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Adjuvant PRGN-2012 in Adult Patients With Recurrent Respiratory Papillomatosis

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ClinicalTrials.gov Identifier: NCT04724980
Recruitment Status : Recruiting
First Posted : January 26, 2021
Last Update Posted : May 11, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

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

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 of 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, 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.

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 22 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I 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

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Dose Levels
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.




Primary Outcome Measures :
  1. to 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. 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.



Information from the National Library of Medicine

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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04724980


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

Locations
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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
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Principal Investigator: Scott M Norberg, D.O. National Cancer Institute (NCI)
Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04724980    
Other Study ID Numbers: 210013
21-C-0013
First Posted: January 26, 2021    Key Record Dates
Last Update Posted: May 11, 2021
Last Verified: May 7, 2021

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