Phase I evaluation of PRGN-2009 alone and in combination with bintrafusp alfa in patients (pts) with recurrent/metastatic (R/M) HPV-associated cancers (HPV-C).

Charalampos S. Floudas Center for Immuno-Oncology, CCR, NCI, NIH, Bethesda, MD info_outline Charalampos S. Floudas, Julius Strauss, Jason M. Redman, Danielle M. Pastor, Evrim B. Turkbey, Renee N. Donahue, Caroline Jochems, Sheri McMahon, Elizabeth Lamping, Lisa M. Cordes, Seth M. Steinberg, Jenn Marte, Douglas E Brough, Amy Lankford, Jeffrey Schlom, James L. Gulley

Authors Charalampos S. Floudas Center for Immuno-Oncology, CCR, NCI, NIH, Bethesda, MD info_outline Charalampos S. Floudas, Julius Strauss, Jason M. Redman, Danielle M. Pastor, Evrim B. Turkbey, Renee N. Donahue, Caroline Jochems, Sheri McMahon, Elizabeth Lamping, Lisa M. Cordes, Seth M. Steinberg, Jenn Marte, Douglas E Brough, Amy Lankford, Jeffrey Schlom, James L. Gulley Organizations Center for Immuno-Oncology, CCR, NCI, NIH, Bethesda, MD, Radiology and Imaging Services, Clinical Center, NIH, Bethesda, MD, Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, Office of Research Nursing, OCD, NCI, NIH, Bethesda, MD, Biostatistics and Data Management Section, OCD, NCI, NIH, Bethesda, MD, Precigen, Inc., Germantown, MD Abstract Disclosures Research Funding U.S. National Institutes of Health U.S. National Institutes of Health, EMD Serono, Precigen Inc Background: Combinatorial treatments may improve efficacy in checkpoint blockade resistant (CBR) R/M HPV-C. PRGN-2009 is a gorilla adenovirus immunotherapy vaccine containing 35 non-HLA-restricted epitopes of HPV-16 and 18. We conducted a first-in-human Phase I study of PRGN-2009 alone and combined with bintrafusp alfa (BA), a bifunctional TGF-β“trap”/anti-PD-L1 fusion protein in adult pts with pretreated R/M HPV-C. We report safety and efficacy results. Methods: Pts received PRGN-2009 1x10 11 or 5x10 11 particle units (PU) SC Q2W for 3 times, then Q4W (dose escalation part, DEP) or the recommended phase 2 dose (RP2D) of PRGN-2009 plus BA 1200 mg IV Q2W (combination part, CP) until progressive disease, unacceptable toxicity or patient withdrawal. Primary endpoints were safety and RP2D; secondary endpoints included overall response rate (RECIST 1.1). Exploratory endpoints included the induction of HPV-16/18 specific T-cell responses in peripheral blood mononuclear cells collected pre- and post-PRGN-2009 treatment. Results: Between August 11, 2020, and May 5, 2022, 17 pts were enrolled. Median follow-up at data cutoff was 7.4 months and 18.6 months for the DEP and CP, respectively. In the DEP, 6 pts received PRGN-2009, for a median duration of 3.0 months (range 1.8-17.9). Five pts had ≥2 prior lines of anticancer therapy. There were no dose limiting toxicities. Adverse events (AE) related to treatment (TRAE) were Grade 1-2 flu-like syndrome, injection site reactions, fatigue, rash. 5x10 11 PU was selected as RP2D. Stable disease was noted in 4 pts, longest duration being 14.9 months. In the CP, 11 high-risk HPV positive pts received PRGN-2009 with BA for a median duration of 10.0 months (range 0.5-23.0). Four pts (36.3%) had received ≥3 prior treatment lines; 10 pts (90.9%) were CBR. Grade 3 TRAEs occurred in 1 pt (9.1%; duodenal hemorrhage [DH] attributable to BA); 2 pts (18.1%) had grade 4 TRAEs (DH, pharyngeal mucositis [n=1 each], attributable to BA). Both pts with DH were concurrently receiving NSAIDs. No treatment-related deaths occurred; one pt with DH died after refusing core standard medical management. Of 10 pts evaluable for response one CBR pt had a complete response (duration 15.3 months); partial responses were seen in two pts (one CBR). Overall response rate was 30.0% (95% CI 6.7-65.3%). Two pts were treated beyond progression without delayed response. Median overall survival was 7.4 months (95% CI, 2.9-26.8 months) for DEP and 12.5 months (95% CI, 9.6-inestimable) for CP. Post vaccination 14/16 (88%) pts developed T-cell responses to HPV-16 and/or HPV-18, with 6/6 in DEP and 8/10 in CP. Conclusions: PRGN-2009 is safe, well-tolerated, and induces HPV-specific T-cell immune responses. Further, PRGN-2009 combined with BA demonstrated clinical activity in pts with pretreated HPV-associated cancers, naïve or resistant to checkpoint blockade. Clinical trial information: NCT04432597.

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