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

Exclusion Criteria

• •1. Medical Conditions
• •* Previous solid organ or allogeneic hematopoietic cell transplantation (HCT).
• •* Known symptomatic untreated brain metastases. Patients with central nervous system (CNS) metastases must have stable neurologic status following local therapy for at least 4 weeks on a stable or decreasing dose of steroids (≤ 10 mg daily prednisone or equivalent). Patients in the M4 lymphoma cohort are excluded 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 of treatment.
• •* 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 antihypertensive therapies.
• •* For Cohorts M1-M6: QT interval corrected by the Fridericia correction formula (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 from any effects of prior major surgery (uncomplicated central line placement or fine needle aspirate are not considered major surgery).
• •* Gastrointestinal disorders that may significantly interfere with the absorption of 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, or antifungal medications within 14 days before the first dose of study drug. Controlled infections on concurrent antimicrobial agents and antimicrobial prophylaxis per institutional guidelines are acceptable.
• •* Suspected pneumonitis or interstitial lung disease (confirmed by radiography or CT) or a history of these conditions.
• •* Current known active or chronic infection with HIV, hepatitis B, or hepatitis C. Screening for these viruses is not required unless there is a past history or 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 or psychiatric illness or abnormal laboratory finding that would increase the risk to the patient associated with participation in the study.
• •* For Cohort M7 Only: Patients not willing to or cannot remain fasted due to a medical 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 received chemotherapy, targeted therapy, small molecules, antibodies, investigational anticancer therapy, or other anticancer therapeutics (except gonadotropin-releasing hormone analogues) within 4 weeks (or 5 half-lives, whichever is shorter) before the first dose of the study drug. For nitrosoureas or mitomycin C, a 6-week washout is required. For prior PD-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, and alopecia, 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 dose of the study drug. However, a single fraction of radiotherapy for palliation confined to one field is permitted within 1 week prior to Day 1 of treatment.
• •* Stereotactic Body Radiation Therapy: Patients must not have received this therapy within 2 weeks before the first dose of the study drug.
• •* Chemoembolization or Radioembolization: Patients must not have received these treatments within 4 weeks before the first dose of the study drug.
• •* Concomitant Medication:
• •* CYP3A4/5 Inducers or Inhibitors: Patients must not take strong CYP3A4/5 inducers 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 for the duration of the study.
• •3. Other Exclusions
• •* General Exclusions:
• •* Pregnancy and Breastfeeding: Patients who are breastfeeding, pregnant (as confirmed by a serum β-hCG pregnancy test within 72 hours prior to the first dose of the study drug), or planning to conceive or father children during the trial and for 183 days after the last dose of the study drug are excluded. Women of nonchildbearing potential (post-menopausal for more than 1 year or surgically sterilized) do not require a serum pregnancy test. A highly sensitive urine test can be used if a serum test is not appropriate. Female patients with false-positive β-hCG values may be enrolled with written consent from the Sponsor's Medical Monitor after pregnancy has been excluded.
• •* Compliance: Patients who are unwilling or unable to comply with the study protocol or requirements are excluded.
• •* Additional Exclusions for Cohort M6 (mCRPC) Only:
• •* Bone-only Disease: Patients with bone-only disease without nodal disease and no evidence of visceral spread are excluded.
• •* Structurally Unstable Bone Lesions: Patients with bone lesions that are structurally unstable and concerning for impending fracture are excluded.
• •* Herbal Products: Patients using herbal products that may decrease prostate-specific antigen (PSA) levels within 4 weeks prior to Day 1 of treatment and during the study are excluded.
• •* Prostate Cancer Treatments: Patients who have received the following treatments for prostate cancer within the specified timeframes prior to Day 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 (including diethylstilbestrol), or progesterones within 2 weeks.
• •* Planned Palliative Procedures: Patients with planned palliative procedures for alleviation of bone pain, such as radiation therapy or surgery, are excluded.
• •* 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 pathway inhibitor (ARPi).
• •* Herbal Products: Use of herbal products that may decrease PSA levels within 4 weeks prior to Day 1 of treatment and during the study.
• •* Planned Palliative Procedures: Planned palliative procedures for alleviation of bone pain, such as radiation therapy or surgery.
• •* Investigational Agents: Treatment with any investigational agent within 4 weeks before 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 or lap band surgery. Gastroesophageal reflux disease under treatment with proton pump inhibitors is allowed.
• •* Seizure History: History of seizure, loss of consciousness, or transient ischemic attack within 12 months of study entry, or any condition that may predispose to seizure (e.g., stroke, brain arteriovenous malformation, head trauma, underlying brain injury).