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Recurrent Respiratory Papillomatosis

Laryngeal Papillomatosis

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Antibodies, Monoclonal

Avelumab

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Antineoplastic Agents, Immunological

Avelumab 10 mg/kg intravenous (IV) every 2 weeks for up to 6 doses.

Scott Norberg, DO

Background:

Recurrent respiratory papillomatosis (RRP) is a rare disease caused by human papillomavirus. It can cause voice changes, airway compromise, pulmonary lesions, and cancers. Programmed death-ligand 1 (PD-L1) is a protein on cells. It may be able to stop or decrease the immune system s response to viruses such as human papillomavirus. The drug Avelumab interferes with the activity of PD-L1. Researchers want to see if Avelumab treats RRP and study its side effects.

Objective:

To see if Avelumab works in treating RRP and is safe.

Eligibility:

People ages 18 and older with aggressive RRP that has not responded to available treatments

Design:

Participants will be screened with:

Medical history

Previously collected tumor tissue

Physical exam

Blood, urine, and heart tests

Endoscopy procedure: A small tube with a camera is used to look in the nose, throat, larynx, and upper windpipe.

Before starting treatment, participants will have:

Endoscopy under anesthesia. A sample of papilloma will be taken.

Voice handicap questionnaire

Computed tomography (CT) scans

Apheresis: An intravenous (IV) is inserted into an arm vein. White blood cells are separated from the rest of the blood and stored for research. The rest of the blood is returned through the same IV or one in the other arm.

Participants will get the study drug by IV every 2 weeks for up to 12 weeks.

Participants will repeat the previous tests throughout the study.

If they respond to treatment, participants will be evaluated every 6 weeks (3 times), then every 12 weeks (3 times), then every 26 weeks (2 times) until their disease progresses.

Participants will be evaluated 30 days after their last infusion. They will then be contacted annually.

Background

* Recurrent respiratory papillomatosis (RRP) is a rare papillomatous disease of the aerodigestive tract that is caused by the Human Papilloma Virus (HPV).
* RRP can progress to cause airway compromise, fatal pulmonary lesions, and invasive cancers.
* There is no effective systemic therapy for RRP. Patients require repeated interventional procedures for disease control.
* Study of a small number of RRP samples has shown programmed death-ligand 1 (PD-L1) expression by inflammatory mononuclear cells and by papilloma epithelial cells.
* This clinical trial will evaluate the activity of a PD-L1-targeted drug, avelumab, in the treatment of RRP. This drug was selected for its demonstrated activity in a variety of cancers and for its acceptable safety profile.

Objective

-Determine the complete response rate for avelumab in the treatment of patients with RRP.

Eligibility

* Histologically confirmed diagnosis of RRP.
* One of the following:

  * A Derkay anatomic score of 10 or greater and a history of two or more endoscopic interventions in the last 12 months for control of RRP.
  * Pulmonary RRP with pulmonary disease that is measurable by computed tomography scan.
  * Tracheal involvement with RRP that has required either two or more endoscopic interventions in the last 12 months or a tracheostomy.
* Age 18 years or greater.
* Eastern Oncology Cooperative Group Performance Score of 0 or 1.

Design

* Phase II clinical trial
* Simon optimal two-stage design with initial enrollment of 12 patients and expansion to 37 patients if one or more complete response(s) is/are observed in the initial patients.

Avelumab for People With Recurrent Respiratory Papillomatosis

A Phase II Study of Avelumab in Subjects With Recurrent Respiratory Papillomatosis

The Derkay is an objective score based on the number of sites and bulkiness of papillomas within the pharynx, larynx and trachea and a subjective score determined by voice and treating symptoms. Complete response is assessed by The Derkay Staging System which is defined as a physical exam and/or clinic-based flexible nasopharyngolaryngoscopy and/or tracheoscopy, exam under anesthesia with endoscopy and biopsies; no evidence of papillomas on physical exam and/or clinic based flexible nasopharyngolaryngoscopy and/or tracheoscopy; and no evidence of papillomas by exam under anesthesia (sedation or general anesthesia) with endoscopy and biopsies.

Complete response is measured by The Response Criteria in Solid Tumors (RECIST) v1.1 calculated from chest CT scans. Complete response is absence of disease (e.g., lesions) by imaging.

The Voice Handicap Index-10 questionnaire (as measured by derkay score) consists of 10 questions and determines whether a participant has a voice handicap. The scoring options for each question range from 0 (for never) to 4 (for always). The total scores (combined value from all 10 questions) range from 0 - 40. Higher scores represent a worse voice handicap. Lower scores represent a less voice handicap.

Partial response is assessed by flexible nasopharyngolaryngoscopy and/or tracheoscopy using the Derkay staging system if the patient does not have pulmonary disease. The Derkay is an objective score based on the number of sites and bulkiness of papillomas within the pharynx, larynx and trachea and a subjective score determined by voice and treating symptoms. Partial response is a decrease in Derkay anatomic score of 30% or greater.

