Abstract
Background: The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a transmembrane protein that is overexpressed in multiple cancers, including lymphomas. HDM2005 is an antibody-drug conjugate comprising a humanized IgG1 monoclonal antibody, a proteolytically cleavable linker, and the antimicrotubule cytotoxic agent monomethyl auristatin E (MMAE)，Preclinical studies have shown potent anti-tumor activity in various lymphomas and solid tumor models. Here, we report the clinical data in patients with relapsed or refractory B-NHL or cHL from the first in human study of HDM2005 (NCT06615193).
Methods: Eligible patients aged ≥18 years with an Eastern Cooperative Oncology Group Performance Status of 0-2 and histological diagnosis of relapsed or refractory B-NHL (mantle cell lymphoma [MCL], diffuse large B-cell lymphoma [DLBCL]) or cHL that had failed ≥2 prior lines of therapies (r/r MCL patients must also fail prior BTK inhibitor and CD20 mAb containing treatments) were enrolled. HDM2005 was administered intravenously every 3 weeks. Phase 1a part commenced at 0.3 mg/kg with one patient and then switched to a bayesian optimal interval scheme at escalated doses 1.0, 1.8, 2.5, 2.75 mg/kg. Dose-limiting toxicity (DLT) for each cohort was evaluated during the first treatment cycle. The primary objectives are to assess the safety and tolerability, to determine the maximum tolerated dose (MTD) and recommended Phase II doses (RP2Ds). Objective responses in lymphomas were assessed by investigators according to the 2014 Lugano response criteria.
Results: As of July 4, 2025, 29 patients were enrolled (n=1, 4, 10, 11 and 3 in the 0.3, 1.0, 1.8. 2.5, 2.75 mg/kg dose cohorts), including 17 pts with MCL, 8 pts with DLBCL, 4 pts with cHL. The median age was 60 years (range, 28-77); 21 (72.4%) patients were male; 9(31%) patients had an ECOG PS of 0 and most patients (21, 72.4%) had ≥3 lines of prior anti-tumor treatments.
One DLT occurred in 1 patient with grade 3 gamma-glutamyltransferase increased in 2.75 mg/kg cohort. No drug related death occurred, no patient permanently discontinued due to treatment related AE. Treatment related adverse events (TRAEs) occurred in 25 (86.2%) patients; most commonly (≥20%) reported TRAEs of any grade were neutrophil count decrease (n=15, 51.7%), aspartate aminotransferase increased (n=11, 37.9%), alanine aminotransferase increased (n=9, 31%), gamma-glutamyltransferase increased (n=6, 20.7%) and alopecia (n=6, 20.7%). Grade ≥3 TRAEs occurred in 10 (34.5%) patients; the most common (≥5%) Grade ≥3 events were neutrophil count decrease (n=6, 20.7%).
Peripheral neuropathy occurred in 4 patients (13.8%), all had severity of Grade 1 or 2.
In efficacy evaluable patients, objective response rate (ORR) was 47.6% (10/21) across all dose levels, with 3 complete responses (CRs) and 7 partial responses (PRs). At 1.8 and 2.5mg/kg cohorts, ORR was 50% (6/12) in MCL patients, with 1 CR and 5 PRs; ORR was 100% (2/2) in cHL patients, both having CRs.
Conclusion: HDM2005 was well tolerated and had promising albeit preliminary anti-tumor activity in patients with relapsed/refractory B-NHL or cHL. MTD not reached at dose of 2.75 mg/kg.
