Lenvatinib and Pembrolizumab Combination Therapy In HPV-associated Recurrent Respiratory Papillomatosis Patients With Laryngeal, Tracheal, and/or Pulmonary Involvement

Eligibility Criteria

• * Participants must have histologically or cytologically confirmed respiratory papillomas that involves the trachea, lungs, and/or larynx. If a subject is enrolled with laryngeal disease only, the subject must have undergone at least 3 or more surgeries/procedures in any one year to remove the lesions from their larynx. Subjects must have at least evaluable disease either based on RECIST 1.1.
• * Be required to provide tissue from a newly obtained biopsy of a lesion. Newly obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to study registration. Subjects for whom newly obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the PI.
• * Have confirmed human papillomavirus-associated lesions based on in-situ hybridization testing and/or polymerase chain reaction which may be performed on a newly obtained biopsy or archived sample.
• * Age ≥18 years.
• * ECOG performance status of 0 to 1.
• * Participants must have adequate organ and marrow function as defined below:
• * System Laboratory Value
• * Hematological
• * Platelets ≥100 000/μL
• * Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L (a)
• * Renal
• * Creatinine OR Measured or calculated (b) creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 × institutional ULN OR ≥30 mL/min for participant with creatinine levels \>1.5 × institutional ULN
• * Hepatic
• * AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × institutional ULN for participants with liver metastases)
• * Thyroid
• * Free T4 Institutional normal limit
• * Pancreatic
• * Coagulation ---- International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT) ≤1.5 × institutional ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
• * ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal.
• * Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for the administration of specific chemotherapies.
• * Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants should be class 2B or better.
• * Adequately controlled blood pressure with or without antihypertensive medications defined as systolic BP ≤ 140 mmHg and diastolic BP ≤ 90 mmHg at screening with no change in antihypertensive medications within 1 week prior to screening.
• * Female subject of childbearing potential should have a negative urine or serum pregnancy test within 28 days of study registration\*. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• * Please refer to the study calendar for requirements regarding a pregnancy test 24 hours prior to receiving any dose of study medication upon subject enrollment into the study.
• * A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• * Is not a WOCBP as defined below.
• * A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention.
• * If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
• * Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of pembrolizumab.
• * Male participants are eligible to participate if they agree to the following during the intervention period and for at least 7 days after the last dose of Lenvatinib:
• * Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent.
• * Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile-vaginal penetration.
• * Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed
• * Ability to complete Patient Medication and Blood Pressure diaries by themselves or with assistance.
• * Ability to understand and the willingness to sign a written informed consent document.
• * Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to study enrollment.
• * Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.
• * Has had major surgery within 3 weeks prior to first dose of study interventions. Note: Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility.
• * Has received a live vaccine within 30 days prior to the first dose of study drug.
• * Is currently participating in or has participated in a study of an investigational agent within 4 weeks prior to the first dose of study treatment. NOTE: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
• * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
• * Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. NOTE: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, well-differentiated thyroid cancer, follicular lymphoma, carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) invasive cancer derived from RRP, or other indolent malignancy not requiring active treatment are not excluded.
• * Patients with invasive squamous cell carcinoma derived from their RRP who are not considered appropriate for surgery, radiation therapy, or chemotherapy by their treating oncology team may be considered eligible for the study.
• * History of allergic reactions (\> Grade 3) attributed to compounds of similar chemical or biologic composition to pembrolizumab or lenvatinib and/or any of its excipients.
• * Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• * Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• * Has an active infection requiring systemic therapy.
• * Has a known history of Human Immunodeficiency Virus (HIV) infection. Note: No HIV testing is required unless mandated by local health authority.
• * Has a known history of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C virus (defined as HCV RNA is detected) infection. NOTE: No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
• * Has a known history of active TB (Bacillus Tuberculosis).
• * Has urine protein \> 1 g/24 hours. Note: Participants with proteinuria \> 2+ (\>100 mg/dL) on urine dipstick testing (urinalysis) will undergo 24-hour urine collection for quantitative assessment of proteinuria.
• * Electrolyte abnormalities that have not been corrected.
• * Has clinically significant cardiovascular disease within 12 months from first dose of study intervention: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 6 months of the first dose of study drug, or cardiac arrhythmia associated with hemodynamic instability and requiring medical treatment at screening. Note: Medically controlled arrhythmia would be permitted.
• * Has a LVEF below the institutional (or local laboratory) normal range, as determined by multigated acquisition (MUGA) or echocardiogram (ECHO).
• * Prolongation of QTcF interval to \>480 msec, as calculated by either the Bazett or Fridericia formula, as per institutional standard.
• * Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. The degree of tumor invasion/infiltration of major blood vessels (e.g. carotid artery) should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy.
• * Has \>1+ proteinuria on urine dipstick testing unless a 24-hour urine collection for quantitative assessment indicates that the urine protein is \< 1g/24 hours.
• * Has clinically significant gastrointestinal malabsorption syndrome or any other condition that might affect the absorption of lenvatinib.
• * Has a known history of colitis.
• * Has preexisting \> Grade 3 gastrointestinal or non-gastrointestinal fistula
• * Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug.
• * Has a known history of posterior reversible encephalopathy syndrome (PRES).
• * Participants with history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• * Participants with psychiatric illness/social situations that would limit compliance with study requirements.
• * Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment. Pregnant women are excluded from this study because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with pembrolizumab and/or lenvatinib, and breastfeeding should be discontinued.