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

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.

• INCLUSION CRITERIA:
• Histological or cytological diagnosis of RRP confirmed by pathology report. Note: If there is no documentation or archival sample, a biopsy will be done to confirm the diagnosis.
• Age >= 18 years old.
• A history of 2 or more surgeries or use of IV bevacizumab in order to control laryngeal and/or tracheal RRP within 12 months prior to the study treatment initiation.
• Previous treatment with PRGN-2012 (zopapogene imadenovec [Papzimeos]).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Participants must have an adequate organ and marrow function as defined below:

• White blood cells (WBC) >2,000/mcL
• Absolute neutrophil count (ANC) >= 1,000/mcL
• Hemoglobin > 9.0 g/dL
• Platelets >= 100,000/mcL
• Total bilirubin <= 1.5 mg/dL. Note: participants with Gilbert s Syndrome must have a total bilirubin < 3.0 mg/dL
• Aspartate aminotransferase (AST) <= 2.5 X institutional upper limit of normal (ULN)
• Alanine aminotransferase (ALT) <=2.5 X institutional ULN
• Creatinine within normal institutional limits OR Creatinine Clearance (CrCl) >= 60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal (calculated using the Cockcroft-Gault formula).
• Prothrombin time (PT) / International normalized ratio (INR) and Partial thromboplastin time (PTT) <= 1 X institutional ULN. In participants on anticoagulation, coagulation tests should be within a therapeutic range.
• Urinalysis Urine dipstick < 2+ proteinuria. Participants with >= 2+ proteinuria on dipstick urinalysis should undergo a 24- hour urine collection and must demonstrate <= 1g of protein in 24 hours to be eligible
• Women of child-bearing potential (WOCBP) must agree to use a highly effective method of contraception (hormonal, intrauterine device (IUD), surgical sterilization, abstinence) for the duration of treatment and up to 6 months after completion of the study treatment.

Men must agree to use an effective method of contraception (barrier, surgical sterilization, abstinence) for the duration of treatment and up to 4 months after the last dose of study drugs. We also recommend men with partners of childbearing potential ask their partners to be on highly effective birth control (hormonal, IUD, surgical sterilization). Men must not freeze or donate sperm within the same period.

• Women who are breastfeeding or plan to breastfeed must agree to discontinue breastfeeding from study treatment initiation.
• Ability of participant to understand and sign a written informed consent document.

Exclusion criteria

• History of significant cardiovascular disease or thromboembolic event: cerebral vascular accident/stroke, myocardial infarction, unstable angina, congestive heart failure (>= New York Heart Association Classification Class II) occurring within 12 months prior to the study treatment initiation
• Serious cardiac arrhythmia requiring medication as assessed by electrocardiogram (EKG) at screening.
• Any investigational agents within 4 weeks prior to the study treatment initiation.
• Systemic medical RRP therapy within 4 weeks or 3 half-lives, whichever is longer prior to the study treatment initiation.
• Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to the study treatment initiation. Note: Inhaled, topical intranasal or intraocular steroids, and adrenal replacement doses <10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• History of abdominal fistula or gastrointestinal perforation within 12 months prior to the study treatment initiation.
• Major surgery within 4 weeks prior to the study treatment initiation. Note: The surgery is considered major if a mesenchymal barrier is opened (pleural cavity, peritoneum, meninges).
• Non-healing wounds, active ulcer, or untreated bone fracture.
• History of hemoptysis (>2.5 mL of bright red blood per episode) within 1 month prior to the study treatment initiation.
• History of serious hemorrhage (CTCAE Grade 4) within 12 months prior to the study treatment initiation.
• Evidence of bleeding diathesis or significant coagulopathy (with or without current therapeutic anticoagulation).
• Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to the study treatment initiation.
• Inadequately controlled hypertension (defined as systolic blood pressure (BP) >150 mmHg and/or diastolic blood pressure > 100 mmHg). Note: an average of 3 BP readings on 2 sessions will be used to measure blood pressure if the initial reading indicates inadequately controlled hypertension. Anti-hypertensive therapy to achieve blood pressures below these parameters is allowed.
• Prior history of hypertensive crisis or hypertensive encephalopathy.
• Persisting toxicity related to prior therapy of Grade >1 per CTCAE. Note: Alopecia, sensory neuropathy Grade <= 2 are acceptable.
• Known, active alcohol or drug abuse.
• History of allergy to study drug components.
• History of >= Grade 3 per CTCAE infusion-related reaction to bevacizumab or PRGN-2012.
• Pregnancy confirmed with beta-human chorionic gonadotropin (beta-HCG) serum or urine pregnancy test in WOCBP at screening.
• Uncontrolled symptomatic, intercurrent illness evaluated by medical history, physical exam, and labs, or social situations that would unacceptably increase risk for the participant or impair the ability to evaluate the endpoints of the study, or that would limit compliance with study requirements.