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).
Authors: Floudas Charalampos S. , Strauss Julius , Redman Jason M. , Pastor Danielle M. , Turkbey Evrim B. , Donahue Renee N. , Jochems Caroline , McMahon Sheri , Lamping Elizabeth , Cordes Lisa M. , Steinberg Seth M. , Marte Jenn , Brough Douglas E , Lankford Amy , Schlom Jeffrey , Gulley James L. 
Published: June 2023

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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 1x1011 or 5x1011 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. 5x1011 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 .