FDA Grants Fast Track Designation to LOAd703 in Pancreatic Cancer

• The FDA granted fast track designation to LOAd703 for treating patients with pancreatic cancer.
• LOAd703 in combination with chemotherapy is being studied in the phase 1/2 LOKON001 trial (NCT02705196) for patients with unresectable or metastatic advanced pancreatic ductal adenocarcinoma (PDAC).
• Early results showed an overall response rate (ORR) of 44% and disease control rate (DCR) of 94% among efficacy-evaluable patients, with no complete responses observed.

The FDA has granted fast track designation to LOAd703, an oncolytic adenovirus with transgenes that encode 4-1BBL and TMZ-CD40L, for the potential treatment of patients with pancreatic cancer.^1,2

LOAd703 is currently being evaluated in the phase 1/2 LOKON001 trial. Here, the agent’s safety and feasibility is being assessed when given in combination with chemotherapy for the treatment of patients with unresectable or metastatic advanced PDAC.²

According to data from arm 1 of the trial which were published in The Lancet Oncology, the ORR among the 18 patients evaluable for activity was 44% (95% CI, 25%-66%). The DCR was 94% (95% CI, 74%-99%), and no complete responses were observed. Eleven patients received dose level 3 and were evaluable for activity, and their ORR and DCR was 55% (95% CI, 28%-79%) and 91% (95% CI, 62%-98%).

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

“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,” said Åsa Holmgren, head of Regulatory Affairs at Lokon Pharma AB, in a press 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.”

With a median follow-up of 6 months (interquartile range, 4-10), 18 patients were evaluated for dose-limiting toxicities (DLTs). No DLTs were observed at dose levels 1 or 2. Among the 11 patients treated at dose level 3, one experienced a DLT, consisting of a transient grade 3 elevation in alanine aminotransferase (ALT) levels following LOAd703 injection into a liver metastasis. This patient continued on protocol treatment at a reduced LOAd703 dose without any further DLTs.

For safety, the most common adverse events (AEs) linked to LOAd703 treatment included fever (67%), fatigue (38%), chills (33%), and elevated liver enzyme levels (ALT, 24%; alkaline phosphatase, 19%; aspartate aminotransferase, 19%). All AEs related to LOAd703 were grade 1 or 2, except for a single transient grade 3 elevation in aminotransferase levels observed at dose level 3.

Additionally, no patients discontinued treatment or experienced fatal adverse events related to LOAd703. The maximum tolerated dose was not identified, with dose level 3 determined as the highest safe dose when LOAd703 was combined with gemcitabine and nab-paclitaxel.

“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,” added Holmgren in the press 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."

cancer of pancreas : © Dr_Microbe - stock.adobe.com

About the Phase 1/2 Trial of LOAd703

In the phase 1/2 LOAd703 trial, patients with unresectable or metastatic advanced PDAC aged 18 years and older with treatment-naive or previously treated unresectable or metastatic PDAC were eligible for enrollment in the study if they had a low tumor burden with at least 1 lesion that is amenable to image-guided intratumoral injection and needle biopsy.³ 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.

Additional enrollment criteria requires patients to be eligible for standard-of-care gemcitabine plus nab-paclitaxel (Abraxane), have an ECOG performance status of 0 to 2, have adequate hepatic and renal function, 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.

Arm 1 of the study gave patients standard intravenous nab-paclitaxel at a dose of 125 mg/m² and gemcitabine at a dose of 1000 mg/m² on days 1, 8, and 15 of each 28-day cycle, combined with LOAd703. LOAd703 was administered every other week for 6 doses, starting on day 15 of the first chemotherapy cycle. Patients who demonstrated benefit from LOAd703 were eligible for an additional 6 doses. LOAd703 was delivered 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 of the study is the number of patients with DLTs and secondary end points include ORR per RECIST 1.1 criteria and OS.

Between December 2, 2016, and October 17, 2019, a total of 22 patients were included in arm 1.² One patient withdrew consent. The remaining 21 patients were assigned to dose levels 1 (n = 3), 2 (n = 4), and 3 (n = 14). Now, arm 2 of the trial evaluating LOAd703 plus atezolizumab (Tecentriq) is ongoing and open to enrollment.

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 17, 2025. https://tinyurl.com/4cbcwdcs

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 17, 2025. https://clinicaltrials.gov/study/NCT02705196