Lenvatinib (E7080/MK-7902) in Combination With Pembrolizumab (MK-3475) vs. Standard Chemotherapy and Lenvatinib Monotherapy in Participants With Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma That Progressed After Platinum Therapy and Immunotherapy (MK-7902-009/E7080-G000-228/LEAP-009)

Study Overview
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Brief Summary
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This study is designed to assess the safety and efficacy of lenvatinib in combination with pembrolizumab versus standard of care (SOC) chemotherapy, and to also assess the safety and efficacy of lenvatinib monotherapy in participants with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) that have progressed after platinum therapy and a programmed cell death protein 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) inhibitor. The primary hypothesis is that lenvatinib + pembrolizumab is superior to SOC chemotherapy with respect to ORR per modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by blinded independent central review.

Official Title
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A Phase 2, Randomized, Open-label Three-arm Clinical Study to Evaluate the Safety and Efficacy of Lenvatinib (E7080/MK-7902) in Combination With Pembrolizumab (MK-3475) Versus Standard of Care Chemotherapy and Lenvatinib Monotherapy in Participants With Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC) That Have Progressed After Platinum Therapy and Immunotherapy (PD-1/PD-L1 Inhibitors) (LEAP-009)

Conditions
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Squamous Cell Carcinoma of Head and Neck

