TULMIMETOSTAT for Advanced solid tumors | Lymphoma | Urothelial carcinoma | Ovarian clear cell carcinoma | Endometrial carcinoma | Peripheral T-cell lymphoma | Diffuse large B-cell lymphoma | Malignant pleural mesothelioma | Peritoneal mesothelioma | Metastatic castration-resistant prostate cancer

Inclusion criteria

• {"criterion_text":"- 1. Adult (aged ≥ 18 years)\n- Male and female patients and their partners with childbearing potential should agree to use at least one of the highly effective contraceptive methods listed in Section 6.12.1.1 while on study therapy and for 93 days after the last dose of DZR123 for male patients and male partners of female patients, and for 183 days- after the last dose of DZR123 for female patients and female partners of male patients. Patients of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.\n- Signed and dated institutional review board (IRB)/independent ethics committee (IEC) approved informed consent form (ICF) before any protocol-directed screening procedures are performed.\n- P1:adults with confirmed locally advanced or metastatic tumors (solid tumors or lymphoma) who have relapsed after or progressed through standard therapy or who have a disease with no standard effective therapy P2, M1: a Confirmed, locally advanced, unresectable or metastatic UC with predominant urothelial histology b confirmed metastatic solid tumor (except OCCC, EC, and pleural or peritoneal mesothelioma) c Known ARID1A mutation d Disease progression during or following prior chemotherapy approved therapies or for which no standard therapy exists) e Measurable disease per RECIST1.1 M2:adults with Confirmed advanced OCCC b ARID1A mutation c received min.1 line of PCC and bevacizumab d Measurable disease per RECIST1.1 e Pt must have PD after receiving effective and available SoC treatment for CCOC M3:adults with Confirmed recurrent, metastatic, or unresectable EC b Known ARID1A mutation c Min.1 line of PCC in recurrent/metastatic setting d documented MSI-high or, dMMR or non-dMMR/microsatellite stable tumors should have received prior anti-PD-1 or anti-PD-L1 therapy e Brachytherapy is allowed if completed >12wks before 1st dose of study drug f Measurable disease per RECIST1.1 g Pt must have received effective and available SoC treatment for EC M4: adults with lymphoma: a Confirmed PTCL or DLBCL with following criteria: PTCL: Documented refractory, relapsed, or PD after min.1 prior line of systemic therapy. Must have min.1 prior line of systemic therapy for PTCL o Pts must be considered HCT ineligible during screening due to disease status (active disease), comorbidities, other factors o In PTCL, pts with ALCL must have prior brentuximab vedotin treatment DLBCL: Relapsed/refractory disease following 2 or more prior lines of SoC therapy Not considered candidates to receive CAR-T or ASCT as assessed by the treating investigator For pts with past ASCT or CAR-T treatment, min.90 days must have elapsed since start of the procedure. For all other pts, min.8 wks must have elapsed since most recent systemic anti-DLBCL therapy b Min.1 bi-dimensionally measurable lesion on imaging scan defined as >1. 5cm in its longest dimension M5: a Pleural or peritoneal relapsed/refractory mesothelioma b Must have progressed on or after min.1 prior line of active therapy c Have measurable disease for pleural mesothelioma (modified RECIST1.1) or for peritoneal mesothelioma (RECIST1.1) d. Known BAP1 loss per IHC or NGS testing M6:adults with mCRPC: a Have measurable soft-tissue disease with CT scan as defined by PCWG3 criteria b Documented metastatic disease c Progression while on prior therapies d Baseline testosterone levels must be ≤50 ng/dL (≤2.0 nM), surgical or ongoing medical castration must be maintained throughout the study M7: a confirmed recurrent, metastatic, or unresectable EC b Known ARID1A wildtype status and up to 5 pts with known TP53 alterations (both confirmed by NGS testing) c Received max. 2 prior lines of systemic therapy for metastatic/recurrent EC incl min. 1 line platinum-based regimen and anti-PD-1 or anti-PD-L1 agent alone or in combination unless these are contraindicated or are not locally accessible d Measurable disease per RECIST 1.1 M8: pts with prostate cancer with metastatic disease documented by bone and/or measurable soft tissue/visceral disease as per PCWG3 criteria, M8 Part 1 only: must have received min.1 ARPi (excl. enzalutamide) treatment in mCRPC or HSPC disease stage. M8 Part 2 only: must have received abiratoerone treatment in mCRPC or HSPC disease stage. For M8 Part 1 only: max 1 previous regimen of taxane-based chemotherapy in mCRPC or HSPC setting. For M8 Part 2 only: max 1 previous regimen of taxane-based chemotherapy in HSPC. For M8 Part 1 and M8 Part 2: pts with prostate cancer progression (per PCWG3) and ongoing ADT with a GnRH analogue, antagonist or bilateral orchiectomy, have baseline testosterone levels ≤ 50 ng/dL (≤ 2.0 nM), have surgical or ongoing medical castration"}

