M7824 in 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 typically require repeated
interventional procedures for disease control.

- A recently completed phase II clinical trial investigating avelumab in subjects with
aggressive RRP demonstrated an acceptable safety profile from Avelumab and a high rate
of partial responses.

- RRP is characterized by frequent expression of PD-L1 and TGF-beta in the tumor
microenvironment.

- This clinical trial will evaluate the activity of M7824, a novel bifunctional fusion
protein composed of a fully human IgG1 monoclonal antibody against human PD-L1
(avelumab) fused, via a flexible glycine-serine linker, to the soluble extracellular
domain of human TGF- B receptor II (TGF-BRII), which functions as a TGF-B trap. 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 M7824 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

- This is a phase II clinical trial with two cohorts that will enroll simultaneously.

- Cohort 1 will consist of subjects who have not been treated previously with an immune
checkpoint inhibitor. Cohort 2 will consist of subjects whose disease has been treated
previously with andrefractory to an immune checkpoint inhibitor. Each cohort will have a
Simon optimal two-stage design with initial enrollment of 12 patients and expans 21
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 and evaluated by RECIST Criteria.

- 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 or1.

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

- No systemic therapy for RRP for at least 3 half-lives of the prior drug(s).

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

- WBC > 2000/ microliter

- Neutrophils > 1000/ microliter

- Platelets > 75 x10(3)/ microliter

- Hemoglobin > 9.0 g/dL

- Serum Creatinine < 1.5 x ULN OR eGFR > 30 mL/min (measured or calculated using
the MDRD equation).

- AST/ALTless than or equal to 2.5 x ULN

- Total Bilirubin :S 1.5 x ULN

- 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 M7824 treatment and for at least 120 days after M7824 treatment. Highly
Effective Methods are defined as: Intrauterine device (IUD), hormonal (birth control
pills, injections, implants), tubal ligation and partner s vasectomy; Other 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 disease, lung disease
(with the exception of what is specified in 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 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.

- 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 5.0), 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), unstab1e angina, congestive heart fai1ure (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 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.

- Vaccination within 4 weeks of the first dose of M7824 and 4 weeks after the last dose
of M7824 are prohibited.

- HPV vaccination within one year of the first dose of M7824