FDA Grants Orphan Drug Designation to Ilixadencel for Soft Tissue Sarcoma

The FDA has granted the cell-based, off-the-shelf immune primer ilixadencel an orphan drug designation for use as a treatment option in patients with soft tissue sarcoma (STS), according to an announcement from Immunicum AB.¹

The decision was based on findings from a phase 1/2 trial (NCT02432846) evaluating the agent in patients with gastrointestinal stromal tumors (GIST). When paired with different TKIs, ilixadencel was found to have a promising toxicity profile with no treatment-related serious toxicities observed, meeting the primary safety end point of the trial.² Moreover, the addition of the agent to a TKI resulted in reduction in tumor size in 2 of 6 patients, despite prior progression on the same TKI.

Moreover, 2 of the 6 patients were found to have partial responses (PRs) to the treatment per Choi response criteria; this equated to a 33% objective response rate in this population. One of the 2 patients achieved disease stability for 9 months on third-line regorafenib (Stivarga), while the other had stable disease for 12 months on second-line sunitinib (Sutent). The PRs achieved with the ilixadencel combination suggest that the agent helped to overcome resistance to TKIs in these patients who had experienced progressive disease on prior TKIs.

“Although the GIST study was a trial with few patients enrolled, they were all at an advanced disease stage, meaning that both the safety data and the signals of clinical efficacy are encouraging and support ilixadencel’s potential as a safe and effective cell-based cancer immune primer,” Alex Karlsson-Para, MD, PhD, CSO and interim CEO of Immunicum, stated in a press release. “The publication of our clinical results in a peer reviewed journal further validates the quality of the data generated from our clinical study.”

In the single-arm, open-label phase 1 trial, which was published in Cancer Immunology, Immunotherapy, investigators evaluated the safety and efficacy of ilixadencel in patients with advanced/metastatic GIST who had experienced disease progression on second or later lines of TKI treatment.³

To be eligible for enrollment, patients had to be at least 18 years of age, have a diagnosis of unresectable or metastatic GIST that had progressed on treatment with a TKI, and have a lesion that was at least 3 cm in longest unidimensional diameter. If patients had an ECOG performance status of greater than 2 or abnormal hematological parameters, they could not participate.

The mean age of participants was 57 years. Three patients had an ECOG performance status of 1, 1 patient had a status of 1, and 2 patients had a status of 2. All participants had previously received TKI treatment with either 2 drugs (50%), 3 drugs (16.7%), or 4 drugs (33.3%). Three patients progressed on second-line sunitinib, 1 on third-line regorafenib, and 2 on fourth-line pazopanib (Votrient). Four patients had liver or abdominal cavity metastases, while 2 had unresectable disease.

Investigators selected the dosing regimen based on data yielded from a prior first-in-human trial that was conducted in patients with metastatic renal cell carcinoma (RCC). In that trial, a low dose of 5 x 10⁶, a medium dose of 10 x 10⁶, and a high dose of 10 x 10⁶ were evaluated. Taking into account safety, as well as efficacy and immunological parameters, investigators selected the medium dose for the trial examining the agent in patients with GIST.

In the trial, patients received a first injectable dose of ilixadencel which contained 10 x 10⁶ viable HLA-DR+ cells on day 1; the second dose was given on day 14 +/- 3 days. Notably, the starting dose for ilixadencel could be reduced to 5 x 10⁶ cells for patients who experienced limiting toxicities (LTs).

The primary objective of the trial was to examine the toxicity profile of ilixadencel and determine any LTs. Secondary objectives comprised tumor response via computed tomography, progression-free survival (PFS), changes in performance status, and the examination of possible auto- and alloimmunization.

Additional results showed that 3 patients experienced disease progression at 3 months per RECIST v1.1 and Choi criteria. One patient had clinical deterioration; results from a CT scan conducted after 2 months revealed disease progression.

The median PFS observed on the trial was 4.0 months (95% CI, 3.2-4.8), while the median overall survival was 19.0 months (95% CI, 11.8-26.2).

Notably, 1 participant experienced a change in ECOG performance status, going from a score of 2 at the time of screening to 3 at the last time point evaluated. All other participants maintained their performance status. Five patients experienced progressive disease. Four patients experienced progression at 3 months, 1 did at 9 months, and 1 patient had stable disease until the end of the trial.

Regarding safety, 5 of the 6 patients reported 19 toxicities; the majority of these were only grade 1 in severity (66.7%). About 33% of patients experienced grade 2 effects, and 16.7% of patients had a grade 3 effect. The toxicities associated with ilixadencel included fever and chills (50%), abdominal pain (33%), and discomfort at the injection site (17%).

The grade 3 toxicity reported on the trial was associated with general health deterioration; it was not associated with study treatment. All toxicities associated with ilixadencel were found to be transient and had resolved before the end of the trial. No dose reductions were required.

In May 2020, ilixadencel was granted a Regenerative Medicine Advanced Therapy designation from the FDA for use in patients with RCC. A few months later, in December 2020, the agent received a fast track designation for use in the treatment of patients with GIST.

References

1. Immunicum AB (publ) receives FDA orphan drug designation for ilixadencel as a treatment of soft tissue sarcomas (STS). News release. Immunocum AB. January 26, 2021. Accessed January 26, 2021. http://bit.ly/36cWET6.
2. Immunicum AB (publ) announces publication of phase I/II clinical trial results of ilixadencel in gastrointestinal stromal tumors (GIST) in Cancer Immunology, Immunotherapy. News release. Immunicum AB. June 16, 2020. Accessed January 26, 2021. http://bit.ly/2YjakHS.
3. Fröbom R, Berglund E, Berglund D, et al. Phase I trial evaluating safety and efficacy of intratumorally administered inflammatory allogeneic dendritic cells (ilixadencel) in advanced gastrointestinal stromal tumors. Cancer Immunol Immunother. 2020;69(11):2393-2401. doi:10.1007/s00262-020-02625-5