Avelumab for People With Recurrent Respiratory Papillomatosis

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 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.

- INCLUSION CRITERIA:

RRP CRITERIA:

- Histological diagnosis of RRP confirmed by pathology report from a CLIA-certified
laboratory.

-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.

- Greater than or equal to 18 years of age.

- Able to understand and sign the Informed Consent Document.

- Clinical performance status of ECOG 0 or 1.

- Willing to undergo endoscopic evaluation with biopsies in compliance with this
protocol.

- No systemic therapy for RRP for four weeks prior to treatment.

- Screening laboratory values must meet the following criteria and should be
obtained within 14 days prior to first dose:

- WBC > 2000/microL

- Neutrophils > 1500/microL

- Platelets > 100 times10(3)/microL

- Hemoglobin > 9.0 g/dL

- Serum creatinine < 1.5 times ULN or creatinine clearance (CrCl) > 30 mL/min (measured
or calculated using the Cockcroft-Gault formula below):

- Female CrCl: (140 - age in years) times weight in kg x 0.85/72 times serum
creatinine in mg/dL

- Male CrCl: (140 - age in years) times weight in kg x 1.00/72 times serum
creatinine in mg/Dl

- AST/ALT less than or equal to 2.5 times ULN; for subjects with documented metastatic
disease to theliver, AST and ALT levels less than or equal to 5 times ULN

- Total Bilirubin less than or equal to 1.5 times ULN

- Sexually active subjects (men and women) and all subjects of reproductive
potential must agree to use two methods of contraception: one highly effective
and one other effective method for at least 28 days prior, throughout the
avelumab treatment and for at least 60 days after avelumab 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 HIV antibody. The experimental treatment being evaluated in this
protocol depends on an intact immune system. Patients who are HIV seropositive
can have decreased immune function and thus are likely less responsive to the
experimental treatment.

- 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 patient can be enrolled.

- Seronegative for hepatitis C antibody unless antigen negative. If hepatitis C
antibody test is positive, then patients must be tested for the presence of
antigen by Hep C RNA Quant, HCV Viral Load and be HCV RNA negative.

EXCLUSION CRITERIA:

- Any severe acute or chronic medical or psychiatric conditions including recent (within
the past year) or active suicidal ideation or behavior; liver, lung disease (with the
exception of what is specified in inclusion criteria above), 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 patient
inappropriate for entry into this study. Patients with mild to moderate asthma or
chronic obstructive pulmonary disease (COPD) well controlled with oral or inhaled
medications are permitted to enroll.

- Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo,
residual hypothyroidism due to autoimmune condition only requiring hormone
replacement, or psoriasis not requiring systemic treatment, 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.

- Prior organ transplantation, including allogeneic stem cell transplantation.

- Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or
any other antibody or drug specifically targeting T-cell co-stimulation or immune
checkpoint pathways.

- Patients who are receiving any other investigational agents

- Pregnant or breast feeding. Women of childbearing potential must have a negative
pregnancy test at screening. Women of childbearing potential include women who have
experienced menarche and who have not undergone successful surgical sterilization
(hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not
postmenopausal. Post-menopause is defined as amenorrhea greater than or equal to 12
consecutive months. Note: women who have been amenorrheic for 12 or more months are
still considered to be of childbearing potential if the amenorrhea is possibly due to
prior chemotherapy, anti-estrogens, ovarian suppression or any other reversible
reason.

- History of allergy to study drug components.

History of severe hypersensitivity reaction to any monoclonal antibody (Grade greater than
or equal to 3 NCI-CTCAE v 4.03), any history of anaphylaxis, or uncontrolled asthma (that
is, 3 or more features of partially controlled asthma).

- Clinically 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.

- Persisting toxicity related to prior therapy of Grade >1 NCI-CTCAE v 4.03; 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.

- Vaccination within 4 weeks of the first dose of avelumab and while on trial is
prohibited except for administration of inactivated vaccines.