First-in-human, open-label, Phase 1 study of a novel CD30-directed antibody-drug conjugate with a topoisomerase 1 inhibitor payload, PF-08046044 (35C), in patients with Relapsed/Refractory lymphomas: Updated safety, PK, preliminary efficacy and ctdna analysis from dose escalation

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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.

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