LOAd703 Oncolytic Adenovirus Receives FDA Fast Track Designation for Pancreatic Cancer

The FDA has granted fast track designation to LOAd703 for the treatment of patients with pancreatic cancer.1

LOAd703 is an oncolytic adenovirus with transgenes that encode 4-1BBL and TMZ-CD40L.2 In preclinical models, this immunostimulatory gene therapy has been shown to selectively lyse cancer cells, activate cytotoxic T cells, and induce tumor regression.

“We are excited to share the news that LOAd703 has been granted fast track designation by the FDA. A fast track designation is intended to expedite the development and review of drugs that have the potential to fill an unmet medical need in treating serious conditions,” Åsa Holmgren, head of Regulatory Affairs at Lokon Pharma AB, stated in a news release.1 “Lokon will now benefit from more frequent interactions with the FDA, and if relevant criteria are met, LOAd703 may be eligible for additional expedited programs offered by the FDA to make LOAd703 available to patients as soon as possible.”

The phase 1/2 LOKON001 trial (NCT02705196) is evaluating the safety and feasibility of LOAd703 in combination with chemotherapy for patients with unresectable or metastatic advanced pancreatic ductal adenocarcinoma (PDAC).2

Findings from arm 1 of the trial were published in April 2024 in The Lancet Oncology. Among the 18 patients evaluable for activity, the overall response rate (ORR) was 44% (95% CI, 25%-66%), and the disease control rate (DCR) was 94% (95% CI, 74%-99%). No complete responses were observed. Among the 11 patients who received dose level 3 and were evaluable for activity, the ORR was 55% (95% CI, 28%-79%), and the DCR was 91% (95% CI, 62%-98%).

Of all efficacy-evaluable patients, the median overall survival (OS) was 9.3 months (95% CI, 6.2-13.6), the median progression-free survival was 5.4 months (95% CI, 4.0-7.5), and the 12-month OS rate was 35% (95% CI, 14%-57%). The median OS in the safety population (n = 21) was 8.7 months (95% CI, 6.0-12.7). At the data cutoff date of January 5, 2023, all patients with known survival status had died due to disease progression.

LOKON001 Trial Overview

This trial is enrolling patients at least 18 years of age with treatment-naive or previously treated unresectable or metastatic PDAC.3 Low tumor burden with at least 1 lesion that is amenable to image-guided intratumoral injection and needle biopsy is required. Patients must not be eligible for complete surgical resection of their disease, and those who planned to receive endoscopic injections should be eligible for sedation. Patients are also required to be eligible for standard-of-care gemcitabine plus nab-paclitaxel (Abraxane); have an ECOG performance status of 0 to 2; and have an absolute neutrophil count of at least 1.0 x 109/L, hemoglobin levels of at least 9 g/dL, platelet counts of at least 100 x 109/L, prothrombin levels of less than 1.5 INR, and adequate hepatic and renal function.

In arm 1, patients received standard intravenous nab-paclitaxel at 125 mg/m2 plus gemcitabine at 1000 mg/m2 on days 1, 8, and 15 of each 28-day cycle in combination with LOAd703, which was administered every other week for 6 doses starting on day 15 of the first chemotherapy cycle. Patients who benefitted from LOAd703 treatment were eligible to receive an additional 6 doses. LOAd703 was administered at 1 of 3 dose levels: 5 x 1010 viral particles per treatment (dose level 1), 1 x 1011 viral particles per treatment (dose level 2), or 5 x 1011 viral particles per treatment (dose level 3).

The primary end point is the number of patients with dose-limiting toxicities (DLTs). Secondary end points include ORR per RECIST 1.1 criteria and OS.

Between December 2, 2016, and October 17, 2019, 22 patients were enrolled to arm 1.2 One patient withdrew consent, and the 21 remaining patients were assigned to dose levels 1 (n = 3), 2 (n = 4), and 3 (n = 14).

Safety Data and Next Steps

At a median follow-up of 6 months (interquartile range, 4-10), 18 patients were evaluable for DLTs. No DLTs were reported in patients who received dose levels 1 or 2. One of the patients who received dose level 3 (n = 11) experienced a DLT; this consisted of a brief grade 3 elevation in alanine aminotransferase (ALT) levels after LOAd703 injection into a liver metastasis. This patient continued to receive on-protocol treatment with a lower dose of LOAd703 and had no further DLTs.

The most common adverse effects (AEs) attributed to LOAd703 were fever (67%), fatigue (38%), chills (33%), and elevated liver enzyme levels (ALT, 24%; alkaline phosphatase, 19%; aspartate aminotransferase, 19%). All LOAd703-related AEs were grade 1/2, except for 1 transient grade 3 aminotransferase level elevation event that occurred at dose level 3. No patients discontinued treatment or died due to LOAd703-related AEs. The maximum tolerated dose was not reached, and dose level 3 was established as the highest-evaluated safe dose when LOAd703 was combined with gemcitabine and nab-paclitaxel.

Arm 2 of the trial, which is evaluating LOAd703 plus atezolizumab (Tecentriq), is ongoing and open to enrollment.

“Pancreatic cancer is a remaining challenge within immuno-oncology. Lokon’s LOAd703 gene engineers the tumor microenvironment to express strong immune activators and thereby induces an inflammation that can sensitize these patients to traditional immunotherapy with checkpoint blockade antibodies,” Holmgren concluded in the news release.1 “LOAd703 is currently evaluated in combination with gemcitabine and nab-paclitaxel plus an anti-PD-L1 antibody in pancreatic cancer, and a randomized phase 2 study is on the way."

References

1. Lokon Pharma receives FDA fast track designation for LOAd703 for the treatment of pancreatic cancer. News release. Lokon Pharma AB. January 10, 2025. Accessed January 15, 2025. https://www.mynewsdesk.com/lokon-pharma-ab/pressreleases/lokon-pharma-receives-fda-fast-track-designation-for-load703-for-the-treatment-of-pancreatic-cancer-3363162
2. Musher BL, Rowinsky EK, Smaglo BG, et al. 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. Lancet Oncol. 2024 Apr;25(4):488-500. doi:10.1016/S1470-2045(24)00079-2
3. LOAd703 oncolytic virus therapy for pancreatic cancer. ClinicalTrials.gov. Updated February 1, 2024. Accessed January 16, 2025. https://clinicaltrials.gov/study/NCT02705196