Eftozanermin alfa (ABBV-621) monotherapy in patients with previously treated solid tumors: findings of a phase 1, first-in-human study.
Apoptosis
Dose-escalation
Dose-optimization
Phase 1
Solid tumor
TRAIL-R agonist
Journal
Investigational new drugs
ISSN: 1573-0646
Titre abrégé: Invest New Drugs
Pays: United States
ID NLM: 8309330
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
received:
04
03
2022
accepted:
12
04
2022
pubmed:
26
4
2022
medline:
20
7
2022
entrez:
25
4
2022
Statut:
ppublish
Résumé
Eftozanermin alfa (eftoza), a second-generation tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R) agonist, induces apoptosis in tumor cells by activation of death receptors 4/5. This phase 1 dose-escalation/dose-optimization study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of eftoza in patients with advanced solid tumors. Patients received eftoza 2.5-15 mg/kg intravenously on day 1 or day 1/day 8 every 21 days in the dose-escalation phase, and 1.25-7.5 mg/kg once-weekly (QW) in the dose-optimization phase. Dose-limiting toxicities (DLTs) were evaluated during the first treatment cycle to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Pharmacodynamic effects were evaluated in circulation and tumor tissue. A total of 105 patients were enrolled in the study (dose-escalation cohort, n = 57; dose-optimization cohort, n = 48 patients [n = 24, colorectal cancer (CRC); n = 24, pancreatic cancer (PaCA)]). In the dose-escalation cohort, seven patients experienced DLTs. MTD and RP2D were not determined. Most common treatment-related adverse events were increased alanine aminotransferase and aspartate aminotransferase levels, nausea, and fatigue. The one treatment-related death occurred due to respiratory failure. In the dose-optimization cohort, three patients (CRC, n = 2; PaCA, n = 1) had a partial response. Target engagement with regard to receptor saturation, and downstream apoptotic pathway activation in circulation and tumor were observed. Eftoza had acceptable safety, evidence of pharmacodynamic effects, and preliminary anticancer activity. The 7.5-mg/kg QW regimen was selected for future studies on the basis of safety findings, pharmacodynamic effects, and biomarker modulations. (Trial registration number: NCT03082209 (registered: March 17, 2017)).
Identifiants
pubmed: 35467243
doi: 10.1007/s10637-022-01247-1
pii: 10.1007/s10637-022-01247-1
pmc: PMC9035501
doi:
Substances chimiques
Antineoplastic Agents
0
Banques de données
ClinicalTrials.gov
['NCT03082209']
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
762-772Subventions
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Informations de copyright
© 2022. The Author(s).
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