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

A Phase II Study of Lenvatinib in Combination With Pembrolizumab in HPV-associated Recurrent Respiratory Papilloma Patients

This research study is studying Lenvatinib in combination with Pembrolizumab in people with human papillomavirus (HPV)-associated recurrent respiratory papillomatosis (RRP).

The names of the study drugs involved in this study are:

• Pembrolizumab
• Lenvatinib

Study Overview

• Status: Not yet recruiting
• Conditions: Human Papilloma Virus; Recurrent Respiratory Papillomatosis
• Intervention / Treatment: Drug: Lenvatinib; Drug: Pembrolizumab

Detailed Description

This is a non-randomized phase II trial in adult male and female subjects diagnosed with human papillomavirus (HPV)-associated Recurrent Respiratory Papilloma to test the safety and efficacy of the drug combination Lenvatinib and Pembrolizumab.

The U.S. Food and Drug Administration (FDA) has not approved Pembrolizumab or Lenvatinib for HPV-associated Recurrent Respiratory Papilloma but they have been approved for other uses. Lenvatinib works by blocking certain proteins that are associated with tumor growth. Lenvatinib also blocks the growth of blood vessels feeding tumors to cause tumor cell death. Pembrolizumab helps the body's immune system destroy cancer cells. This study is investigating whether the combination of Lenvatinib and Pembrolizumab may eliminate HPV-associated RRPs.

The research study procedures include screening for eligibility, study treatment and evaluations and follow up visits.

Participants will receive study treatment for up to 2 years and will be followed for 1 year.

It is expected that about 21 people will take part in this research study.

Merck is supporting this research study by providing Pembrolizumab and supporting the research study procedures.

Eisai is supporting this research study by providing Lenvatinib.

• Study Type: Interventional
• Enrollment (Estimated): 21
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Sara I Pai, MD, PHD; Phone Number: 617-726-5251; Email: sara.pai@mgh.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Cancer Center
      • Contact: Sara I Pai, MD, PHD; Phone Number: 617-726-5251; Email: sara.pai@mgh.harvard.edu
      • Principal Investigator: Sara I Pai, MD, PHD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion 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 and/or endoscopic parameters, as discussed above.
• 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:

Table 1 Adequate Organ Function Laboratory Values

• System Laboratory Value

  • Hematological

    • Absolute neutrophil count (ANC) ≥1500/μL
    • 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

    • Total bilirubin ≤1.5 × institutional ULN OR direct bilirubin ≤ institutional ULN for participants with total bilirubin levels >1.5 × institutional ULN
    • AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × institutional ULN for participants with liver metastases)

  • Thyroid

    • TSH Institutional normal limit
    • Free T4 Institutional normal limit

  • Pancreatic

    • Amylase < 1.5 x institutional ULN
    • Lipase < 1.5 x institutional ULN

  • 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.

  1. Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks.
  2. Creatinine clearance (CrCl) should be calculated per institutional standard.

• 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 ≤ 150 mmHg and diastolic BP ≤ 90 mmHg at 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 72 hours prior to receiving any dose of study medication upon subject enrollment into the study.

• Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year. The methods of surgical sterilization include having had a hysterectomy (removal of the uterus), bilateral oophorectomy (removal of both ovaries), tubal ligation (having your tubes tied), and transvaginal occlusion (blocking the tubes with a coil).
• 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 study drugs administration.
• 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.

Exclusion Criteria:

• Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to study enrollment. Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible. Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.Endoscopic debridement of RRP lesions is NOT considered a major surgery.
• 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 received a live vaccine within 30 days prior to the first dose of study drug.

Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.

• 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) 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).
• Uncontrolled blood pressure (systolic BP>150 mmHg or diastolic BP >90 mmHG) in spite of an optimized regimen of antihypertensive medication.
• Significant cardiovascular impairment: 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 requiring medical treatment at screening.
• Has QTc prolongation >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.
• Has a known history of colitis.
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Lenvatinib + Pembrolizumab; Participants will take: Lenvatinib - At a pre-determined dose, 1x daily during each 3 week study cycle up to 35 cycles/2 years Pembrolizumab - At a pre-determined dose, 1x on Day 1 of each 3 week study cycle up to 35 cycles/2 years Participants will be given a drug diary and asked to document information in the drug diary about the study treatment. Participants will be asked to check their blood pressure 3x every week and document in a supplied diary. Participants will be followed up to one (1) year after study treatment.

Drug: Lenvatinib; Pill taken by mouth, once daily.; Other Names: Lenvima; Drug: Pembrolizumab; Intravenous injection through a vein (IV).; Other Names: Keytruda

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR)	Based on clinical assessment and/or RECIST 1.1 criteria for those patients with RECIST evaluable disease.	3 weeks
Number of Adverse Events	Adverse events will be classified and graded according to the CTCAE v.5.0. Frequencies of adverse events will be summarized overall.	3 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood Biomarkers Changes	Changes from baseline to a post-baseline timepoint will also be compared between patients whose disease responded (CR,PR) and those whose disease did not respond using the Wilcoxon rank-sum test .	Baseline to a post-baseline timepoint up to 2 years and/or end of treatment
Tissue Biomarkers Changes	Changes from baseline to a post-baseline timepoint will also be compared between patients whose disease responded (CR,PR) and those whose disease did not respond using the Wilcoxon rank-sum test .	Baseline to a post-baseline timepoint up to 2 years and/or end of treatment
Quality of Life Assessment	Quality of life (QOL) will be assessed via self-report questionnaires	Baseline to a post-baseline timepoint up to 2 years and/or end of treatment

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: Merck Sharp & Dohme LLC; Eisai Inc.
• Investigators: Principal Investigator: Sara I Pai, MD, PHD, Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2024
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: November 20, 2020
• First Submitted That Met QC Criteria: November 20, 2020
• First Posted (Actual): November 27, 2020

Study Record Updates

• Last Update Posted (Estimated): February 9, 2024
• Last Update Submitted That Met QC Criteria: February 7, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Human Papilloma Virus; Recurrent Respiratory Papillomatosis
• Additional Relevant MeSH Terms: Pathologic Processes; Virus Diseases; Infections; Respiratory Tract Diseases; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Disease Attributes; DNA Virus Infections; Tumor Virus Infections; Neoplasms, Squamous Cell; Urogenital Diseases; Genital Diseases; Recurrence; Respiratory Tract Infections; Papillomavirus Infections; Papilloma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Immune Checkpoint Inhibitors; Pembrolizumab; Lenvatinib
• Other Study ID Numbers: 20-493

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
• IPD Sharing Time Frame: Data can be shared no earlier than 1 year following the date of publication
• IPD Sharing Access Criteria: Contact the Partners Innovations team at http://www.partners.org/innovation
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No