A Study of Tulmimetostat DZR123 (CPI-0209) in Patients With Advanced Solid Tumors and Lymphomas

Key Inclusion Criteria:

• Eligible Phase 1 patients are adults who have a confirmed locally advanced ormetastatic tumors (solid tumors or lymphoma) that have relapsed following standardtherapy or progressed through standard therapy or who have a disease for which nostandard effective therapy exists.

• Eligible Phase 2 patients in cohorts M1 to M3 are adults who are known to have theARID1A mutation by next-generation sequencing (NGS) testing; have measurable diseaseper Response Evaluation Criteria in Solid Tumors 1.1 and who have confirmed relapsedurothelial or other advanced/metastatic solid tumors (M1), ovarian clear cellcarcinoma (M2), or endometrial carcinoma (M3).

• Eligible Phase 2 patients in Cohort M4 are adults who have either relapsed orrefractory PTCL (at least 10 patients) or DLBCL (up to 10 patients), includingpatients with documented GCB DLBCL with EZH2 hotspot mutation. Patients with PTCLmust have at least 1 prior line of therapy and patients with DLBCL must have atleast 2 prior lines of standard therapy; and are not considered candidates toreceive CAR-T or ASCT therapy.

• Eligible Phase 2 patients in Cohort M5 are adults who are known to the have the BAP1loss, have malignant pleural or peritoneal mesothelioma, and have progressed on atleast 1 prior line of active therapy.

• Eligible Phase 2 patients in Cohort M6 are adults who have mCRPC with measurablesoft tissue disease with CT scan as defined by PCWG3 criteria, have baselinetestosterone levels ≤ 50 ng/dL (≤ 2.0 nM) and have surgical or ongoing medicalcastration and who have progressed on at least 1 androgen-receptor signalinginhibitor and at least 1 taxane-based chemotherapy (cabazitaxel, France only).

• Eligible Phase 2 patients in Cohort M7 are adults with recurrent, advanced ARID1A WTendometrial carcinoma confirmed by NGS testing and have measurable disease perResponse Evaluation Criteria in Solid Tumors 1.1 Patients will be enrolled withmaximum up to 2 prior lines of systemic therapy for treating endometrial carcinomathat must include at least one treatment line with systemic platinum-basedchemotherapy in advanced/ recurrent disease setting, and anti-programmed cell deathprotein 1 (PD-1)/ anti-programmed death-ligand 1 (PD-L1) therapy, either incombination or separately, unless these are contraindicated or are not locallyaccessible.

• Eligible Part 1 and Part 2 patients in Cohort M8 are adults who have mCRPC withmeasurable soft tissue disease as per PCWG3 criteria, have baseline testosteronelevels ≤ 50 ng/dL (≤ 2.0 nM), have surgical or ongoing medical castration or hormonesensitive prostate cancer (HSPC) disease stage. In addition, Eligible part 1patients in Cohort M8 may have received abiraterone treatment in mCRPC whileeligible part 2 patients in Cohort M8 must have received abiraterone treatment inmCRPC. In addition, only for M8 Part 1: Patients may have received no more than oneprevious regimen of taxane-based chemotherapy in mCRPC or HSPC setting. For M8 Part 2: Patients may have received no more than one previous regimen of taxane-basedchemotherapy in HSPC setting. Patients for both M8 Part 1 and M8 Part 2 must haveevidence of prostate cancer progression (per PCWG3) and must have ongoing ADT (androgen deprivation therapy) with a GnRH analogue, antagonist or bilateralorchiectomy (i.e., surgical or medical castration).

• All patients will have Eastern Cooperative Oncology Group (ECOG) performance statusof ≤ 1 and adequate organ function.

Key Exclusion Criteria:

1. Medical Conditions

• Previous solid organ or allogeneic hematopoietic cell transplantation (HCT).

• Known symptomatic untreated brain metastases. Patients with central nervoussystem (CNS) metastases must have stable neurologic status following localtherapy for at least 4 weeks on a stable or decreasing dose of steroids (≤ 10mg daily prednisone or equivalent). Patients in the M4 lymphoma cohort areexcluded if they have known CNS involvement by lymphoma.

• Clinically significant cardiovascular disease, including:

• Myocardial infarction or stroke within 3 months (6 months for M8 cohort)prior to Day 1 of treatment.

• Unstable angina within 3 months (6 months for M8 cohort) prior to Day 1 oftreatment.

• Congestive heart failure or cardiomyopathy with New York Heart Association (NYHA) Class 3 or 4.

• History of clinically significant ventricular arrhythmias (e.g.,ventricular tachycardia, ventricular fibrillation, torsades de pointes).

• Uncontrolled hypertension despite 2 concomitant antihypertensivetherapies.

• For Cohorts M1-M6: QT interval corrected by the Fridericia correctionformula (QTcF) > 480 msec on the Screening ECG.

• For Cohorts M7 and M8: QTcF interval ≥ 450 msec at screening.

• Major surgery within 4 weeks before starting study drug or not recovered fromany effects of prior major surgery (uncomplicated central line placement orfine needle aspirate are not considered major surgery).

• Gastrointestinal disorders that may significantly interfere with the absorptionof the study medication, such as ulcerative colitis, malabsorption syndrome,refractory nausea and vomiting, biliary shunt, significant bowel resection.

• Uncontrolled active infection requiring intravenous antibiotic, antiviral, orantifungal medications within 14 days before the first dose of study drug.Controlled infections on concurrent antimicrobial agents and antimicrobialprophylaxis per institutional guidelines are acceptable.

• Suspected pneumonitis or interstitial lung disease (confirmed by radiography orCT) or a history of these conditions.

