Abstract CT067: The anti-BCMA antibody-drug conjugate HDP-101 with a novel amanitin payload shows promising initial first in human results in relapsed multiple myeloma

Abstract

Abstract Background: HDP-101 is a new antibody drug conjugatetargeting B-cell maturation antigen (BCMA) that carries a synthetic amanitin payload with a new mode of action. Amanitin inhibits RNA polymerase II, effectively stopping transcription and inducing apoptosis in tumor cells, regardless of their proliferation status. It's shown cytotoxicity in vitro against BCMA-positive myeloma cell lines and non-proliferating primary CD138+ cells from refractory myeloma patients withefficacy even in cells with low BCMA density. Clinical Study: HDP-101-01 is a first-in-human, open label, non-randomized, multicenter, phase 1/2a trial in patients with multiple myeloma whose disease has progressed or is refractory, aiming to determine the Maximum Tolerated Dose and/or the Recommended phase 2 Dose in Phase 1. Dose escalation is guided by an adaptive Bayesian logistic regression model with overdose control. The primary objective in phase 2 is to assess anti-tumor activity. Study Progress: As of November 2023, 18 patients (7 females, 11 males) were enrolled in 5 consecutive dose cohorts of 20, 30, 60, 80, and 100µg/kg. Patients had a median age of 70 years (48-82), were heavily pre-treated and multidrug-resistant, and had a median of 6,5 prior treatments (2-15). Study Results: Preliminary data shows that pharmacokinetics of HDP-101 aligns with expectations, and exposure to HDP-101 is dose proportional. Free payload was not detected in serum at a limit of detection of 30 ng/mL, and no anti-drug antibodiesor immunogenic reactions were noted. 17 of 18 patients were evaluable for dose limiting toxicities (DLT) in the 5 treatment cohorts. Initial cohorts were well tolerated, without any DLTs, including no signs of hepatic and renal toxicities, infusions reactions, or ocular disorders. All patients in Cohort 5 had Grade 1-4 transient thrombocytopeniawith platelet reductions starting on Cycle 1/Day 2 (C1/D2), a nadir on C1D5, and full recovery by C1D15 at the latest without any clinical sequelae or interventions. Notably, subsequent dosing with HDP-101 did not produce similarly deep episodes of thrombocytopenia, supporting the possibility that this event is not due to a direct cytotoxic effect against megakaryocytes. After Cohort 5, mitigation strategies are being considered and further dose and schedule optimization is planned with fractionated dosing and/or with premedication. Efficacy: Cohort3 has a patient with stable disease (SD) after 15 cycles. Cohort 5 has 4 ongoing patients with promising results after 3-4 cycles: 2 patients achieved PR, and 2 have SD. Updated data will be presented at the AACR2024 meeting. Citation Format: Jonathan Kaufman, Marc Raab, Shambavi Richard, Sebastian Grosicki, István Takács, András Strassz, Andreas Pahl, Michael Kulke, Thorsten Michael, Anette Last, Hajnalka Szabóki, Garrit Jentsch, Oliver Schönborn-Kellenberger, Robert Orlowski. The anti-BCMA antibody-drug conjugate HDP-101 with a novel amanitin payload shows promising initial first in human results in relapsed multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT067.