Adjuvant PRGN-2012 in Adult Patients With Recurrent Respiratory Papillomatosis

• ClinicalTrials.gov Identifier: NCT04724980
• Recruitment Status: Recruiting
• First Posted: January 26, 2021
• Last Update Posted: February 28, 2022
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Study Description

Brief Summary:

Background:

Recurrent respiratory papillomatosis (RRP) is a rare disease. It is caused by the human papillomavirus (HPV). RRP affects the upper and lower respiratory tracts. It is difficult to treat and can be fatal. Researchers want to see if PRGN-2012 can help.

Objective:

To find a safe, tolerable dose of PRGN-2012 and to see if it works in treating RRP.

Eligibility:

Adults 18 and older who have RRP

Design:

Participants will be screened with a medical history and physical exam. They will have blood tests and viral studies. They may have a computed tomography (CT) scan of the neck and/or chest. The structures inside their nose, throat, larynx (voice box), and upper windpipe will be viewed using a small tube with a built-in camera (endoscope). Their arm veins will be evaluated. They will have a pregnancy test, if needed.

Screening tests will be repeated during the study.

Participants will have surgery. Their papilloma will be removed. They will have another surgery if it grows back. They will have to stay at the hospital for 1 to 2 days after each surgery.

Participants will complete questionnaires about how much RRP affects their voice.

Participants will get PRGN-2012 as an injection under the skin on days 1, 15, 43, and 85.

Participants may have optional leukapheresis.

Participants will have visits 6, 12, and 24 weeks after their last dose of PRGN-2012. These visits will assess the safety of PRGN-2012 and disease response to the treatment. After the 24-week visit, participants will be called every 3 months for 2 years.

Participation will last for up to 3 years.

Condition or disease	Intervention/treatment	Phase
Recurrent Respiratory Papillomatosis; Papillomavirus Infections; Papillomaviridae	Drug: PRGN-2012	Phase 1; Phase 2

Detailed Description:

Background:

Recurrent respiratory papillomatosis (RRP) is a rare papillomatous disease of the aerodigestive tract that is caused by Human Papilloma Virus (HPV) types 6 or 11.

RRP can progress to cause severe voice disturbance, airway compromise, fatal pulmonary lesions, and invasive cancers.

There is no proven effective systemic therapy for RRP that leads to cure. Participants require repeated surgical procedures for disease debridement and control.

A recently completed phase II clinical trial investigating avelumab in subjects with RRP demonstrated an acceptable safety profile from avelumab and a high rate of partial responses, but no participants were cured.

Laboratory analysis revealed that the ability to measure infiltration of papillomas by HPV antigen-specific T-cells is rare.

A therapeutic vaccine may induce de novo HPV antigen-specific T-cell responses and decrease incidence of recurrence after surgical debulking.

Objectives:

To determine the safety and tolerability and recommended phase II adjuvant dosing (RP2D) of PRGN-2012.

To determine the percentage of participants with an increase in their surgery-free interval following adjuvant treatment with PRGN-2012

Eligibility:

Histologically confirmed diagnosis of laryngeal RRP

A history of 2 or more interventions in the last 12 months for the control of RRP

Age 18 years and older

Eastern Oncology Cooperative Group (ECOG) Performance Score of 0 or 1

Design:

This is a phase I/II, 3+3 dose escalation clinical trial evaluating PRGN-2012 at two dose levels (1x10^11 and 5x10^11 particle units (PU)) administered as adjuvant therapy after standard-of-care debulking surgery.

Participants will receive up to 4 separate injections of PRGN-2012 in separate limbs.

In the phase I portion the study will enroll up to 3-6 subjects at each dose level, and 12 subjects treated at the maximum tolerated dose.

In the phase II portion of the study, up to 40 participants (including participants treated at the RP2D in the phase I portion of the study may be treated in order to determine the percentage of participants who have an increase in their surgery-free interval following adjuvant treatment with PRGN-2012.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 48 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Study of Adjuvant PRGN-2012 in Adult Patients With Recurrent Respiratory Papillomatosis
• Actual Study Start Date: March 16, 2021
• Estimated Primary Completion Date: October 20, 2022
• Estimated Study Completion Date: October 20, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Dose Levels 1 and 2; Adjuvant PRGN-2012 at escalating doses	Drug: PRGN-2012; This is a phase I, 3+3 dose escalation clinical trial evaluating PRGN-2012 at two dose levels (1x10^11 and 5x10^11 particle units (PU)) administered as adjuvant therapy prior to standard-of-care debulking surgery.
Experimental: RP2D; Adjuvant PRGN-2012 at the RP2D	Drug: PRGN-2012; This is a phase I, 3+3 dose escalation clinical trial evaluating PRGN-2012 at two dose levels (1x10^11 and 5x10^11 particle units (PU)) administered as adjuvant therapy prior to standard-of-care debulking surgery.

Outcome Measures

Primary Outcome Measures :

1. determine the percentage of patients with an increase in their surgery-free interval following adjuvant treatment with PRGN-2012 [ Time Frame: 12 months ]
   measuring the mean duration between successive clinically-indicated surgeries in the 12 months after treatment for that patient and determining whether that duration is longer than the mean duration between successive clinically-indicated surgeries in the 12 months prior to treatment. This fraction of patients who are classified as having a success will be reported along with a 95% confidence interval.
2. determine the safety and tolerability and recommended phase II adjuvant dosing (RP2D) of PRGN-2012 [ Time Frame: 1 month ]
   The toxicities experienced by patients at each dose level will be reported per dose level. The grade as well as the type of toxicity will be tabulated per dose level. The fraction of patients who experience a DLT will be identified at a given dose level, with information reported about the number and grade of each type of DLT identified.