• History of a concurrent or second malignancy except for certain adequatelytreated cancers such as local basal cell or squamous cell carcinoma of theskin, cervical carcinoma in situ, superficial bladder cancer, asymptomaticprostate cancer without known metastatic disease, adequately treated Stage 1 or 2 cancer currently in complete remission, or any other cancer in completeremission for ≥ 3 years. Patients with a history of T-cell lymphoblasticlymphoma or T-cell lymphoblastic leukemia are not eligible.

• Current known active or chronic infection with HIV, hepatitis B, or hepatitisC. Screening for these viruses is not required unless there is a past historyor current suspicion of viral hepatitis.

• Clinically active or symptomatic viral hepatitis or chronic liver disease.

• Unstable or severe uncontrolled medical condition or any important medical orpsychiatric illness or abnormal laboratory finding that would increase the riskto the patient associated with participation in the study.

• For Cohort M7 Only: Patients not willing to or cannot remain fasted due to amedical condition for 2 hours before and 1 hour after dose administration.

2. Prior/Concomitant Therapy:

• Prior Anticancer Treatment:

• Systemic Anticancer Treatment: Patients must not have receivedchemotherapy, targeted therapy, small molecules, antibodies,investigational anticancer therapy, or other anticancer therapeutics (except gonadotropin-releasing hormone analogues) within 4 weeks (or 5half-lives, whichever is shorter) before the first dose of the study drug.For nitrosoureas or mitomycin C, a 6-week washout is required. For priorPD-1 or PD-L1 therapy, a washout period of at least 4 weeks is acceptable.All toxicities from prior therapies must have resolved to Grade 1 or less,except for endocrinopathies requiring medication, neuropathy, andalopecia, which must have resolved to Grade 2 or less.

• EZH2 Inhibitor: Previous treatment with an EZH2 inhibitor is not allowed.

• Radiation Therapy: Patients must not have received radiation therapy (including radiofrequency ablation) within 4 weeks before the first doseof the study drug. However, a single fraction of radiotherapy forpalliation confined to one field is permitted within 1 week prior to Day 1of treatment.

• Stereotactic Body Radiation Therapy: Patients must not have received thistherapy within 2 weeks before the first dose of the study drug.

• Chemoembolization or Radioembolization: Patients must not have receivedthese treatments within 4 weeks before the first dose of the study drug.

• Concomitant Medication:

• CYP3A4/5 Inducers or Inhibitors: Patients must not take strong CYP3A4/5inducers or inhibitors (except enzalutamide in Cohort M8) within 7 days or 5 times the reported half-life of the CYP3A4/5 inhibitor or inducer (whichever is longer) prior to the first dose of the study drug and forthe duration of the study.

3. Other Exclusions

• General Exclusions:

• Pregnancy and Breastfeeding: Patients who are breastfeeding, pregnant (asconfirmed by a serum β-hCG pregnancy test within 72 hours prior to thefirst dose of the study drug), or planning to conceive or father childrenduring the trial and for 183 days after the last dose of the study drugare excluded. Women of nonchildbearing potential (post-menopausal for morethan 1 year or surgically sterilized) do not require a serum pregnancytest. A highly sensitive urine test can be used if a serum test is notappropriate. Female patients with false-positive β-hCG values may beenrolled with written consent from the Sponsor's Medical Monitor afterpregnancy has been excluded.

• Compliance: Patients who are unwilling or unable to comply with the studyprotocol or requirements are excluded.

• Additional Exclusions for Cohort M6 (mCRPC) Only:

• Bone-only Disease: Patients with bone-only disease without nodal diseaseand no evidence of visceral spread are excluded.

• Structurally Unstable Bone Lesions: Patients with bone lesions that arestructurally unstable and concerning for impending fracture are excluded.

• Herbal Products: Patients using herbal products that may decreaseprostate-specific antigen (PSA) levels within 4 weeks prior to Day 1 oftreatment and during the study are excluded.

• Prostate Cancer Treatments: Patients who have received the followingtreatments for prostate cancer within the specified timeframes prior toDay 1 of treatment are excluded:

1. First-generation androgen receptor antagonists (e.g., bicalutamide,nilutamide, flutamide) within 4 weeks.
2. 5α reductase inhibitors, ketoconazole, estrogens (includingdiethylstilbestrol), or progesterones within 2 weeks.

• Planned Palliative Procedures: Patients with planned palliative proceduresfor alleviation of bone pain, such as radiation therapy or surgery, areexcluded.

4. Additional Exclusion Criteria for Cohort M8 (DZR123 and Enzalutamide Combination inmCRPC) only:

• Biochemical recurrence/prostate-specific antigen (PSA)-only disease.

• Prior Enzalutamide Treatment:

• For M8 Part 1: Patients who have received prior enzalutamide.

• For M8 Part 2: Patients who have received prior enzalutamide, apalutamide,darolutamide, or any other investigational androgen receptor pathwayinhibitor (ARPi).

• Herbal Products: Use of herbal products that may decrease PSA levels within 4weeks prior to Day 1 of treatment and during the study.

• Planned Palliative Procedures: Planned palliative procedures for alleviation ofbone pain, such as radiation therapy or surgery.

• Investigational Agents: Treatment with any investigational agent within 4 weeksbefore Day 1 of M8 Part 1 or M8 Part 2.

• Bone Marrow Irradiation: Prior irradiation to more than 25% of the bone marrow.

• Gastrointestinal Conditions: Active inflammatory gastrointestinal disease,chronic diarrhea, known diverticular disease, or previous gastric resection orlap band surgery. Gastroesophageal reflux disease under treatment with protonpump inhibitors is allowed.

• Seizure History: History of seizure, loss of consciousness, or transientischemic attack within 12 months of study entry, or any condition that maypredispose to seizure (e.g., stroke, brain arteriovenous malformation, headtrauma, underlying brain injury).