FDA Grants Orphan Drug Designation to CF33-hNIS for Cholangiocarcinoma

The FDA has granted orphan drug designation to the novel oncolytic virotherapy CF33-hNIS (Vaxinia) for the treatment of patients with cholangiocarcinoma, according to an announcement from Imugene.¹

CF33-hNIS is a novel chimeric oncolytic poxvirus encoded with the hNIS transgene, which has been inserted in place of the viral thymidine kinase gene at the J2R locus. This is intended to reduce the replication of the virus in normal cells and produce selective replication in cancer cells, leading to tumor cell lysis.²

The agent is currently under investigation in the phase 1 MAST trial (NCT05346484) as a single agent or in combination with pembrolizumab (Keytruda) in patients with metastatic or advanced solid tumors.^1,3

“Receiving orphan drug designation from the FDA is a major milestone for us. It reflects the potential of [CF33-hNIS] to address the urgent need for new treatments for cholangiocarcinoma, a disease with limited therapeutic options. We are excited to continue advancing this program, which has already shown meaningful clinical responses in patients,” Leslie Chong, managing director and chief executive officer of Imugene, stated in a news release.¹

Previous data from MAST presented at the 2024 Gastrointestinal Cancers Symposium showed that patients treated with Cf33-hNIS monotherapy (n = 7) experienced an objective response rate (ORR) of 14% and a disease control rate of 86%. One patient with cholangiocarcinoma experienced an immunological complete response by the fourth cycle of treatment and had no known recurrence after 1 year. Another patient with bile duct cancer experienced stable disease for more than 5 months.²

MAST is enrolling patients at least 18 years of age with any metastatic or advanced solid tumor with documented radiological progression following at least 2 prior lines of therapy, which could have included an immune checkpoint inhibitor. Key inclusion criteria include an ECOG performance status of 0 to 2; at least 1 measurable lesion; and adequate renal, liver, and hematologic function.³

Patients are being excluded if they received prior treatment with a poxvirus-based oncolytic virus; are receiving continuous systemic treatment with corticosteroids or other immunosuppressive drugs within 4 weeks of first study dose; receive radiotherapy within 2 weeks of enrollment; have active autoimmune disease; underwent prior allogenic tissue or organ transplant; have inadequate pulmonary function; or have uncontrolled brain or other central nervous system metastases.

During the dose escalation portion, CF33-hNIS is being administered at 1 of 7 doses, ranging from 8.6 x 10⁵ plaque-forming units (PFU) to 3 x 10⁹ PFU. The oncolytic virus is being administered on days 1 and 8 of the first 21-day cycle, then on day 1 of each subsequent cycle. CF33-hNIS is also being evaluated at the same range of doses in combination with pembrolizumab. For the combination cohorts, pembrolizumab is being given once every 3 weeks starting on day 1 of cycle 2.2

The primary end points of the study are safety and identifying the recommended phase 2 dose. Secondary end points included ORR per RECIST 1.1 and iRECIST criteria, as well as the assessment of viral replication in tumor lesions via single-photon emission computerized tomography.

Previously reported safety data showed that CF33-hNIS monotherapy was well tolerated, and the most common treatment-related adverse effects (TRAEs) included flu-like symptoms. No dose-limiting toxicities were reported, and TRAEs did not lead to discontinuation in any patients.

The most common TRAEs included pyrexia (grade 1, 14.3%; grade 2, 28.6%), fatigue (0%; 14.3%), injection site pain (14.3%; 0%), folliculitis (0%, 14.3%), pneumonia (0%; 14.3%), pustular rash (14.3%; 0%), muscle spasms (0%; 14.3%), myalgia (0%; 14.3%), lymphadenopathy (14.3%; 0%), vomiting (14.3%; 0%), decreased appetite (14.3%; 0%), headache (0%; 14.3%), blister (14.3%; 0%), and erythema (14.3%; 0%). No grade 3 or higher TRAEs were reported.

References

1. Imugene receives orphan drug designation for treatment of bile tract cancer. News release. Imugene. September 18, 2024. Accessed September 18, 2024. https://app.sharelinktechnologies.com/announcement/asx/32f19541537309fb869a824e78f3e5e3
2. Li D, Shields AF, Mamdani H, et al. Oncolytic virus CF33-hNIS monotherapy for the treatment of gastrointestinal (GI) malignancies. J Clin Oncol. 2024;42(suppl 3):749. doi:10.1200/JCO.2024.42.3_suppl.749
3. A study of CF33-hNIS (Vaxinia), an oncolytic virus, as monotherapy or in combination with pembrolizumab in adults with metastatic or advanced solid tumors (MAST). ClinicalTrials.gov. Updated May 16, 2024. Accessed September 18, 2024. https://clinicaltrials.gov/study/NCT05346484