Safety and efficacy of the tumor-selective adenovirus enadenotucirev with or without paclitaxel in platinum-resistant ovarian cancer: A phase 1 clinical trial

Moreno, V. ; Barretina-Ginesta, M.-P. ; García-Donas, J. ; Jayson, G.C. ; Roxburgh, P. ; Márquez Vázquez, R. ; Michael, A. ; Antón-Torres, A. (Universidad de Zaragoza) ; Brown, R. ; Krige, D. ; Champion, B. ; McNeish, I.

Resumen: Background Treatment outcomes remain poor in recurrent platinum-resistant ovarian cancer. Enadenotucirev, a tumor-selective and blood stable adenoviral vector, has demonstrated a manageable safety profile in phase 1 studies in epithelial solid tumors. Methods We conducted a multicenter, open-label, phase 1 dose-escalation and dose-expansion study (OCTAVE) to assess enadenotucirev plus paclitaxel in patients with platinum-resistant epithelial ovarian cancer. During phase 1a, the maximum tolerated dose of intraperitoneally administered enadenotucirev monotherapy (three doses; days 1, 8 and 15) was assessed using a 3+3 dose-escalation model. Phase 1b included a dose-escalation and an intravenous dosing dose-expansion phase assessing enadenotucirev plus paclitaxel. For phase 1a/b, the primary objective was to determine the maximum tolerated dose of enadenotucirev (with paclitaxel in phase 1b). In the dose-expansion phase, the primary endpoint was progression-free survival (PFS). Additional endpoints included response rate and T-cell infiltration. Results Overall, 38 heavily pretreated patients were enrolled and treated. No dose-limiting toxicities were observed at any doses. However, frequent catheter complications led to the discontinuation of intraperitoneal dosing during phase 1b. Intravenous enadenotucirev (1×10 12 viral particles; days 1, 3 and 5 every 28-days for two cycles) plus paclitaxel (80 mg/m 2; days 9, 16 and 23 of each cycle) was thus selected for dose-expansion. Overall, 24/38 (63%) patients experienced at least 1 Grade =3 treatment-emergent adverse event (TEAE); most frequently neutropenia (21%). Six patients discontinued treatment due to TEAEs, including one patient due to a grade 2 treatment-emergent serious AE of catheter site infection (intraperitoneal enadenotucirev monotherapy). Among the 20 patients who received intravenous enadenotucirev plus paclitaxel, 4-month PFS rate was 64% (median 6.2 months), objective response rate was 10%, 35% of patients achieved stable disease and 65% of patients had a reduction in target lesion burden at =1 time point. Five out of six patients with matched pre-Treatment and post-Treatment biopsies treated with intravenous enadenotucirev plus paclitaxel had increased (mean 3.1-fold) infiltration of CD8 +T cells in post-Treatment biopsies. Conclusions Intravenously dosed enadenotucirev plus paclitaxel demonstrated manageable tolerability, an encouraging median PFS and increased tumor immune-cell infiltration in platinum-resistant ovarian cancer. Trial registration number NCT02028117. © 2021 BMJ Publishing Group. All rights reserved.

Idioma: Inglés

DOI: 10.1136/jitc-2021-003645

Año: 2021

Publicado en: Journal for immunotherapy of cancer 9, 12 (2021), e003645 [14 pp.]
ISSN: 2051-1426

Factor impacto JCR: 12.485 (2021)

Categ. JCR: ONCOLOGY rank: 25 / 245 = 0.102 (2021) - Q1 - T1
Categ. JCR: IMMUNOLOGY rank: 18 / 163 = 0.11 (2021) - Q1 - T1

Factor impacto CITESCORE: 14.3 - Biochemistry, Genetics and Molecular Biology (Q1) - Immunology and Microbiology (Q1) - Pharmacology, Toxicology and Pharmaceutics (Q1) - Medicine (Q1)

Factor impacto SCIMAGO: 3.45 - Cancer Research (Q1) - Immunology (Q1) - Pharmacology (Q1) - Oncology (Q1) - Molecular Medicine (Q1)

Tipo y forma: Article (Published version)

Área (Departamento): Area Medicina (Dpto. Medicina, Psiqu. y Derm.)