Key eligibility requires relapsed/refractory B-cell malignancies (MCL post ≥2 therapies including BTKi+CAR-T; FL/CLL post ≥2 lines) with histologic confirmation (WHO 2016). Exclusions encompass active CVD, Grade >1 neuropathy, prior solid organ transplant, uncontrolled infections (HBV/HCV/HIV), recent anticancer therapy (within 2-4 weeks), CNS lymphoma, or corticosteroid use >30mg prednisone equivalent. HBV+ candidates require antiviral therapy with undetectable viral load.

Eligible patients must have rrDLBCL failing ≥2 prior therapies (including alkylator/anthracycline/anti-CD20) and be post-CAR-T failure or ineligible, with ECOG 0-2 and adequate organ function. Exclusions: PMBCL, solid organ transplants, active cardiovascular/liver disease, neuropathy (>Grade 1), transformed DLBCL, GVHD, recent anticancer therapies/vaccines, uncontrolled infections, HIV/HBV/HCV, or CNS involvement. Prednisone >30mg/day or live vaccines within 30 days are prohibited.

The objective response rate (ORR) is defined as the percentage of participants achieving complete response (CR) or partial response (PR) per Lugano 2014 criteria, assessed by blinded independent central review (BICR), in relapsed/refractory DLBCL patients treated with zilovertamab vedotin Q3W. CR requires full radiologic resolution, while PR necessitates ≥50% reduction in tumor burden across target lesions.

Key eligibility requires relapsed/refractory B-cell malignancies (MCL post ≥2 therapies including BTKi+CAR-T; FL/CLL post ≥2 lines) with histologic confirmation (WHO 2016). Exclusions encompass active CVD, Grade >1 neuropathy, prior solid organ transplant, uncontrolled infections (HBV/HCV/HIV), recent anticancer therapy (within 2-4 weeks), CNS lymphoma, or corticosteroid use >30mg prednisone equivalent. HBV+ candidates require antiviral therapy with undetectable viral load.

Key eligibility requires relapsed/refractory B-cell malignancies (MCL post ≥2 therapies including BTKi+CAR-T; FL/CLL post ≥2 lines) with histologic confirmation (WHO 2016). Exclusions encompass active CVD, Grade >1 neuropathy, prior solid organ transplant, uncontrolled infections (HBV/HCV/HIV), recent anticancer therapy (within 2-4 weeks), CNS lymphoma, or corticosteroid use >30mg prednisone equivalent. HBV+ candidates require antiviral therapy with undetectable viral load.

Eligible patients (≥18 years, ECOG 0-2) must have relapsed/refractory CLL/SLL, NHL (MCL/FL/DLBCL/etc.), ALL, or AML with measurable disease and adequate organ function. Key exclusions include CNS malignancy, uncontrolled infections, Grade >1 neuropathy, recent major surgery, strong CYP3A4 modulators, HSCT/CAR-T candidates, prior ROR1-targeted therapy, or concurrent corticosteroids >30mg prednisone equivalent. Baseline tumor tissue and resolution of prior therapy toxicities (≤Grade 1) are required.

Participants will be administered escalating doses of zilovertamab vedotin at 0.50, 1.00, 1.50, 2.25, 2.50, 2.75, and 3.00 mg/kg IV on Day 1 of repeated 21-day cycles (Q1/3W); Participants will be administered escalating doses of zilovertamab vedotin at 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, and 2.25 mg/kg IV on Day 1 and 8 of repeated 21-day cycles (Q2/3W); Participants will be administered escalating doses of zilovertamab vedotin at 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, and 2.25 mg/kg IV on Day 1, 8, and 15 of repeated 21-day cycles (Q3/4W).

Key safety assessments include TEAEs, SAEs, AESIs (Grade ≥3 infusion reactions, TLS, peripheral neuropathy), treatment discontinuations, and DLTs over ~3.5 years. Pharmacokinetic parameters (Cmax, Tmax, AUC, Vd, CL, t½) for zilovertamab vedotin, UC-961 antibody, and MMAE will be evaluated across treatment cycles (up to ~3.5 years), alongside immunogenicity (anti-drug antibodies) and efficacy measures (OR, CRMRD-, tumor dimension changes, TTR, DOR, PFS, TTF, OS) in hematologic malignancies.

Eligibility requires untreated, PET-positive DLBCL (Lugano 4-5) confirmed by BICR, ECOG 0-1. Exclusions encompass transformed lymphoma, organ transplant history, active CVD (recent MI/stroke, NYHA &ge;II), Grade >1 neuropathy, prior radiotherapy (<28 days), corticosteroids >30mg prednisone daily, strong CYP3A4 modulators (<7 days), active infections (HBV/HCV/HIV), CNS involvement, or second malignancies (<2 years remission except certain skin cancers).

Approximately 60 patients will be enrolled (part 1, n = 45; part 2, n = 15). Part 1 will use a modified toxicity probability interval design to establish the RP2D of ZV when administered with R-CHP. The starting dose of ZV will be 1.75 mg/kg (modified to 1.5, 2.0, 2.25, or 2.5 mg/kg) administered as an intravenous infusion every 3 weeks (Q3W) in combination with R-CHP.