Partial response assessed by imaging using RECIST v1.1. is defined as a ≥ 30% decrease in the sum of the longest diameters of target lesions compared with baseline.

The duration of clinical responses to Avelumab is calculated from the protocol end of treatment endoscopic debulking to the next clinically indicated endoscopic debulking procedure.

Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

National Cancer Institute (NCI)

Principal Investigator

Avelumab 10 mg/kg intravenous (IV) every 2 weeks for up to 6 doses.

Avelumab: Avelumab 10 mg/kg intravenous (IV) every 2 weeks for up to 6 doses.

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

All patients underwent multiple surgeries as part of standard of care treatment for Recurrent Respiratory Papillomatosis (RRP) prior to enrolling in this protocol.

Patients Who Had Repeated Endoscopic Debulking to Remove Paillomatosis Lesions Prior to Treatment

Nine of twelve patients had evaluable laryngotracheal disease as assessed by clinical endoscopy.

Number of Patients With Laryngotracheal Recurrent Respiratory Papillomatosis (RPP) Who Achieve a Complete Response With Avelumab as Measured by Derkay Score Calculated From Clinical Endoscopy

Four of twelve patients had evaluable pulmonary disease as assessed by CT scan.

Number of Patients With Pulmonary Recurrent Respiratory Papillomatosis (RPP) Who Achieve a Complete Response With Avelumab as Measured by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Calculated From Chest Computed Tomography (CT) Scans

Patient 1

Patient 2

Patient 3

Patient 4

Patient 5

Patient 6

Patient 7

Patient 8

Patient 9

Patient 10

Patient 11

Patient 13

All participants Voice Handicap Index-10 Score at Baseline.

Avelumab 10 mg/kg intravenous (IV) every 2 weeks for up to 6 doses. Avelumab: Avelumab 10 mg/kg intravenous (IV) every 2 weeks for up to 6 doses.

All Participants at Baseline

All participants Voice Handicap Index-10 Score at 6 Weeks.

Avelumab 10 mg/kg intravenous (IV) every 2 weeks for up to 6 doses.

Avelumab: Avelumab 10 mg/kg intravenous (IV) every 2 weeks for up to 6 doses.

All Participants at 6 Weeks

All participants Voice Handicap Index-10 Score at 12 Weeks.

Avelumab 10 mg/kg intravenous (IV) every 2 weeks for up to 6 doses.

Avelumab: Avelumab 10 mg/kg intravenous (IV) every 2 weeks for up to 6 doses.

All Participants at 12 Weeks

Only one participant in each row contributed data in each row.

Effect of Treatment With Avelumab on Voice Handicap Index-10 Score

Number of Patients With Laryngotracheal Recurrent Respiratory Papillomatosis (RPP) Who Achieve a Partial Response With Avelumab as Measured by Derkay Score Calculated From Clinical Endoscopy

Number of Patients With Pulmonary Recurrent Respiratory Papillomatosis (RPP) Who Achieve a Partial Response With Avelumab as Measured by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Calculated From Chest Computed Tomography (CT) Scans

5/12 participants were evaluable for this outcome measure.

Duration of Clinical Responses to Avelumab

Number of Participants With Serious and Non-serious Adverse Events

Overall Study

Pembrolizumab

Immune Checkpoint Inhibitors

Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks. Treatment will be administered on Day 1 of each cycle after all procedures/assessments have been completed

200 mg will be administered as a 30 minute IV infusion every 3 weeks on day 1 of each cycle after all procedures/assessments have been completed.

Sara Pai, MD PhD

This research study is evaluating an immune modulatory agent as a possible treatment for patients with Recurrent Respiratory Papillomatosis (RRP) with significant disease involving the larynx, trachea, and/or lungs. The investigators will be using Pembrolizumab as the treating agent.

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. The FDA (the U.S. Food and Drug Administration) has not approved Pembrolizumab for your specific disease but it has been approved for other uses.

Pembrolizumab is a humanized monoclonal antibody. Pembrolizumab is being studied in several other clinical trials to see if it has an effect in helping the immune system to recognize and eliminate abnormal cells in the body. The antibody blocks a receptor expressed on immune cells, called T cells, and by blocking this receptor it has the potential to activate the T cells to kill abnormal cells, such as virally infected cells.

In this research study, the investigators are looking at whether Pembrolizumab can restore the natural ability of the immune system to recognize and eliminate Human papillomavirus (HPV)-infected cells from the body.

Pembrolizumab for HPV-associated Recurrent Respiratory Papilloma Patients

Pembrolizumab for HPV-associated Recurrent Respiratory Papilloma Patients With Laryngeal, Tracheal and/or Pulmonary Involvement

A Simon two-stage design was used to assess best objective response rate based on endoscopic lesional burden and Response Evaluation Criteria in Solid Tumors (RECIST)

To determine the safety and tolerability of pembrolizumab in subjects with RRP.

