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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
50
PRGN-2012 (5x10\^11 PU) will be administered on Days 85, 100, 128, and 170.
Administration of IV bevacizumab will be done on D1, D22, D43, D85, and D170 at a dose of 10 mg/kg during Course 1 (and Course 2 if applicable).
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
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-...
Determined by measuring the number of participants (evaluable for clinical response) who do not require an intervention (either medical or surgical) in the 12 months following completion of treatment. This fraction of participants who are classified as having a complete response at 12 months will be reported along with 80% and 95% two-sided confidence intervals. For participants receiving re-treatment, any increase in their treatment-free interval following re-treatment will not be used for evaluation of the primary endpoint.
Time frame: From baseline to 12 months after treatment
To determine the recurrence-free interval of laryngotracheal papillomatous disease after combination treatment
The time to recurrence of papillomatous disease after completion of treatment will be recorded and reported descriptively.
Time frame: Baseline through 3 years after treatment
To determine the safety of the combination of bevacizumab and PRGN-2012
AEs will be reported by type and grade.
Time frame: Between the first dose of drug on D1 through 6 weeks, as well as on the 6-week safety follow-up visit. After 6-week safety follow-up visit, only adverse events that are serious and related to the study interventions
To determine the treatment-free interval (either medical or surgical) after completion of treatment with combination systemic bevacizumab and PRGN-2012
Reported descriptively by measuring the duration between completion of combination treatment and the time to the requirement of the first clinical intervention (either medical or surgical) following completion of protocol therapy.
Time frame: Up to 3 years after treatment
To determine the overall response rate (ORR) of pulmonary RRP defined as complete response (CR) and partial response (PR) by RECIST 1.1 in participants with measurable pulmonary disease after combination treatment
The fraction of participants with a pulmonary RRP partial response and a pulmonary RRP complete response will be reported in all treated pulmonary participants, along with 95% confidence intervals for each.
Time frame: Baseline and 6 weeks after completion of treatment
To determine the treatment-free interval (either medical or surgical) after completion of retreatment with combination systemic bevacizumab and PRGN-2012
Reported descriptively following completion of protocol retreatment.
Time frame: Baseline through 3 years after treatment
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