TY - JOUR
T1 - A First-in-Human Phase I Study of BXQ-350, a First-in-Class Sphingolipid Metabolism Regulator, in Patients with Advanced/Recurrent Solid Tumors or High-Grade Gliomas
AU - Rixe, Olivier
AU - Villano, John L.
AU - Wesolowski, Robert
AU - Noonan, Anne M.
AU - Puduvalli, Vinay K.
AU - Wise-Draper, Trisha M.
AU - Curry, Richard
AU - Yilmaz, Emrullah
AU - Cruze, Charlie
AU - Ogretmen, Besim
AU - Tapolsky, Gilles
AU - Takigiku, Ray
N1 - Publisher Copyright:
© 2024 American Association for Cancer Research.
PY - 2024/11/15
Y1 - 2024/11/15
N2 - Purpose: BXQ-350, a nanovesicle formulation of saposin C, is an allosteric sphingolipid metabolism regulator that increases proapoptotic ceramide and decreases oncogenic sphingosine-1- phosphate levels. We conducted a first-in-human phase I study of BXQ-350. Patients and Methods: Adults (≥18 years old) with advanced/ recurrent, treatment-refractory solid tumors or high-grade gliomas received BXQ-350 intravenously in five dose cohorts (0.7- 2.4 mg/kg) in a 3+3 dose escalation and expansion design. The primary endpoints during dose escalation were dose-limiting toxicities and maximum tolerated dose; the primary objective in expansion parts was assessment of antitumor activity (RECIST v1.1/Response Assessment in Neuro-Oncology criteria). Results: Eighty-six patients were enrolled. Dose-limiting toxicities were not observed during dose escalation (n = 18), and a maximum tolerated dose was not identified. An additional 68 patients received the 2.4 mg/kg dose. Nine patients (10%) discontinued due to adverse events. The most common treatmentrelated adverse events were nausea (24%) and fatigue (23%). Eight patients had a progression-free survival of ≥6 months. Two of these achieved a partial response, and six had stable disease, among whom three had a reduction in ≥1 target lesion. Of those with progression-free survival of ≥6 months, seven remained on study for >12 months, five for >24 months, and after 7 years, two remained on study without disease progression. Conclusions: BXQ-350 was well-tolerated as monotherapy at doses up to 2.4 mg/kg. It provided some lasting clinical benefit in patients with recurrent solid malignancies across several tumor types, consistent with a decreased systemic sphingosine-1-phosphate/ ceramide metabolic rheostat. BXQ-350 warrants further clinical investigation alone and combined with standard of care for advanced solid tumors.
AB - Purpose: BXQ-350, a nanovesicle formulation of saposin C, is an allosteric sphingolipid metabolism regulator that increases proapoptotic ceramide and decreases oncogenic sphingosine-1- phosphate levels. We conducted a first-in-human phase I study of BXQ-350. Patients and Methods: Adults (≥18 years old) with advanced/ recurrent, treatment-refractory solid tumors or high-grade gliomas received BXQ-350 intravenously in five dose cohorts (0.7- 2.4 mg/kg) in a 3+3 dose escalation and expansion design. The primary endpoints during dose escalation were dose-limiting toxicities and maximum tolerated dose; the primary objective in expansion parts was assessment of antitumor activity (RECIST v1.1/Response Assessment in Neuro-Oncology criteria). Results: Eighty-six patients were enrolled. Dose-limiting toxicities were not observed during dose escalation (n = 18), and a maximum tolerated dose was not identified. An additional 68 patients received the 2.4 mg/kg dose. Nine patients (10%) discontinued due to adverse events. The most common treatmentrelated adverse events were nausea (24%) and fatigue (23%). Eight patients had a progression-free survival of ≥6 months. Two of these achieved a partial response, and six had stable disease, among whom three had a reduction in ≥1 target lesion. Of those with progression-free survival of ≥6 months, seven remained on study for >12 months, five for >24 months, and after 7 years, two remained on study without disease progression. Conclusions: BXQ-350 was well-tolerated as monotherapy at doses up to 2.4 mg/kg. It provided some lasting clinical benefit in patients with recurrent solid malignancies across several tumor types, consistent with a decreased systemic sphingosine-1-phosphate/ ceramide metabolic rheostat. BXQ-350 warrants further clinical investigation alone and combined with standard of care for advanced solid tumors.
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U2 - 10.1158/1078-0432.CCR-24-1721
DO - 10.1158/1078-0432.CCR-24-1721
M3 - Article
C2 - 39264252
AN - SCOPUS:85209827879
SN - 1078-0432
VL - 30
SP - 5053
EP - 5060
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 22
ER -