A Phase I First-in-Human, Open-Label Trial to Investigate the Safety, Tolerability, Pharmacokinetics and Preliminary Antitumor Activity of SIM0500, a Humanized GPRC5D-BCMA-CD3 Trispecific Antibody, in Participants with Relapsed or Refractory Multiple Myeloma
Authors: Xu Yan , Cai Zhen , Xia Zhongjun , Yang Chen , Chen Jia , Zhu Zewen , Jing Xiaojuan , Tian Ji , Zhang Nating , Cui Ailing , Tang Jianxing , Sun Haolin , Qiu Lugui 
Published: December 2024

Background
Multiple myeloma (MM) is a malignancy of plasma cells that is characterized by the clonal expansion of neoplastic plasma cells, leading to the production of paraprotein, anemia, renal impairment, bone metastases, and humoral and cellular immunosuppression. MM represents 1% of all cancers, and is estimated to account for 10% of all hematologic malignancies globally. Although therapeutic options have expanded substantially in the past decade, MM remains an incurable disease with limited options for patients who have relapsed or are refractory to standard therapies, i.e., proteasome inhibitors (PIs), immunomodulatory imide drugs (IMiDs), and monoclonal antibodies. Thus, identification and characterization of new therapeutic targets and treatment modalities are areas of active investigation.
SIM0500 is an IgG4-based tri-specific T-cell engager that consists of a CD3-specific single-chain Fv flanked by anti-BCMA and anti-GPRC5D antibodies with the molecular weight of about 186.9 kDa. SIM0500 binds to human T-cells through CD3, and to MM cells that expresses BCMA and/or GPRC5D, thereby recruiting activated T cells to kill BCMA or GPRC5D expressing MM cells. Based on results from the nonclinical studies, the anti-tumor activity, tolerability, safety, pharmacokinetic (PK) /toxicokinetic (TK) properties of SIM0500 support the clinical development for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM). The study design has been approved by both the China Center for Drug Evaluation (CDE) and the US Food and Drug Administration (FDA). Fast Track Designation was granted by the FDA in the patients with RRMM.
Study Design and Methods
This global, Phase I, open-label, multi-cohort study (NCT06375044) consists of two parts, Part 1 (dose escalation) and Part 2 (dose optimization). In both parts, SIM0500 will be administered until disease progression, intolerable toxicity, withdraw of consent or end of trial.
Estimated total enrollment is up to 130 patients. The study will accrue patients with RRMM who have received at least ≥3 prior lines of anti- multiple myeloma therapy and prior lines of therapy must include a PI, an IMiD, and an anti-CD38 monoclonal antibody. Eligible patients must be aged ≥18 years, have an Eastern Cooperative Oncology Group performance status ≤1, and have adequate kidney and liver function. Key exclusion criteria are previous treatment with concurrent or sequential GPRC5D and BCMA antibody and the presence of known active, or prior history of CNS involvement or exhibits clinical signs of meningeal involvement of MM. This study is actively recruiting patients at sites across China and three patients have been enrolled thus far.
Part 1: SIM0500 Dose Escalation:
The SIM0500 will be administered subcutaneously. Dose escalation will be guided by 2-parameter Bayesian Logistic Regression Model with escalation with overdose control.
Dose escalation will begin with an accelerated phase in which 1-3 participants will be enrolled into each dose cohort. Accelerated dose escalation will be ended and the standard dose escalation will be started in the event of the occurrence of one Grade 2 or higher adverse events (AEs) in the dose-limiting toxicity (DLT) evaluation period, or at dose level 4 if no ≥ Grade 2 AEs are observed in the first three dose levels during accelerated dose escalation. Then 3-6 participants will be enrolled into each dose cohort in the standard dose escalation phase. A total of 6-12 participants may be enrolled in the potential recommended doses (RDs)/ maximum tolerated dose (MTD) level. A priming dose may be implemented if a Grade ≥2 CRS event occurs during the DLT assessment window.
Part 2: SIM0500 Dose Optimization:
The RD(s) will be further explored in the Part 2 dose optimization: Approximately 40 participants will be treated with two potential RD levels to further characterize preliminary antitumor activity and safety profile. Participants will be randomized at 1:1 ratio to either dose level.
Study Endpoints
The primary endpoint is safety and tolerability of the SIM0500, in terms of DLTs and treatment-emergent adverse events (TEAEs) for part 1, overall response rate and TEAEs for Part 2. Secondary endpoints are duration of response, clinical benefit rate, time to response, progression-free survival, overall survival, minimal residual disease status, pharmacokinetics, pharmacodynamics and incidence of anti-drug antibodies.