Eligibility requires histologically confirmed DLBCL (Lugano-measurable, ECOG 0-2) with relapsed/refractory status post &ge;1 prior therapy (including ASCT/CAR-T failure). Exclusions: transformed DLBCL, organ transplant history, active CVD/GVHD, Grade >1 neuropathy, second malignancy (<2 years remission), recent anticancer therapy/radiotherapy (4 weeks), CNS involvement, active infections (HIV/HCV), or uncontrolled psychiatric/substance disorders. Prior CNS disease requires confirmed remission.

Approximately 420 patients will be enrolled in the study (cohort A, n = 230; cohort B, n = 190). In the part 1 dose confirmation phase, 30 patients from cohort A will receive ZV (at increasing doses: 1.5, 1.75, 2.0, 2.25, and 2.5 mg/kg; starting at 1.75 mg/kg) plus gemcitabine-oxaliplatin + rituximab (R-GemOx) to establish the recommended phase 2 dose using the mTPI design.

Safety analysis includes dose-limiting toxicities (DLTs) in Part 1 (6 weeks, per CTCAE v5.0), overall AE incidence (68 months), and treatment discontinuations due to AEs (68 months). Key efficacy endpoints are overall survival (OS, 35 months) and progression-free survival (PFS, 26 months) - both assessed from randomization to disease progression (Lugano/BICR) or death.

Eligible patients have untreated PET-positive DLBCL (Lugano 4-5), ECOG 0-2, and adequate cardiac/organ function; HIV/HBV/HCV control is required if applicable. Exclusions: transformed DLBCL, PMBCL, Stage I disease, active CVD/neuropathy (>Grade 1), CNS involvement, uncontrolled infections/autoimmunity, or concurrent malignancies within 2 years. Live vaccines and allogeneic transplants are prohibited.

Primary endpoints include PFS (50 months, time from randomization to progression/death per Lugano/BICR) and CR at EOT (32 months, BICR-assessed complete response excluding early discontinuations). Secondary efficacy measures comprise OS (74 months), EFS (74 months, covering progression/recurrence/second malignancy/death), and DurCR (74 months, sustained CR until progression/death).

Eligible patients must have confirmed B-ALL, DLBCL/Burkitt lymphoma, neuroblastoma, or Ewing sarcoma per WHO/histologic criteria. Exclusions: solid organ transplants, active cardiovascular disease (e.g., arrhythmias, cirrhosis), neuropathy (>Grade 1), Down syndrome, GVHD, HIV/HBV/HCV, or recent cytotoxic/CYP3A4-modulating therapies. Prohibited: live vaccines (30 days prior), chronic steroids (>10mg prednisone/day), unresolved post-surgical complications, or concurrent malignancies requiring treatment. Prior radiotherapy/systemic therapy requires washout (4 weeks).

The primary objectives assess safety and efficacy in pediatric patients (aged 1-18 years). Part 1 evaluates dose-limiting toxicities (DLTs) within 42 days and tracks adverse events (AEs), treatment discontinuations, and dose modifications over 60 months. Efficacy endpoints include objective response rates (ORR) per disease-specific criteria: CR/CRi for B-ALL (Ponte-di-Legno) and CR/PR for DLBCL/Burkitt lymphoma (IPNHL), neuroblastoma (INRC), and Ewing sarcoma (RECIST 1.1). Key secondary measures include duration of response (DOR) and rates of subsequent SCT or CAR-T therapy.

Pharmacokinetic analyses measure exposure (AUC), peak/trough concentrations (Cmax/Ctrough), and half-life (t1/2) for total antibody, ADC, and MMAE across cycles (21-day intervals) over 60 months. Immunogenicity is assessed via antidrug antibody (ADA) incidence. Part 2 monitors AE-related outcomes (incidence, discontinuations, dose modifications) alongside efficacy metrics. Treatment impact is further characterized by post-therapy SCT/CAR-T utilization rates.

Efficacy endpoints included Objective Response Rate (ORR) assessed by both Blinded Independent Central Review (BICR) and investigators per RECIST v1.1, with key measures like Time to Response (TTR), Duration of Response (DOR), Progression-Free Survival (PFS), Time to Treatment Failure (TTF), and Overall Survival (OS) tracked over ~30 months. Safety assessments involved monitoring Adverse Events (AEs), treatment discontinuations due to AEs, and pharmacokinetic parameters (Cmax, AUC) for zilovertamab vedotin, total antibody, and MMAE under Q1/3W and Q2/3W dosing schedules.

The study enrolled patients with metastatic solid tumors (TNBC, HER2-negative breast cancer, NSCLC, gastric, pancreatic, or platinum-resistant ovarian cancer) who progressed after prior therapy, had measurable disease, and adequate organ function. Key exclusions included Grade >1 neuropathy, CNS malignancies, other major cancers, uncontrolled infections, cardiovascular disease, liver cirrhosis, pregnancy, recent major surgery, MMAE intolerance, or concurrent trial participation.

Eligible participants had histologically confirmed locally advanced/unresectable or metastatic urothelial cancer (mUC), refractory to PD-1/L1 therapy, with available tumor biopsy for biomarker analysis. Key exclusions included other active malignancies, recent systemic therapy (within 4 weeks), active infections requiring treatment, recent live vaccines (within 30 days), and HIV/hepatitis B/C infections.

The safety and efficacy endpoints involved tracking adverse events (AEs) over ~5 years, including discontinuation rates due to AEs, while efficacy was assessed via Objective Response Rate (ORR) using RECIST 1.1 criteria (CR: disappearance of all target lesions; PR: ≥30% decrease in sum of lesion diameters) over ~2 years, with results reviewed by Blinded Independent Central Review (BICR).