Secondary Outcome Measures :

1. Time to recurrence of papillomatous disease after completion of treatment will be recorded [ Time Frame: 1 year ]
   Time to recurrence of papillomatous disease after completion of treatment will be recorded. The frequency of surgery in the 12 months before or after treatment will be assessed across all treated patients for a statistically significant difference using Wilcoxon matched-pairs analysis.
2. Rate of pulmonary RRP partial response in participants with pulmonary disease [ Time Frame: ongoing ]
   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.
3. Frequency of debulking surgery during the 12 months pre and 12 months post treatment [ Time Frame: 1 year ]
   Time to recurrence of papillomatous disease after completion of treatment will be recorded. The frequency of surgery in the 12 months before or after treatment will be assessed across all treated patients for a statistically significant difference using Wilcoxon matched-pairs analysis.
4. Rate of pulmonary RRP complete response in participants with pulmonary disease [ Time Frame: ongoing ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

• INCLUSION CRITERIA:
• Age 18 years and older

• Clinical diagnosis of RRP

  • Histological diagnosis of papilloma confirmed by pathology report from a CLIA-certified laboratory
  • Presence of laryngotracheal papillomas with or without pulmonary RRP
  • A history of 2 or more interventions in the last 12 months for control of RRP
• Clinical performance status of ECOG of 0-1
• Willing to undergo endoscopic evaluation and operative interventions with biopsies in compliance with this protocol
• No systemic therapy for RRP for at least 3 half-lives of the prior drug(s). A 30-day washout is required for systemic bevacizumab treatment
• Participants who have received prior immunotherapy for RRP are permitted
• Participants must have adequate organ and marrow function as defined below:

WBC >2,000/mcL

absolute neutrophil count greater than or equal to 1,500/mcL

hemoglobin >9.0 g/dL

platelets greater than or equal to 100,000/mcL

total bilirubin within normal institutional limits

AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional upper limit of normal creatinine within normal institutional limits

OR

creatinine clearance greater than or equal to 60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal.

PT/INR and PTT less than or equal to upper limit of normal

• Participants sexually active subjects (men and women) of reproductive potential must agree to use two methods of contraception: one highly effective and one other effective method throughout vaccine treatment and for at least 120 days after vaccine treatment. Highly effective methods are defined as: Intrauterine device (IUD), hormonal (birth control pills, injections, implants), tubal ligation and partner s vasectomy; other effective methods are defined as: latex condom, diaphragm and cervical cap.
• Seronegative for hepatitis B antigen, positive hepatitis B tests can be further evaluated by confirmatory tests (Hep B DNA quant, HBV viral load), and if confirmatory tests are negative, the participant can be enrolled.
• Seronegative for hepatitis C antibody unless antigen negative. If hepatitis C antibody test is positive, then participants must be tested for the presence of antigen by Hep C RNA quant, HCV viral load and be HCV RNA negative
• All participants must have the ability to understand and willingness to sign a written informed consent

EXCLUSION CRITERIA:

• A history of surgical debridement of papillomas such that in the opinion of the study team a participant is unlikely to be able to safely have a six-week interval between surgical interventions.
• History of significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (greater than or equal to New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
• Any severe acute or chronic medical or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior, liver disease, lung disease (with the exception of what is specified in the inclusion criteria) , or laboratory abnormalities that, in the opinion of the investigators, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results and in the judgment of the investigator, would make the participant inappropriate for entry into this study. Participants with mild to moderate asthma or chronic obstructive pulmonary disease (COPD) well controlled with oral or inhaled medications are permitted to enroll.
• Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled, topical intranasal or intro-ocular steroids, and adrenal replacement doses <10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Participants who are receiving any other investigational agents
• Persisting toxicity related to prior therapy of Grade >1 NCI-CTCAE v 5.0; however, alopecia, sensory neuropathy Grade less than or equal to 2 or other Grade less than or equal to 2 AEs not constituting a safety risk based on investigator's judgment are acceptable.
• Known alcohol or drug abuse.
• Participant, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study.
• History of allergy to study drug components.
• Pregnant women are excluded from this study because PRGN-2012 is an agent with unknown potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with PRGN-2012, breastfeeding should be discontinued if the mother is treated with PRGN-2012. These potential risks may also apply to other agents used in this study.

Contacts and Locations

Contacts

Contact: Erin W Ferraro, R.N.; (240) 760-6163; erin.ferraro@nih.gov

Locations

United States, Maryland

National Institutes of Health Clinical Center; Recruiting

Bethesda, Maryland, United States, 20892

Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office 888-624-1937

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Scott M Norberg, D.O.; National Cancer Institute (NCI)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT04724980
• Other Study ID Numbers: 210013; 21-C-0013
• First Posted: January 26, 2021
• Last Update Posted: February 28, 2022
• Last Verified: February 23, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):

Human Papilloma Virus; Dose excalation; laryngotracheal disease; papillomatous disease; Avelumab

Additional relevant MeSH terms:

Papillomavirus Infections; Respiratory Tract Infections; Papilloma; DNA Virus Infections; Virus Diseases; Infections; Tumor Virus Infections; Neoplasms, Squamous Cell; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Respiratory Tract Diseases