Exclusion criteria

• {"criterion_text":"- Previous solid organ or allogeneic HCT.\n- Have a history of a concurrent or second malignancy except for adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for ≥ 1 year prior to randomization, adequately treated Stage 1 or 2 cancer currently in complete remission, or any other cancer that has been in complete remission for ≥ 3 years. Patients with a history of T-cell lymphoblastic lymphoma or T-cell lymphoblastic leukemia are not eligible.\n- Have current known active or chronic infection with HIV, hepatitis B, or hepatitis C. Screening of patients with serologic testing for these viruses is not required. However, patients who have a past history of viral hepatitis or in whom there is a current suspicion of viral hepatitis should have serologic testing for hepatitis B and hepatitis C performed to determine whether there is any current evidence for ongoing infection with these viruses. Patients considered to be at risk for HIV infection should have HIV testing performed.\n- 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 the dose administration.\n- For Cohort M8 only: - Biochemical recurrence/prostate-PSA-only disease - ONLY FOR M8 PART 1: Patients who received prior enzalutamide. ONLY FOR M8 PART 2: Patients who received prior enzalutamide, apalutamide, darolutamide or any other investigational ARPi. - Herbal products that may decrease PSA levels within 4 weeks prior to Day 1 of treatment and while on study - Planned palliative procedures for alleviation of bone pain such as radiation therapy or surgery. - Treatment with any investigational agent within 4 weeks before Day 1 of M8 Part 1 or M8 Part 2. - Prior irradiation to >25% of the bone marrow. - 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. - 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).\n- Clinically active or symptomatic viral hepatitis or chronic liver disease.\n- Unstable or severe uncontrolled medical condition or any important medical or psychiatric illness or abnormal laboratory finding that would, in the Investigator’s judgment, increase the risk to the patient associated with his or her participation in the study.\n- Known symptomatic untreated brain metastases. Patients with CNS metastases must have stable neurologic status following local therapy for at least 4 weeks on stable or decreasing dose of steroid ≤ 10 mg daily prednisone (or equivalent). Patients in the M4 lymphoma cohort will not be eligible if they have known CNS involvement by lymphoma.\n- Clinically significant cardiovascular disease including: a. Myocardial infarction/stroke within 3 months prior (6 months for M8 cohort) to Day 1 of treatment. b. Unstable angina within 3 months (6 months for M8 cohort) prior to Day 1 of treatment. c. Congestive heart failure or cardiomyopathy with New York Heart Association (NYHA; see APPENDIX 3) Class 3 or 4. d. History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes). e. Uncontrolled hypertension (as defined per institutional standards) despite 2 concomitant antihypertensive therapies. f. For Cohorts M1-M6: QT interval corrected by the Fridericia correction formula (QTcF) ≥ 480 msec on the Screening ECG. For Cohort M7 and M8: QTcF interval ≥450 msec at screening\n- 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).\n- Gastrointestinal disorders, ie, ulcerative colitis, malabsorption syndrome, refractory nausea and vomiting, biliary shunt, significant bowel resection, or any other condition that may significantly interfere with absorption of the study medication by Investigator’s assessment.\n- Uncontrolled active infection requiring intravenous antibiotic, antiviral, or antifungal medications within 14 days before the first dose of study drug. Infections (eg, urinary tract infection) controlled on concurrent antimicrobial agents and antimicrobial prophylaxis per institutional guidelines are acceptable.\n- Suspected pneumonitis or interstitial lung disease (confirmed by radiography or CT) or a history of pneumonitis or interstitial lung disease."}

Primary endpoints

• {"endpoint_text":"- DZR123 Monotherapy Phase 1 and Cohort M8 Part 1 Occurrence of Dose-limiting toxicities during the 1st treatment cycle DZR123 Monotherapy Phase 2 ORR: proportion of pts with a BOR of CR or PR as per RECIST 1.1 (pts with solid tumors or peritoneal mesothelioma), 2014 Lugano criteria (pts with lymphoma), Modified RECIST 1.1 criteria (pts with pleural mesothelioma), PCWG3 criteria and per Investigator assessment (pts with prostate cancer including Cohort M8 Part 2)","definition_or_measurement_approach":"Occurrence of dose-limiting toxicities (DLTs) during the first treatment cycle for Phase 1 and M8 Part 1. ORR (Phase 2) measured as proportion of patients with best overall response (BOR) of complete response (CR) or partial response (PR) assessed by RECIST 1.1 for solid tumors/peritoneal mesothelioma, 2014 Lugano criteria for lymphoma, Modified RECIST 1.1 for pleural mesothelioma, and PCWG3 criteria and investigator assessment for prostate cancer (including M8 Part 2)."}

