Article ; Online: LOAd703, an oncolytic virus-based immunostimulatory gene therapy, combined with chemotherapy for unresectable or metastatic pancreatic cancer (LOKON001): results from arm 1 of a non-randomised, single-centre, phase 1/2 study.
2024 Volume 25, Issue 4, Page(s) 488–500
Abstract: Background: Pancreatic ductal adenocarcinoma is characterised by low immunogenicity and an immunosuppressive tumour microenvironment. LOAd703, an oncolytic adenovirus with transgenes encoding TMZ-CD40L and 4-1BBL, lyses cancer cells selectively, ... ...
| Abstract | Background: Pancreatic ductal adenocarcinoma is characterised by low immunogenicity and an immunosuppressive tumour microenvironment. LOAd703, an oncolytic adenovirus with transgenes encoding TMZ-CD40L and 4-1BBL, lyses cancer cells selectively, activates cytotoxic T cells, and induces tumour regression in preclinical models. The aim of this study was to evaluate the safety and feasibility of combining LOAd703 with chemotherapy for advanced pancreatic ductal adenocarcinoma. Methods: LOKON001 was a non-randomised, phase 1/2 study conducted at the Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA, and consisted of two arms conducted sequentially; the results of arm 1 are presented here. In arm 1, patients 18 years or older with previously treated or treatment-naive unresectable or metastatic pancreatic ductal adenocarcinoma were treated with standard 28-day cycles of intravenous nab-paclitaxel 125 mg/m Findings: Between Dec 2, 2016, and Oct 17, 2019, 23 patients were assessed for eligibility, leading to 22 patients being enrolled. One patient withdrew consent, resulting in 21 patients (13 [62%] men and eight [38%] women) assigned to a dose group (three to dose 1, four to dose 2, and 14 to dose 3). 21 patients were evaluable for safety. Median follow-up time was 6 months (IQR 4-10), and data cutoff was Jan 5, 2023. The most common treatment-emergent adverse events overall were anaemia (96 [8%] of 1237 events), lymphopenia (86 [7%] events), hyperglycaemia (70 [6%] events), leukopenia (63 [5%] events), hypertension (62 [5%] events), and hypoalbuminaemia (61 [5%] events). The most common adverse events attributed to LOAd703 were fever (14 [67%] of 21 patients), fatigue (eight [38%]), chills (seven [33%]), and elevated liver enzymes (alanine aminotransferase in five [24%], alkaline phosphatase in four [19%], and aspartate aminotransferase in four [19%]), all of which were grade 1-2, except for a transient grade 3 aminotransferase elevation occurring at dose 3. A maximum tolerated dose was not reached, thereby establishing dose 3 as the highest-evaluated safe dose when combined with nab-paclitaxel plus gemcitabine. Proportions of CD8 Interpretation: Combining LOAd703 with nab-paclitaxel plus gemcitabine in patients with advanced pancreatic ductal adenocarcinoma was feasible and safe. To build upon this novel chemoimmunotherapeutic approach, arm 2 of LOKON001, which combines LOAd703, nab-paclitaxel plus gemcitabine, and atezolizumab, is ongoing. Funding: Lokon Pharma, the Swedish Cancer Society, and the Swedish Research Council. |
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| MeSH term(s) | Male ; Humans ; Female ; Gemcitabine ; Oncolytic Viruses/genetics ; Bayes Theorem ; Pancreatic Neoplasms/therapy ; Pancreatic Neoplasms/drug therapy ; Paclitaxel ; Anemia/chemically induced ; Thrombocytopenia/chemically induced ; Adenocarcinoma/therapy ; Adenocarcinoma/drug therapy ; Albumins ; Genetic Therapy/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Tumor Microenvironment |
| Chemical Substances | Gemcitabine ; Paclitaxel (P88XT4IS4D) ; Albumins |
| Language | English |
| Publishing date | 2024-03-28 |
| Publishing country | England |
| Document type | Clinical Trial, Phase II ; Clinical Trial, Phase I ; Journal Article |
| ZDB-ID | 2049730-1 |
| ISSN | 1474-5488 ; 1470-2045 |
| ISSN (online) | 1474-5488 |
| ISSN | 1470-2045 |
| DOI | 10.1016/S1470-2045(24)00079-2 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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