A phase I/II study of LOAd703, a TMZ-CD40L/4-1BBL-armed oncolytic adenovirus, combined with nab-paclitaxel and gemcitabine in advanced pancreatic cancer

Autor: Benjamin Leon Musher, Brandon George Smaglo, Wasif Abidi, Mohamed Othman, Kalpesh Patel, Salmaan Jawaid, James Jing, Amanda Brisco, Jessica Wenthe, Emma Eriksson, Gustav J. Ullenhag, Linda Sandin, Bambi Grilley, Justyna Leja-Jarblad, Susan G. Hilsenbeck, Malcolm K. Brenner, Eric Keith Rowinsky, Angelica Sara Ingrid Loskog
Rok vydání: 2022
Předmět:
Zdroj: Journal of Clinical Oncology. 40:4138-4138
ISSN: 1527-7755
0732-183X
Popis: 4138 Background: Due to its low tumor immunogenicity and immunosuppressive microenvironment, pancreatic ductal adenocarcinoma (PDAC) remains an immunotherapeutic challenge. LOAd703, an oncolytic adenovirus with transgenes encoding TMZ-CD40L and 4-1BBL, has been shown to lyse tumor cells selectively, induce anti-tumor cytotoxic T-cell responses, reduce myeloid-derived suppressor cell (MDSC) infiltration, and induce tumor regression in preclinical studies. Methods: In this phase I/II trial, patients with unresectable or metastatic PDAC were treated with intratumoral injections of LOAd703 and standard intravenous nab-paclitaxel/gemcitabine (nPG) chemotherapy. Starting on cycle 1 day 15 of nPG, LOAd703 was injected with image guidance into the primary pancreatic tumor or a metastasis every 2 weeks for 6 injections. In the event of sustained tumor control, subjects were eligible to receive up to 6 more injections. Three dose levels of LOAd703 were investigated using a BOIN dose escalation design. Primary endpoints were safety and feasibility. Results: Of the 22 subjects enrolled, 21 received at least 1 LOAd703 injection, and 18 received at least 3 LOAd703 injections (the a priori definitions of evaluability for dose limiting toxicity [DLT] and efficacy, respectively). Of the 21 subjects injected, median age was 61, 81% had stage IV disease, and 57% had already received chemotherapy for advanced disease. Median CA 19-9 was 1494. Of the 18 response evaluable subjects, 3 were treated at dose level 1 (5x10e10 VP), 4 at dose level 2 (1x10e11 VP), and 11 at dose level 3 (5x10e11 VP). The most common adverse events (AEs) attributable to LOAd703 were fever, chills, nausea, and increased liver enzymes. AEs were short-lived and grade 1/2, except for a grade 3 transaminase elevation in one subject receiving dose level 3 (the only DLT). Objective response rate (ORR) among those treated at the highest dose level was 55% (5/11 subjects), thus meeting the predefined criterion for efficacy. Among all response evaluable patients, overall response rate (ORR) was 44%, and disease control rate (DCR) was 94%. CA 19-9 decreased by ≥50% in 61% of evaluable patients. Median overall survival (OS) among the 21 subjects receiving at least 1 LOAd703 injection was 8.7 months. The proportion of T effector memory cells increased after initiation of on-protocol treatment (p = 0.0232) while the proportion of T regulatory cells and myeloid-derived suppressor cells decreased (p = 0.0410, p = 0.0256, respectively). Conclusions: Combining intratumoral injections of LOAd703 with standard nPG chemotherapy was safe and feasible. The target response rate at the highest dose level was met, and treatment-emergent immune responses were observed. A follow-up clinical trial combining LOAd703, nPG, and the anti-PDL-1 inhibitor atezolizumab is underway. Clinical trial information: NCT02705196.
Databáze: OpenAIRE
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