Combination Bevacizumab and PRGN-2012 in Adults With Recurrent Respiratory Papillomatosis (RRP)

Human Papillomavirus (HPV), Laryngeal Diseases, Papillomavirus Infection, Respiratory Recurrent Papillomatosis (RRP), Respiratory Tract Neoplasm, Tracheal Diseases

HPV Vaccine, Gardasil, Papzimeos (zopapogene imadenovec-drba), Bevacizumab (Avastin)

Background: Recurrent respiratory papillomatosis (RRP) is a rare disease that causes wart-like growths called papillomas to grow in the airway, most often in the voice box, windpipe, or lungs. These growths can make it hard to speak or breathe. Surgery can remove the papillomas, but they often come back. In some cases, they can become cancerous. Objective: This study istesting whether two treatments used together (PRGN-2012, a vaccine-based treatment and bevacizumab, a drug that affects blood vessel growth) can help control RRP and reduce the chance that papillomas will grow back. Eligibility: Adults aged 18 years and older may be able to join the study if they have RRP and meet certain treatment history requirements. This may include people who have previously received PRGN-2012 or bevacizumab, or people who have needed more than 2 surgeries to remove papillomas. Design: Before starting treatment, participants will have screening tests to make sure the study is safe for them. These tests may include a physical exam with blood and urine tests, heart function testing, imaging scans, and an endoscopy. During an endoscopy, a thin, flexible tube with a small camera will look at the inside of the nose, throat, voice box, and upper windpipe. Participants will receive study treatment during 7 clinic visits over about 6 months. Bevacizumab is given through a vein amd PRGEN-2012 is given as an injection under the skin of the arm or leg. Participants may receive 1 or both drugs at each visit. After completing treatmen, participants will return for 4 follow-up visits over 1 year. These visits may include repeat imaging, blood and urine tests, and other exams. After that, the study team will contact participantsby phone or email every 3 months for 2 years. If their RRP gets worse during the follow-up period, they may be able to receive a second course of treatment using the same schedule....

Background: * Recurrent respiratory papillomatosis (RRP) is a rare papillomatous disease of the respiratory tract caused by Human Papilloma Virus (HPV) types 6 or 11. * RRP can progress to cause severe voice disturbance, airway compromise, fatal pulmonary lesions, and, rarely, invasive cancers. * Our group conducted the pivotal phase 1/2 clinical study of PRGN-2012 (NCT04724980), a gorilla adenovirus vector-based gene therapy capable of eliciting HPV6/11-specific T cell immunity. * The study was found to be positive, and a Biologics License Application (BLA) submission for this agent was accepted by the US Food and Drug Administration (FDA). On August 15th, 2025, the FDA granted full approval of PRGN-2012, making it the first FDA-approved medical therapy for adult patients with RRP. Unfortunately, 50% of study participants did not achieve a complete response in the pivotal study, indicating that additional research into therapeutic strategies is still needed. * We are currently conducting a phase 2 clinical trial of bevacizumab (NCT00803062) to assess the safety and clinical benefit of this agent in adults with RRP. * Bevacizumab has demonstrated an acceptable safety profile with consistent and rapid clinical benefit by significantly reducing papillomatous disease burden and eliminating the need for clinical interventions in 20 consecutively treated patients. Unfortunately, disease regrowth occurs following cessation of bevacizumab therapy, and prolonged treatment can lead to systemic toxicity. * Community physicians will soon be using both PRGN-2012 and systemic bevacizumab in clinical practice, but the combined safety and appropriate sequencing of these agents has yet to be studied. Objective: -To determine the complete response rate, defined as the percentage of participants who do not require an intervention (either medical or surgical) in the 12 months following completion of treatment with combination systemic bevacizumab and PRGN-2012 Eligibility: * Histologically or cytologically confirmed diagnosis of RRP * Age \>= 18 years old * A history of 2 or more surgeries or use of IV bevacizumab in the last 12 months to control laryngeal and/or tracheal RRP * Previous treatment with PRGN-2012 (zopapogene imadenovec \[Papzimeos\]) Design: * This is phase II, single-arm clinical trial evaluating the combination of systemic bevacizumab and PRGN-2012. * All participants will receive monotherapy with bevacizumab alone for every 3 weeks for 3 doses followed by bevacizumab in combination with PRGN-2012 (2 doses) and PRGN- 2012 alone (2 doses). * Participants will be assessed for papilloma recurrence at 6, 12, 24, 52 weeks, and every 3 months for an additional 2 years following completion of treatment (total follow-up of 3 years). * A total of 21 evaluable participants will be treated in the study.

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