Intervention / Treatment
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* Drug: Lenvatinib
* Biological: Pembrolizumab
* Drug: Docetaxel
* Drug: Capecitabine
* Drug: Paclitaxel
* Drug: Cetuximab
* Drug: Lenvatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically confirmed recurrent (not amenable to curative treatment with local and/or systemic therapies) or metastatic (disseminated) HNSCC of the oral cavity, oropharynx, hypopharynx, and/or larynx that is considered incurable by local therapies Disease progression at any time during or after treatment with a platinum-containing (e.g., carboplatin or cisplatin) regimen Disease progression on or after treatment with an anti-PD-1/PD-L1 mAb (programmed cell death protein 1/programmed death-ligand 1 monoclonal antibody) Pre-study imaging that demonstrates evidence of disease progression based on investigator review of at least 2 pre-study images per RECIST 1.1, following initiation of treatment with a PD-1/PD-L1 inhibitor Measurable disease by CT or MRI based on Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as verified by blinded independent central review (BICR). Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions ECOG performance status of 0 or 1 assessed within 7 days of the first dose of study intervention Male participants are eligible to participate if they agree to the following during the intervention period and for at least 1 week after the last dose of lenvatinib, 3 months after the last dose of capecitabine and paclitaxel, and and 6 months after the last dose of docetaxel: Refrain from donating sperm Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent; or must agree to use contraception unless confirmed to be azoospermic Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies 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 woman of childbearing potential (WOCBP) Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period and for at least 120 days post pembrolizumab or 1 month post lenvatinib, whichever occurs last (Arms 1 and 3), or during the intervention period and for at least 6 months after the last dose of capecitabine, docetaxel, paclitaxel; and 2 months after the last dose of cetuximab (Arm 2) Female participants who randomize to Arm 2 must also agree not to donate or freeze/store eggs during the intervention period and for at least 6 months after the last dose of capecitabine, docetaxel, paclitaxel; and 2 months after the last dose of cetuximab Adequately controlled blood pressure (BP) with or without antihypertensive medications Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization Participants with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening Adequate organ function Exclusion Criteria: Disease that is suitable for local therapy administered with curative intent Life expectancy of less than 3 months and/or has rapidly progressing disease in the opinion of the treating investigator History of (noninfectious) pneumonitis/interstitial lung disease that required steroids, or has current pneumonitis/interstitial lung disease Active infection requiring systemic therapy 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 Known active central nervous system (CNS) metastases and/or carcinomatous meningitis Known additional malignancy that is progressing or has required active systemic treatment within the past 3 years, except basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ that have undergone potentially curative therapy Active autoimmune disease that has required systemic treatment in the past 2 years Had an allogeneic tissue/solid organ transplant Known history of human immunodeficiency virus (HIV) infection History of any contraindication or has a severe hypersensitivity to any components of pembrolizumab, lenvatinib or SOC chemotherapy. Pre-existing ≥Grade 3 gastrointestinal or non-gastrointestinal fistula History of a gastrointestinal malabsorption or any other condition or procedure that may affect oral study drug absorption Had major surgery within 3 weeks prior to first dose of study interventions Clinically significant cardiovascular impairment within 12 months of the first dose of study drug Active tuberculosis Has difficulty swallowing capsules or ingesting a suspension orally, or by a feeding tube Prior treatment with lenvatinib Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to Study Day 1 or has not recovered from adverse events (AEs) due to a previously administered agent. Participants with endocrine-related AEs Grade ≤2 requiring treatment or hormone replacement may be eligible Has received a live or live attenuated vaccine within 30 days prior to the first dose of study intervention. Note: Administration of killed vaccines is allowed Previously treated with 4 or more systemic regimens given for recurrent/metastatic disease Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration Known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lenvatinib + Pembrolizumab<br>Participants will be treated with the combination of lenvatinib (once daily 20 mg oral dose) plus pembrolizumab (200 mg 30-minute intravenous (IV) infusion on Day 1 of each 21-day cycle for 35 cycles), until centrally verified disease progression, or until a protocol-specified discontinuation criterion is met. Participants may receive up to an additional 17 cycles of pembrolizumab as Second Course treatment, with or without lenvatinib. | Drug: Lenvatinib<br>* 20 mg once daily, taken as oral capsules<br>* Other names: E7080;Biological: Pembrolizumab<br>* 200 mg 30-minute IV infusion on day 1 of each 21-day cycle<br>* Other names: SCH 900475;|
| Active Comparator: SOC Chemotherapy<br>Participants will be treated with investigator's choice of standard of care (SOC) chemotherapy (docetaxel, paclitaxel, cetuximab, or capecitabine) until centrally verified disease progression, or until a protocol-specified discontinuation criterion is met. | Drug: Docetaxel<br>* 75 mg/m^2 administered as an IV infusion on day 1 of each 21-day cycle<br>* Other names: TAXOTERE®;Drug: Capecitabine<br>* 1250 mg/m^2 twice daily on days 1-14 of each 21-day cycle, taken as oral tablets<br>* Other names: Xeloda®;Drug: Paclitaxel<br>* 80 mg/m^2 administered as an IV infusion on days 1, 8, and 15 of each 21-day cycle<br>* Other names: Taxol;Drug: Cetuximab<br>* 400 mg/m^2 loading dose, followed by 250 mg/m^2 administered as an IV infusion on days 1, 8, and 15 of each 21-day cycle<br>* Other names: ERBITUX®;|
| Active Comparator: Lenvatinib Monotherapy<br>Participants will be treated with lenvatinib monotherapy (once daily 24 mg oral dose) until centrally verified disease progression, or until a protocol-specified discontinuation criterion is met. | Drug: Lenvatinib<br>* 24 mg once daily, taken as oral capsules<br>* Other names: E7080;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR is defined as the percentage of participants who have a confirmed complete response (CR: disappearance of all target lesions) or partial response (PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of the diameters of target lesions) until progressive disease (PD) or death due to any cause, whichever occurs first. Responses are according to modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by blinded independent central review (BICR). | Up to approximately 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Responses are according to modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by blinded independent central review (BICR). | Up to approximately 4 years | 
| Overall Survival (OS) | OS is defined as the time from randomization to death due to any cause. | Up to approximately 4 years | 
| Duration of Response (DOR) | DOR is defined as the time from the first documented evidence of complete response (CR: disappearance of all target lesions) or partial response (PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of the diameters of target lesions) until progressive disease (PD) or death due to any cause, whichever occurs first. Responses are according to modified RECIST 1.1 as assessed by BICR. | Up to approximately 4 years | 
| Number of Participants Who Experienced One or More Adverse Events (AEs) | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who experience an AE will be presented. | Up to approximately 4 years | 
| Number of Participants Who Discontinued Study Intervention Due to an Adverse Event (AE) | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who discontinue study treatment due to an AE will be presented. | Up to approximately 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1)