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

Abstract

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 (1×1012 viral particles; days 1, 3 and 5 every 28-days for two cycles) plus paclitaxel (80 mg/m2; 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.

Keywords: clinical trials as topic; immunotherapy; investigational; oncolytic viruses; therapies.

Conflict of interest statement

Competing interests: VM: Consulting fees: Roche, Bayer, Pieris, Bristol Myers Squibb, Janssen, Basilea. Regeneron/Sanofi, Bayer, Nanobiotix; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Bristol Myers Squibb, Bayer; participation on a Data Safety Monitoring Board or Advisory Board: Bristol Myers Squibb; M-PB-G: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AstraZeneca, MSD, GlaxoSmithKline, Clovis, Pharmamar, Roche; Support for attending meetings and/or travel: AstraZeneca, Roche, MSD, Pharmamar, GlaxoSmithKline; participation on a Data Safety Monitoring Board or Advisory Board: AstraZeneca, MSD, GlaxoSmithKline, Clovis, Pharmamar, Roche; JG-D: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AstraZeneca, Bristol Myers Squibb, Pfizer, Astellas; Support for attending meetings and/or travel: Roche; GCJ and IM: nothing to declare; PR: Institutional grant/contract: PsiOxus Therapeutics Ltd, Tesaro, GlaxoSmithKline; consulting fees: Tesaro, GlaxoSmithKline; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Tesaro, GlaxoSmithKline, AstraZeneca; Support for attending meetings and/or travel: Tesaro, GlaxoSmithKline, AstraZeneca; Participation on a Data Safety Monitoring Board or Advisory Board: Tesaro, GlaxoSmithKline, AstraZeneca; provided drugs to the health board: Tesaro, GlaxoSmithKline, Novartis. RMV: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Roche, GlaxoSmithKline, Pharmamar, AstraZeneca; Support for attending meetings and/or travel: Roche, GlaxoSmithKline, Pharmamar; Participation on a Data Safety Monitoring Board or Advisory Board: GlaxoSmithKline, Pharmamar, AstraZeneca; AM: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Ipsen, GlaxoSmithKline, Clovis; Support for attending meetings and/or travel: Merck, Tesaro; Participation on a Data Safety Monitoring Board or Advisory Board: Tesaro, ESAI, GlaxoSmithKline, Clovis; AA-T: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Roche; Payment for expert testimony: Pfizer; Participation on a Data. Safety Monitoring Board or Advisory Board: Bayer Hispania; RB, DK and BC: employees of and hold share options in PsiOxus Therapeutics.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1

OCTAVE study design (A) and patient disposition (B). (A) IP enadenotucirev monotherapy escalation (phase 1a) was conducted in parallel with the phase 1a combination dose-escalation, starting when the first feasible level of enadenotucirev monotherapy was determined in Phase Ia. In the combination therapy cohorts, paclitaxel was given on days 9, 16 and 23 of each cycle. (B) OCTAVE study patient disposition. aPlanned dose level of 1×1013. EnAd, enadenotucirev; IP, intraperitoneal; IV, intravenous; PD, progressive disease; vp, viral particle.

Figure 2

Progression-free survival (PFS) per independent review (A) and long-term follow-up for overall survival (OS) (B) (patients receiving intravenous enadenotucirev plus paclitaxel). NA, not available.

Figure 3

Change in target lesion burden over time (A) and best change in target lesion burden (B) per Independent assessment (RECIST V.1.1; patients receiving intravenous enadenotucirev plus paclitaxel). Evaluable patients: n=17. (A) Percentage change from baseline in target lesion burden over time in the phase 1b intravenous enadenotucirev plus paclitaxel cohort. Each line represents an individual patient. (B) Best percentage change from baseline in target lesion burden (sum of diameters of target lesions per RECIST V.1.1) according to Independent review. Dashed line indicates 30% decrease in target lesion burden. Each bar represents an individual patient. *Patient achieved PR at one assessment, but then had new lesion progression on the confirmatory scan so response was categorized as PD. PD, progressive disease; PR, partial response.

Figure 4

T-cell infiltration and cytotoxic activity after enadenotucirev treatment. Representative pre-treatment (A) and post-treatment (B) biopsy samples after immunohistochemistry (IHC) staining for intratumoral CD8+ T cells (shown in brown). Post-treatment biopsies were taken ~5 weeks after first enadenotucirev dosing. Automated imaging analysis was performed for the six patients treated with enadenotucirev intravenous plus paclitaxel to quantify CD8 +T cell tumor infiltration (C) and percentage of CD8 +cells which were also granzyme B+ (D).