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Histologically 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 |
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Disease progression at any time during or after treatment with a platinum-containing (eg, carboplatin or cisplatin) regimen |
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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) |
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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 |
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Measurable disease by CT or MRI based on Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as confirmed 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 |
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ECOG performance status of 0 or 1 assessed within 7 days of the first dose of study intervention |
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Male participants are eligible to participate if they agree to the following during the intervention period and for at least 30 days after the last dose of pembrolizumab \+ lenvatinib (Arm 1) or lenvatinib monotherapy (Arm 3), and 180 days after the last dose of standard of care (SOC) chemotherapy (Arm 2) |
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Refrain from donating sperm |
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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 |
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Agree to use a male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex |
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A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies |
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Is not a woman of childbearing potential (WOCBP) |
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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 30 days post lenvatinib, whichever occurs last (Arms 1 and 3), or during the intervention period and for at least 180 days after the last dose of SOC chemotherapy (Arm 2) |
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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 180 days after the last dose of SOC chemotherapy |
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Adequately controlled blood pressure (BP) with or without antihypertensive medications |
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Adequate organ function |
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Carcinoma of the nasopharynx, salivary gland, unknown primary origin, or nonsquamous histologies as primary tumors
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Disease that is suitable for local therapy administered with curative intent
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Life expectancy of less than 3 months and/or has rapidly progressing disease in the opinion of the treating investigator
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History of noninfectious pneumonitis that required systemic steroids, or current pneumonitis/interstitial lung disease
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Active infection requiring systemic therapy
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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
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Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
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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
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Active autoimmune disease that has required systemic treatment in the past 2 years
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Had an allogeneic tissue/solid organ transplant
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Known history of human immunodeficiency virus (HIV) infection
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History of hepatitis B or known active hepatitis C virus
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History of any contraindication or has a severe hypersensitivity to any components of pembrolizumab, lenvatinib or SOC chemotherapy
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Pre-existing Grade 3 gastrointestinal or non-gastrointestinal fistula
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History of a gastrointestinal condition or procedure that, in the opinion of the investigator, may affect oral study drug absorption
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Had major surgery within 3 weeks prior to first dose of study interventions
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Clinically significant cardiovascular impairment within 12 months of the first dose of study drug
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Active tuberculosis
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Difficulty swallowing capsules or ingesting a suspension either orally, by a nasogastric (NG) tube, or by a gastrostomy tube
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Prior treatment with lenvatinib
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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
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Received a live vaccine within 30 days of planned start of study intervention
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Previously treated with 4 or more systemic regimens given for recurrent/metastatic disease
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Currently participating in or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to the first dose of study intervention
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Known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study
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