Secondary endpoints

• {"endpoint_text":"- DZR123 Monotherapy Phase 1: Adverse events (AEs) and change in laboratory values. DZR123 Monotherapy Phase 2: PFS: the time from first dose to confirmed disease progression or death. Cohort M8 Part 1 and Cohort M8 Part 2: Incidence of AEs characterized by type, severity (graded by NCI CTCAE effective version), timing, seriousness and relationship to DZR123 and enzalutamide combination treatment.","definition_or_measurement_approach":"Phase 1: adverse events reporting and laboratory value changes per NCI CTCAE. Phase 2: progression-free survival (PFS) defined as time from first dose to confirmed disease progression or death. Cohort M8: incidence and characterization of AEs (type, severity graded per NCI CTCAE, timing, seriousness, relationship to study drugs)."}
• {"endpoint_text":"- DZR123 Monotherapy Phase 1 PK and PD parameters DZR123 Monotherapy Phase 2 Time-to-progression Cohort M8 Part 1 Pharmacokinetics: plasma concentration-time profiles and standard pharmacokinetic parameters including but not limited to Cmax, Tmax, AUC0-last, AUC0-inf, t1/2, Cmin. Cohort M8 Part 2 Pharmacokinetics: plasma concentration-time profiles and standard pharmacokinetic parameters including but not limited to Cmax, Tmax, AUC0-last, AUC0-inf, t1/2, Cmin.","definition_or_measurement_approach":"PK and PD parameters per standard PK sampling; PK parameters listed include Cmax, Tmax, AUC0-last, AUC0-inf, t1/2, Cmin. Phase 2 Time-to-progression defined as time from first dose to progression."}
• {"endpoint_text":"- DZR123 Monotherapy Phase 1 ORR:proportion of patients with a BOR of CR or PR, per Investigator assessment based on RECIST 1.1 or applicable response criteria DZR123 Monotherapy Phase 2 DOR:the time from the date of first response to the date of confirmed disease progression Cohort M8 Part 1 Change of pharmacodynamic biomarkers from baseline Cohort M8 Part 2 Change of pharmacodynamic biomarkers from baseline","definition_or_measurement_approach":"ORR per investigator assessment using RECIST1.1 or applicable criteria. DOR = time from first response to confirmed progression. Pharmacodynamic biomarker changes measured from baseline."}
• {"endpoint_text":"- DZR123 Monotherapy Phase 1 ORR per Gynecologic Cancer Intergroup (GCIG)-defined CA-125 response criteria (ovarian cancer patients) DZR123 Monotherapy Phase 2 TTR, defined as the time from first dose to date of first response Cohort M8 Part 1 Objective response, per Investigator assessment based on PCWG3 Cohort M8 Part 2 DOR, defined as the time from the date of first response to the date of confirmed disease progression.","definition_or_measurement_approach":"ORR for ovarian cancer per GCIG CA-125 criteria. TTR = time from first dose to first response. Objective response in M8 per PCWG3. DOR defined as time from first response to confirmed progression."}
• {"endpoint_text":"- DZR123 Monotherapy Phase 1 ORR per PCWG3 (in Phase 1 prostate cancer patients only) DZR123 Monotherapy Phase 2 Disease control rate: the proportion of patients with a BOR of CR, PR, or SD per cohort and DZR123 dose level Cohort M8 Part 1 DOR: the time from the date of first response to the date of disease progression per PCWG3 Cohort M8 Part 2 Progression-free survival (PFS) as per PCWG3 and defined as the time from first dose to confirmed disease progression or death","definition_or_measurement_approach":"ORR per PCWG3 for prostate cancer Phase 1 patients. Disease control rate = proportion with BOR of CR, PR or SD per cohort/dose. DOR and PFS per PCWG3 definitions."}
• {"endpoint_text":"- DZR123 Monotherapy Phase 1 Progression-free survival (PFS), defined as the time from first dose to confirmed disease progression or death DZR123 Monotherapy Phase 2 ORR per GCIG-defined CA-125 response criteria (ovarian cancer patients) Cohort M8 Part 1 Disease control defined as best overall response of CR, PR, or stable disease (SD) per PCWG3. Cohort M8 Part 2 Proportion of patients with PSA response ≥50%.","definition_or_measurement_approach":"PFS as time from first dose to confirmed progression or death. ORR per GCIG CA-125 for ovarian cancer patients. Disease control per PCWG3. PSA response defined as ≥50% decline from baseline."}
• {"endpoint_text":"- DZR123 Monotherapy Phase 1 DOR, defined as the time from the date of first response to the date of confirmed disease progression DZR123 Monotherapy Phase 2 Overall survival (OS), defined as the time from first dose to death Cohort M8 Part 1 PSA50 response, defined as PSA decline by >=50% from baseline. Cohort M8 Part 2 Time to PSA progression.","definition_or_measurement_approach":"DOR defined as time from first response to confirmed progression. OS defined as time from first dose to death. PSA50 = ≥50% PSA decline. Time to PSA progression per PCWG3."}
• {"endpoint_text":"- DZR123 Monotherapy Phase 1 Time to response (TTR), defined as the time from first dose to date of first response DZR123 Monotherapy Phase 2 AEs and changes in laboratory values Cohort M8 Part 1 Probability of DLT over dose range Cohort M8 Part 2 Overall survival (OS), defined as the time from first dose to death in patients with mCRPC","definition_or_measurement_approach":"TTR = time from first dose to first response. Safety assessed via AEs and laboratory changes. Probability of DLT assessed across dose range. OS defined as time from first dose to death for mCRPC patients."}
• {"endpoint_text":"- DZR123 Monotherapy Phase 1 Disease control rate, defined as the proportion of patients with a best overall response of CR, PR, or stable disease (SD) DZR123 Monotherapy Phase 2 9. PK and PD parameters In Cohort M7 only: PK parameters of DZR123 monotherapy at 300 mg dose with and without a HFHC meal in patients with ARID1A WT endometrial carcinoma","definition_or_measurement_approach":"Disease control rate = proportion with BOR of CR/PR/SD. PK/PD parameters as listed; Cohort M7: PK comparison at 300 mg with and without a high-fat high-calorie (HFHC) meal in ARID1A WT endometrial carcinoma patients."}

