Abstract INTRODUCTION 35C is an investigational antibody-drug conjugate (ADC) comprising a chimeric immunoglobulin G1 CD30-directed monoclonal antibody, conjugated to a camptothecin-derived topoisomerase 1 inhibitor payload via a glucuronide linker. 35C shares its antibody backbone with brentuximab vedotin (BV). Preclinical data have shown that 35C induces cytotoxicity in Hodgkin lymphoma and BV-resistant cell lines and inhibits tumor growth in animal models of lymphoma. Here we present updated data from the ongoing dose escalation. METHODS This is a phase 1, open-label, multicenter study (NCT06254495), consisting of 3 parts: dose escalation (A), dose/schedule optimization (B), and dose expansion (C). The primary objective is to characterize safety and tolerability of 35C in patients (pts) with relapsed/refractory (R/R) lymphomas (classical Hodgkin lymphoma cHL; peripheral T cell lymphoma PTCL, and diffuse large B cell lymphoma DLBCL; for PTCL and DLBCL CD30+≥1%). Secondary objectives include pharmacokinetics (PK) and preliminary antitumor activity; select biomarkers are assessed as an exploratory objective. In ongoing part A, 35C has been administered as an intravenous infusion every 3 weeks (Q3W) in escalating doses. Efficacy is assessed by investigators using Lugano criteria (2014). Plasma samples were collected for ctDNA analysis using the PhasEDseq assay Foresight Diagnostics. RESULTS As of June 9, 2025, 50 pts received ≥1 dose of 35C. The group consisted of 35 pts with cHL, 10 with PTCL (including 6 sALCL and 4 PTCL-NOS), and 5 with DLBCL. Median age was 44 years (range: 24–87), 56% were male, and median prior lines of treatment for all pts was 5 (range: 1–15). Among pts with cHL, median prior lines of therapy was 6 (range: 2–15), 94% of pts had prior treatment with BV, and 97% had prior PD-1 inhibitor therapy; 57% of pts with cHL had received autologous stem cell transplant. Median duration of follow-up across all dose levels was 4.6 months (range: 0.1–12.4), and the median duration of 35C treatment was 3.7 months (range: 0.2–10.3). As of June 9, 2025, 28 (56%) pts remained on study treatment with ongoing follow-up. Overall, 44 (88%) pts experienced a treatment-emergent adverse event (TEAE), and 38 (76%) experienced a treatment-related adverse event (TRAE). The most common TEAEs were nausea (54%), fatigue (28%), neutropenia (26%), constipation (24%), alopecia (22%), and anemia (20%). The most common TRAEs were nausea (50%), fatigue (26%), neutropenia (24%), anemia (20%) and alopecia (18%). SAEs occurred in 8 (16%) pts, with 6 (12%) treatment related. Sixteen pts had grade ≥3 TRAEs, and the most frequent grade ≥3 TRAE was neutropenia (20%). There were no fatal TEAEs. Thirteen pts (26%) experienced TEAEs that led to a dose modification, mostly to dose delay (14%). Four dose-limiting toxicities were observed: thrombocytopenia G3≥7d (2.0 mg/kg; 1/15 pts), syncope G3(2.5 mg/kg; 1/12 pts), and febrile neutropenia and neutropenia G4≥7d (4.0 mg/kg; 2/3 pts). The PK analysis indicated that the ADC PK is approximately dose-proportional for the evaluated 35C doses (0.6–3.2 mg/kg Q3W); estimated terminal half-life is 6–7 days. Among response-evaluable pts from dose levels 0.6 mg/kg – 3.2 mg/kg, the objective response rate (ORR) was 73.8% (31/42), including 9 complete responses, (CR rate of 21.4% 9/42) and 22 partial responses (PRs). Among the 29 response-evaluable pts with cHL, ORR was 76% (22/29) with 5 CRs (CR rate 17.2% (5/29), at dose level: 2.0, 2.5 and 3.2 mg/kg) and 17 PRs. Among 9 response-evaluable pts with PTCL, ORR was 78% (7/9) with 3 CRs and 4 PRs. Among 4 response-evaluable pts with DLBCL, ORR was 50% (2/4) with 1 CR and 1 PR. A total of 22 pts discontinued treatment: 17 due to PD, 1 due to AE, 1 due to PI decision, and 3 pts proceeded to alloSCT. ctDNA reduction at C3D1 as compared to baseline was observed in 15/16 evaluable cHL pts, including ≥90% reduction in 8/16 pts, and a higher magnitude of reduction was associated with better clinical response.CONCLUSIONS:35C was well tolerated at the evaluated dose levels, with a manageable safety profile and PK with a linear disposition, in pts with R/R lymphomas. 35C demonstrated promising antitumor activity in heavily pretreated pts with R/R cHL that progressed after prior BV and PD-1 inhibitors, and in pts with R/R PTCL and DLBCL. These data suggest 35C as a potential treatment option for pts with R/R lymphomas, both as a monotherapy and in combination.
Poh et al. (Mon,) studied this question.