To evaluate the response duration in subjects receiving pembrolizumab

Merck Sharp & Dohme LLC

Massachusetts General Hospital

Sara Pai, MD, PhD

Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks. Treatment will be administered on Day 1 of each cycle after all procedures/assessments have been completed

Pembrolizumab: 200 mg will be administered as a 30 minute IV infusion every 3 weeks on day 1 of each cycle after all procedures/assessments have been completed.

Dr. Sara Pai, Principal Investigator

Overall Response Rate Via Endoscopic Lesional Burden Score and/or RECIST

Number of Participants With Adverse Events Through CTCAE

Assess Duration of Response

Central Nervous System Depressants

Anesthetics

Patient will receive conventional tubeless anesthesia

Patient will receive Transnasal humidified high-flow oxygen delivery (Optiflow)

The Optiflow system consists of an apparatus that is capable of delivering humidified oxygen, room air, or a mixture of variable oxygen concentration. The oxygen concentration can be precisely varied from 21-100% (or 0.21 - 1.00 FiO2). The gas is warmed to 37°C with a 100% relative humidity. The humidified and warmed gas can be delivered to the patient at high-flows (up to 70 L/min) using various delivery mechanisms. The investigators will be using a nasal cannula to deliver high flow oxygen (2-3 L/kg/min) to the patient.

Transnasal humidified high-flow oxygen delivery

This is a randomized cross over study of high flow oxygen delivery via nasal cannula vs. conventional tubeless anesthesia for patients undergoing dubulking surgery for laryngeal papilloma. Ten patients aged 2-17 with laryngeal papilloma that are eligible for debulking surgery will be consented and enrolled.

This trial will be a randomized unmasked open-label study of Transnasal humidified high-flow oxygen/air delivery compared to conventional tubeless anesthesia during airway surgery in pediatric patients. This will be a single center study at MEE main campus on 243 Charles St, Boston, MA for the use of the high-flow oxygen delivery device.

Two study arms will be used in this study. Subjects will be treated with both study arms over the course of two study visits. Enrolled patients will be patients that present themselves routinely for removal of laryngeal papilloma. These patients, once enrolled, will be randomized to either receive conventional tubeless anesthesia or standard anesthesia with the addition of transnasal high-flow oxygen/air for their next scheduled anesthetic. Oxygen flows for the high-flow nasal cannula will be titrated down to achieve a FiO2 value of 21% during lasering. The anesthesia method not chosen will be used for the following anesthetic for each patient. Intraoperatively patients will be monitored for number of desaturations below 90 percent, length of these desaturations and severity, number and type of interventions necessary by the anesthesiologist, and number of intubations necessary by the anesthesiologist. Flow rates appropriate for the age of the patient will be used and also be recorded within these cases. Adverse events and complications will also be recorded for both anesthetics.

Optiflow vs. Convential Anesthesia During Pediatric Laryngeal Papilloma Removal

Transnasal Humidified High-Flow Oxygen Delivery (Optiflow) vs. Conventional Tubeless Anesthesia for the Prevention of Desaturations During Pediatric Laryngeal Papilloma Removal

The primary objective of this study is to investigate the effects of transnasal humidified high-flow oxygen/air system to maintain safe intraoperative oxygen saturations in pediatric patients undergoing procedures for removal of laryngeal papilloma, thereby improving the quality of care. Number, duration and severity of intraoperative desaturations below 90 percent.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Avelumab for People With Recurrent Respiratory Papillomatosis	NCT02859454	Recurrent Respi... Juvenile Laryng... Laryngeal Papil... Respiratory Pap... Human Papilloma...	Avelumab	18 Years - 99 Years	National Institutes of Health Clinical Center (CC)
Pembrolizumab for HPV-associated Recurrent Respiratory Papilloma Patients	NCT02632344	Recurrent Respi...	Pembrolizumab	12 Years -	Massachusetts General Hospital
Optiflow vs. Convential Anesthesia During Pediatric Laryngeal Papilloma Removal	NCT05215249	Laryngeal Papil...	Transnasal humi...	2 Years - 17 Years	Massachusetts Eye and Ear Infirmary
Pembrolizumab for HPV-associated Recurrent Respiratory Papilloma Patients	NCT02632344	Recurrent Respi...	Pembrolizumab	12 Years -	Massachusetts General Hospital
Avelumab for People With Recurrent Respiratory Papillomatosis	NCT02859454	Recurrent Respi... Juvenile Laryng... Laryngeal Papil... Respiratory Pap... Human Papilloma...	Avelumab	18 Years - 99 Years	National Institutes of Health Clinical Center (CC)
Optiflow vs. Convential Anesthesia During Pediatric Laryngeal Papilloma Removal	NCT05215249	Laryngeal Papil...	Transnasal humi...	2 Years - 17 Years	Massachusetts Eye and Ear Infirmary

Spots Global Cancer Trial Database for laryngeal papilloma, recurrent