A Randomized, Open-label, Two-arm, Multicenter Phase 2 Study to Evaluate Efficacy and Safety of PRGN-2009 in Combination With Pembrolizumab Versus Pembrolizumab Monotherapy in Patients With Recurrent or Metastatic Cervical Cancer.

This randomized trial will evaluate the efficacy and safety of PRGN-2009 in combination with pembrolizumab compared to pembrolizumab alone in patients with pembrolizumab-resistant recurrent or metastatic cervical cancer.

More details:

This is a randomized, two-arm study of PRGN-2009 in patients with recurrent or metastatic cervical cancer who are pembrolizumab resistant. Patients meeting all eligibility criteria who consent to participate in the study will be randomized 1:1 to receive a combination of PRGN-2009, plus pembrolizumab, or to receive pembrolizumab alone.

Overview

PRGN-2009 is an investigational, off‑the‑shelf therapeutic cancer vaccine built on a replication‑defective gorilla adenoviral vector (AdenoVerse/GC46) designed to elicit T‑cell responses against high‑risk human papillomavirus (HPV) oncoproteins. It is being studied across HPV‑associated malignancies, including recurrent/metastatic disease and in neoadjuvant settings. (pmc.ncbi.nlm.nih.gov)

Mechanism of action

• Vector/platform: nonreplicating gorilla adenovirus (GC46) engineered with deletions in E1/E4, allowing repeated dosing with minimal impact from anti‑vector antibodies. (pmc.ncbi.nlm.nih.gov)
• Antigen design: encodes multiple non‑HLA‑restricted cytotoxic T‑cell epitopes from HPV16/18 E6 and E7; the first‑in‑human study also describes targeting HPV16 E5. Resulting vaccination expands multifunctional HPV‑specific CD8+ and CD4+ T cells and increases intratumoral T‑cell infiltration in preclinical models. (pmc.ncbi.nlm.nih.gov)

Efficacy

Phase 1 (NCT04432597), first‑in‑human, at the NCI: - Monotherapy (n=6): no objective responses; disease control included durable stable disease in some patients. (ascopubs.org) - Combination with bintrafusp alfa (anti‑PD‑L1/TGF‑β trap) (n=11; 10 evaluable):
- Peer‑reviewed report (2025): ORR 20% (2/10; 1 complete response [CR], 1 partial response [PR]); median overall survival (OS) 24.6 months (95% CI 9.6–not reached). HPV‑specific T cells increased or were induced in 80% of patients. (pmc.ncbi.nlm.nih.gov)
- ASCO 2023 meeting abstract: ORR 30% (95% CI 6.7–65.3) among 10 evaluable patients; one CR and two PRs reported at that cutoff; 88% (14/16) developed HPV16/18‑specific T‑cell responses across arms. Note: subsequent peer‑reviewed publication above reports ORR 20%. (ascopubs.org)

Ongoing phase 2 studies: - Recurrent/metastatic cervical cancer, pembrolizumab‑resistant (randomized PRGN‑2009+pembrolizumab vs pembrolizumab; NCT06157151). Status: recruiting; key eligibility includes PD‑L1+ and HPV16/18+ tumors. (ichgcp.net, cdek.pharmacy.purdue.edu) - Neoadjuvant PRGN‑2009+pembrolizumab in newly diagnosed HPV‑associated oropharyngeal cancer (single‑arm; NCT05996523); primary endpoint is ≥2‑fold increase in tumor‑infiltrating CD3+ T cells. (ascopubs.org, ichgcp.net)

Safety

• Monotherapy: no dose‑limiting toxicities (DLTs); treatment‑related adverse events (TRAEs) mostly grade 1–2 (flu‑like symptoms, injection‑site reactions, fatigue, rash). (ascopubs.org)
• Combination with bintrafusp alfa: grade 3/4 TRAEs occurred in 27% of patients in the peer‑reviewed report; overall safety considered manageable. The ASCO 2023 abstract notes grade 3 duodenal hemorrhage and grade 4 duodenal hemorrhage/pharyngeal mucositis events attributed to bintrafusp alfa; both hemorrhage cases were on concurrent NSAIDs. No treatment‑related deaths were reported. (pmc.ncbi.nlm.nih.gov, ascopubs.org)

Further reading

• Preclinical characterization of PRGN‑2009 (JCI Insight, 2021). (pmc.ncbi.nlm.nih.gov)
• Phase 1 clinical trial: PRGN‑2009 ± bintrafusp alfa (Cancer Immunology, Immunotherapy, 2025). (pmc.ncbi.nlm.nih.gov)
• ASCO 2023 meeting abstract for Phase 1 PRGN‑2009 ± bintrafusp alfa (JCO abstract). (ascopubs.org)
• Phase 2 randomized study in pembrolizumab‑resistant cervical cancer (NCT06157151). (ichgcp.net, cdek.pharmacy.purdue.edu)
• Neoadjuvant PRGN‑2009 + pembrolizumab in oropharyngeal cancer (NCT05996523; ASCO 2024 TPS). (ascopubs.org)

Notes: All efficacy data to date are from early‑phase studies with small cohorts; magnitudes and durability of benefit remain to be confirmed in randomized trials. (pmc.ncbi.nlm.nih.gov, ascopubs.org)

Last updated: Sep 2025

Inclusion Criteria:

* Age 18 years and older.

* Recurrent or metastatic cervical cancer (histologically or cytologically confirmed) that meets the criteria of pembrolizumab-resistant.

* Must have been treated with pembrolizumab, either as monotherapy or in combination

* Patients must have received no more than two prior systemic regimens in the recurrent or metastatic setting

* Tumors are confirmed positive for PD-L1 and HPV16/18

* Measurable disease that can be accurately measured by RECIST v1.1 criteria

* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

* Life expectancy ≥ 12 weeks from the time of enrollment.

* Must have adequate organ function

* Negative serum pregnancy test. Women of child-bearing potential (WOCBP) must agree to use adequate contraception prior to study entry and for at least 6 months following completion of study treatment.

* All patients must have the ability to understand and willingness to sign a written informed consent.

Exclusion Criteria:

* Patients with presence of other active malignancy within 1 year prior to study entry

* Known Central Nervous System (CNS) disease

* Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.

* Known history of active tuberculosis (TB, Bacillus tuberculosis).

* Pregnant and lactating women are excluded from this study.

* Patients with a history of solid organ transplant.

* Patients currently participating in a study of an investigational agent or have used an investigational device within 4 weeks prior to the first dose of study treatment.

* Patients, who in the opinion of the investigator, may not be able to comply with the monitoring requirements of the study.