostate cancer (mCRPC) with documented progression after AR targeted therapy and taxane chemotherapy
- M7: ARID1A wild type endometrial carcinoma (exploratory food-effect cohort)
- M8: mCRPC treated with DZR123 in combination with enzalutamide, with cohort specific requirements for prior androgen receptor pathway inhibitor and chemotherapy exposure
- Exclusion Criteria:
- All Patients:
- Medical Conditions:
- Prior solid organ or allogeneic hematopoietic cell transplant
- Active or untreated symptomatic CNS metastases (with limited exceptions)
- Clinically significant cardiovascular disease, including uncontrolled arrhythmias or prolonged QTc
- Active interstitial lung disease or pneumonitis
- Uncontrolled infections or significant gastrointestinal disorders affecting absorption
- Active HIV or hepatitis B/C infection
- Concurrent malignancy requiring active treatment (with protocol-defined exceptions)
- Pregnancy, breastfeeding, or inability to comply with protocol requirements
- Prior or Concomitant Therapy:
- Recent anticancer therapy within protocol-defined washout periods
- Prior EZH2 inhibitor treatment
- Recent radiation or liver-directed therapies outside allowed windows
- Use of strong CYP3A4/5 inhibitors or inducers
- Additional Cohort-Specific Exclusions:
- M6 (mCRPC): Bone-only disease, unstable bone lesions, PSA-lowering herbal products, recent prohibited prostate cancer therapies
- M8 (Combination): PSA-only disease, prior investigational androgen receptor pathway inhibitors, significant seizure risk, extensive prior bone marrow irradiation, active inflammatory gastrointestinal disease
Clinical Study Information for Healthcare Providers
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