Pembrolizumab and Lenvatinib After Definitive Chemoradiation of Locally Advanced HNSCC

Study Overview
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Brief Summary
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Open-label, single-arm, prospective multicenter phase II clinical trial to determine the efficacy and safety combined pembrolizumab and lenvatinib as maintenance therapy after definitive radiochemotherapy of locally advanced head and neck squamous cell carcinoma (HNSCC).

Detailed Description
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This is an open-label, single-arm, prospective multicenter phase II clinical trial to determine the efficacy and safety combined pembrolizumab and lenvatinib as maintenance therapy after definitive radiochemotherapy of locally advanced head and neck squamous cell carcinoma (HNSCC). The trial will be conducted in conformance with Good Clinical Practices and subjects will be enrolled into the trial by signing the informed consent form (ICF). Only subjects with PD-L1 positive (CPS≥1) tumors according to centralized reference pathologic assessment can be enrolled. Subjects without disease progression in the study screening CT (compared to radiochemotherapy baseline CT) that fulfil all further eligibility criteria can enter the trial after completion of definitive radiochemotherapy. Sites will be required to submit tissue samples for translational research to central pathology. After confirmed study inclusion, patients will receive combined pembrolizumab and lenvatinib treatment. Pembrolizumab will be administered intravenously at a dose of 200mg q3w and lenvatinib at a dose of 20mg once daily orally. The first dose of pembrolizumab has to be administered within 14 days after completion of radiochemotherapy. Treatment with lenvatinib will start concomitant to cycle 2 of pembrolizumab. Treatment will be continued until disease progression, unacceptable adverse event(s) or until the subject has received 12 months of treatment (i.e. 17 doses of pembrolizumab). Afterwards patients will enter follow-up until 24months since study inclusion. It is planned to enroll 47 patients. Primary endpoint of the trial is the event-free survival (EFS) rate at 2 years. The aim of the trial is to achieve a 2-year EFS rate of 70% (compared to 55% in the historic controls). This improvement is considered to be a clinically relevant advantage.

Official Title
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Combined Pembrolizumab and Lenvatinib After Definitive Chemoradiation of Locally Advanced HNSCC in PD-L1 Positive Patients (CPS≥1)

Conditions
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Head and Neck Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: Pembrolizumab
* Drug: Lenvatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants are eligible to be included in the study only if all of the following criteria apply: Male/female participants who are at least 18 years of age on the day of signing informed consent Pathologically proven new diagnosis of squamous cell carcinoma (HNSCC) of the oral cavity, oropharynx, hypopharynx or supraglottic larynx stage III-IVB according to TMM 8th edition PD-L1 combined positive score (CPS) ≥1 (in sample prior to radiochemotherapy) by central pathology review Completed definitive radiochemotherapy up to at least 68Gy with at least 200mg/m² body surface area concomitant Cisplatin. No progression during radiochemotherapy. Study screening CT has to be compared to radiochemotherapy baseline CT. (Study screening CT may be performed before the end of radiochemotherapy, whereas a minimum radiation dose of 50Gy has to be administered at the time point of the study screening CT.) Male participants: A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 120 days after the last dose of study treatment (pembrolizumab or lenvatinib, whichever is administered last) and refrain from donating sperm during this period. In addition, contraception has to be used for 180 days after the last dose of cisplatin. Female participants: A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: a. Not a woman of childbearing potential (WOCBP) OR b. A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment (pembrolizumab or lenvatinib, whichever is administered last). In addition, contraception has to be used for 180 days after the last dose of cisplatin. The participant provides written informed consent for the trial. Have measurable disease based on RECIST 1.1. Have provided archival tumor tissue sample with sufficient tumor content. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention. Have adequate organ function. Specimens must be collected within 10 days prior to the start of study intervention. Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply: Have tumor infiltration/perforation of the skin or cervical fistula (either at timepoint of study inclusion or prior to radiochemotherapy) Have radiographic evidence of major blood vessel invasion/infiltration or tumor demonstrates >90-degree abutment or encasement of a major blood vessel. Had prior radical surgery for the head and neck cancer under study or induction chemotherapy with more than one cycle prior to definitive radiochemotherapy. Patients with single cycle induction chemotherapy prior radiochemotherapy can be included. WOCBP who have a positive urine or serum pregnancy test within 72 hours prior to. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Have received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137). Have received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to study drug administration (except from cisplatin concomitant to radiochemotherapy). Have received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed. Are currently participating in or have participated in a study of an investigational agent or have used an investigational device within 4 weeks prior to the first dose of study intervention. Have 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. Have a known additional malignancy that is progressing or have required active treatment within the past 3 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded. Have distant metastases. Have severe hypersensitivity (≥Grade 3) to pembrolizumab, lenvatinib and/or any of their excipients. Have 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 (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed. Have a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. Have an active infection requiring systemic therapy. Have a known history of Human Immunodeficiency Virus (HIV) infection. Have 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. Have a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator. Have known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Are 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. (as documented by a positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]). Have had an allogenic tissue/solid organ transplant. Have uncontrolled blood pressure (Systolic BP>140 mmHg or diastolic BP >90 mmHg) in spite of an optimized regimen of antihypertensive medication. Have clinically relevant electrolyte abnormalities that have not been corrected. Have 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. Have/had 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. Have > 1+ proteinuria on urine dipstick testing unless a 24-hour urine collection for quantitative assessment indicates that the urine protein is <1 g/24 hours.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm<br>combined pembrolizumab (200mg q3w) and lenvatinib treatment (20mg once daily) | Drug: Pembrolizumab<br>* i.v., 200mg absolute, q3w, starting within 14 days after completion of radiochemotherapy<br>* Other names: Keytruda;Drug: Lenvatinib<br>* 20mg once daily orally, start concomitant to cycle 2 of pembrolizumab<br>* Other names: Lenvima;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival (EFS) rate | To study efficacy of pembrolizumab/lenvatinib maintenance therapy after definitive radiochemotherapy of locally advanced HNSCC to prolong the event-free survival (EFS) rate at 2 years | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival (EFS) (continuous) | Pembrolizumab/lenvatinib maintenance therapy will improve further efficacy endpoints compared to historic control | 2 years | 
| Locoregional control | Locoregional progression will be evaluated by RECIST 1.1 criteria | Restaging 12-13 weeks after completion of radiotherapy; Follow-up every 24 weeks | 
| Toxicity of Pembrolizumab/lenvatinib | Toxicity will be evaluated according to CTCAE v5.0 criteria | until safety follow-up (1 year treatment + 30 days) |