Journal for immunotherapy of cancer · 2025
First-in-human phase I trial of the bispecific CD47 inhibitor and CD40 agonist Fc-fusion protein, SL-172154 in patients with platinum-resistant ovarian cancer.
СтатьяКлиническое исследование I фазыНазвание и аннотация: Перевод в очереди
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Lakhani Nehal J, Stewart Daphne, Richardson Debra L, Dockery Lauren E, Van Le Linda, Call Justin, Rangwala Fatima, Wang Guanfang, Ma Bo, Metenou Simon, Huguet Jade, Offman Elliot, Pandite Lini, Hamilton Erika
Аннотация
BACKGROUND: SL-172154 is a hexameric fusion protein adjoining the extracellular domain of SIRPα to the extracellular domain of CD40L via an inert IgG4-derived Fc domain. In preclinical studies, a murine equivalent SIRPα-Fc-CD40L fusion protein provided superior antitumor immunity in comparison to CD47- and CD40-targeted antibodies. A first-in-human phase I trial of SL-172154 was conducted in patients with platinum-resistant ovarian cancer.
METHODS: SL-172154 was administered intravenously at 0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg. Dose escalation followed a modified toxicity probability interval-2 design. Objectives included evaluation of safety, dose-limiting toxicity, recommended phase II dose, pharmacokinetic (PK) and pharmacodynamic (PD) parameters, and antitumor activity.
RESULTS: 27 patients (median age 66 years (range, 33-85); median of 4 prior systemic therapies (range, 2-9)) with ovarian (70%), fallopian tube (15%), or primary peritoneal (15%) cancer received SL-172154. Treatment-emergent adverse events (TEAEs) were reported for 27 patients (100%), with 24 (88.9%) having a drug-related TEAE and infusion-related reactions being the most common. 12 patients (44.4%) had grade 3/4 TEAEs, and half of these patients (22.2%) had a drug-related grade 3/4 TEAE. There were no fatal adverse events, and no TEAEs led to drug discontinuation. SL-172154 Cmax and area under the curve increased with dose with greater than proportional exposure noted at 3.0 and 10.0 mg/kg. CD47 and CD40 target engagement on CD4+ T cells and B cells, respectively, approached 100% by 3.0 mg/kg. Dose-dependent responses in multiple cytokines (eg, interleukin 12 (IL-12), IP-10) approached a plateau at ≥3.0 mg/kg. Paired tumor biopsies demonstrated a shift in macrophages from an M2- to an M1-dominant phenotype and increased infiltration of CD8 T cells. PK/PD modeling showed near maximal margination of B cells and a dose-dependent production of IL-12 nearing a plateau at >3.0 mg/kg. The best response was stable disease in 6/27 (22%) patients.
CONCLUSIONS: SL-172154 was tolerable as monotherapy and induced, dose-dependent, and cyclical immune cell activation, increases in multiple serum cytokines, and trafficking of CD40-positive B cells and monocytes following each infusion. The safety, PK, and PD activity support 3.0 mg/kg as a safe and pharmacologically active dose.
TRIAL REGISTRATION NUMBER: NCT04406623.
METHODS: SL-172154 was administered intravenously at 0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg. Dose escalation followed a modified toxicity probability interval-2 design. Objectives included evaluation of safety, dose-limiting toxicity, recommended phase II dose, pharmacokinetic (PK) and pharmacodynamic (PD) parameters, and antitumor activity.
RESULTS: 27 patients (median age 66 years (range, 33-85); median of 4 prior systemic therapies (range, 2-9)) with ovarian (70%), fallopian tube (15%), or primary peritoneal (15%) cancer received SL-172154. Treatment-emergent adverse events (TEAEs) were reported for 27 patients (100%), with 24 (88.9%) having a drug-related TEAE and infusion-related reactions being the most common. 12 patients (44.4%) had grade 3/4 TEAEs, and half of these patients (22.2%) had a drug-related grade 3/4 TEAE. There were no fatal adverse events, and no TEAEs led to drug discontinuation. SL-172154 Cmax and area under the curve increased with dose with greater than proportional exposure noted at 3.0 and 10.0 mg/kg. CD47 and CD40 target engagement on CD4+ T cells and B cells, respectively, approached 100% by 3.0 mg/kg. Dose-dependent responses in multiple cytokines (eg, interleukin 12 (IL-12), IP-10) approached a plateau at ≥3.0 mg/kg. Paired tumor biopsies demonstrated a shift in macrophages from an M2- to an M1-dominant phenotype and increased infiltration of CD8 T cells. PK/PD modeling showed near maximal margination of B cells and a dose-dependent production of IL-12 nearing a plateau at >3.0 mg/kg. The best response was stable disease in 6/27 (22%) patients.
CONCLUSIONS: SL-172154 was tolerable as monotherapy and induced, dose-dependent, and cyclical immune cell activation, increases in multiple serum cytokines, and trafficking of CD40-positive B cells and monocytes following each infusion. The safety, PK, and PD activity support 3.0 mg/kg as a safe and pharmacologically active dose.
TRIAL REGISTRATION NUMBER: NCT04406623.