Spain

Earliest CTIS Part Ii Submission Date

08-11-2023

Latest Decision Or Authorization Date

20-10-2025

Processing Time Days

712

Number Of Sites

18

Number Of Participants

44

Poland

Earliest CTIS Part Ii Submission Date

08-11-2023

Latest Decision Or Authorization Date

21-10-2025

Processing Time Days

713

Number Of Sites

5

Number Of Participants

12

Italy

Earliest CTIS Part Ii Submission Date

08-11-2023

Latest Decision Or Authorization Date

21-10-2025

Processing Time Days

713

Number Of Sites

7

Number Of Participants

10

France

Earliest CTIS Part Ii Submission Date

08-11-2023

Latest Decision Or Authorization Date

22-10-2025

Processing Time Days

714

Number Of Sites

7

Number Of Participants

38

Primary sponsor

Full Name

Novartis Pharma AG

Organisation Type

Pharmaceutical company

Country Of Registered Address

Switzerland

Contract research organisations

Name

Parexel International (IRL) Limited

Responsibilities

sponsorDuties codes: 12, 8

Name

Psi Cro AG

Responsibilities

sponsorDuties codes: 1,10,12,13,14,2,5,6,7

Name

Icon Clinical Research LLC

Responsibilities

ECG analysis/review; Medical image analysis/review - X-ray, MRI ultrasound, etc.

Name

Navigate Biopharma Services Inc.

Responsibilities

sponsorDuties codes: 4

Name

4g Clinical LLC

Responsibilities

sponsorDuties codes: 3

Third parties

• {"country":"United States","full_name":"Xenobiotic Laboratories Inc.","duties_or_roles":"Pharmacokinetic bioanalysis","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Ireland","full_name":"Parexel International (IRL) Limited","duties_or_roles":"sponsorDuties codes: 12, 8","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"sponsorDuties codes: 7","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Xenobiotic Laboratories Inc.","duties_or_roles":"Pharmacokinetic bioanalysis","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Navigate Biopharma Services Inc.","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Predicine Inc.","duties_or_roles":"ARID1A mutation (NGS testing)","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United States","full_name":"4g Clinical LLC","duties_or_roles":"sponsorDuties codes: 3","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Psi Cro AG","duties_or_roles":"sponsorDuties codes: 1,10,12,13,14,2,5,6,7","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Foundation Medicine Inc.","duties_or_roles":"Biomarker Analysis via Liquid Biopsy","organisation_type":"Pharmaceutical company"}
• {"country":"Belgium","full_name":"CellCarta","duties_or_roles":"Blood Processing / Circulating Tumor Cell (CTC) Banking","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Icon Clinical Research LLC","duties_or_roles":"ECG analysis/review; Medical image analysis/review - X-ray, MRI ultrasound, etc.","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Qiagen GmbH","duties_or_roles":"Circulating Tumor Cell (CTC) Enrichment and AR-V7 Testing","organisation_type":"Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Labcorp Central Laboratory Services S.a.r.l.","duties_or_roles":"Pharmacokinetic and pharmacodynamic analyses","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Xenobiotic Laboratories Inc.","duties_or_roles":"Pharmacokinetic bioanalysis","organisation_type":"Laboratory/Research/Testing facility"}