Inclusion criteria, exclusion criteria and study summary
1. Be male or female and at least 18 years of age on the day of signing informed consent. 2. Have 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. 3. Have experienced disease progression at any time during or after treatment with a platinum-containing (eg, carboplatin or cisplatin) regimen with or without cetuximab. 4. Have disease progression on treatment with an anti-PD-1/PD-L1 mAb administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies. Anti-PD-1/PD-L1 treatment progression is defined by meeting all the following criteria: • Most recent treatment with an anti-PD-1/PD-L1 mAb. • Has received at least 2 doses of an anti-PD-1/PD-L1 mAb. • Has demonstrated disease progression after an anti-PD-1/PD-L1 mAb as defined by RECIST 1.1. • Progressive disease has been documented within 12 weeks from the last dose of anti-PD-1/PD-L1 mAb. Note: Eligible participants may have received anti-PD-1/PD-L1 mAb and platinum-containing therapy concomitantly. 5. Have submitted pre-study imaging that confirmed 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. • Note: These pre-study images must be submitted to the iCRO for confirmation that they are of acceptable diagnostic quality. The iCRO must have received these images and confirmed that they are of acceptable diagnostic quality before randomization. • Note: The pre-study imaging submitted to the iCRO will be from disease progression on treatment with an anti-PD-1/PD-L1 mAb; NOT from images associated with disease progression on platinum-containing chemotherapy given sequentially. 6. Have documentation of results from testing of HPV status for oropharyngeal cancer defined as p16 IHC testing using the CINtec® p16 Histology assay and a 70% cutoff point. Refer to Section 8.8.2 for details. If HPV status has previously been tested using this procedure, no retesting is required. 7. Have provided tissue for biomarker analysis from a core or excisional biopsy (fine needle aspirate is not adequate). Repeat samples may be required if adequate tissue is not provided. A newly obtained biopsy (within 90 days prior to start of study treatment) is strongly preferred, but an archival sample is acceptable. 8. Have measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) based on RECIST 1.1 as confirmed by BICR. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. 9. Have an ECOG performance status of 0 or 1 assessed within 7 days of the first dose of study intervention. 10. 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). • 180 days after the last dose of SOC chemotherapy (Arm 2), and agree to the following: • Refrain from donating sperm PLUS either: • 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 (vasectomized or secondary to medical cause [Appendix 5]) as detailed below: - 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. • Male participants must also agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex. Please note that 30 days after lenvatinib is stopped, if the participant is on pembrolizumab only, no male contraception measures are needed. 11. 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. OR - Is a WOCBP randomized to pembrolizumab + lenvatinib (Arm 1) or lenvatinib monotherapy (Arm 3) and using a contraceptive method that is highly effective (with a failure rate of < 1% per year), with lower user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), as described in Appendix 5 during the intervention period and for at least 120 days post pembrolizumab or 30 days post lenvatinib, whichever occurs last. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention. - A WOCBP randomized to SOC chemotherapy is eligible to participate if she is using a contraceptive method that is highly effective with low user dependency or abstinent from heterosexual intercourse as her preferred and usual lifestyle and agrees not to donate or freeze/store eggs during the intervention period and for at least 180 days after the last dose of SOC chemotherapy. - 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. • Additional requirements for pregnancy testing during and after study intervention are located in Appendix 5. • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. 12. The participant (or legally acceptable representative if applicable) provides written informed consent for the study. 13. Have adequately controlled BP with or without antihypertensive medications, defined as BP ≤ 150/90 mm Hg with no change in antihypertensive medications for at least 1 week prior to randomization. 14. Have adequate organ function as defined in Table 1. • Note: Specimens must be collected within ≤ 10 days prior to the start of study intervention.
1. Has carcinoma of the nasopharynx, salivary gland, unknown primary origin, or nonsquamous histologies as primary tumors. 2. Has a history of re-irradiation to any head and neck sites of disease including the cervical, infraclavicular or supraclavicular lymph nodes for head and neck cancer. 3. Has disease that is suitable for local therapy administered with curative intent. 4. Has a life expectancy of less than 3 months and/or has rapidly progressing disease (eg, tumor bleeding, uncontrolled tumor pain), in the opinion of the treating investigator. 5. Has any evidence of symptoms or signs of active tumor bleeding within 6 months prior to randomization. 6. Has ulceration and/or fungation of disease onto the skin surface. 7. Has radiographic evidence of major blood vessel invasion/infiltration or tumor demonstrates > 90 degree abutment or encasement of a major blood vessel. • Note: The degree of proximity to major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis after lenvatinib therapy. 8. Has a history of (noninfectious) pneumonitis that required systemic steroids, or current pneumonitis/interstitial lung disease. 9. Has an active infection requiring systemic therapy. 10. 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. 11. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated metastases may participate provided they have completed local therapy (eg, whole brain radiation therapy [WBRT], surgery or radiosurgery) and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting study intervention. Any signs (eg, radiologic) or symptoms of CNS metastases must be stable for at least 4 weeks before starting study intervention. 12. Has a known additional malignancy that is progressing or has required active systemic treatment within the past 3 years. • Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded. Participants with low-risk early stage prostate cancer defined as follows are not excluded; Stage T1c or T2a with a Gleason score ≤ 6 and prostatic-specific antigen (PSA) < 10 ng/mL either treated with definitive intent or untreated in active surveillance that has been stable for the past year prior to study enrollment. Other exceptions may be considered after consultation with the Sponsor. 13. Has an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). • Note: Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed. 14. Has had an allogeneic tissue/solid organ transplant. 15. Has a known history of human immunodeficiency virus (HIV) infection. • Note: No HIV testing is required unless mandated by local health authority. 16. Has a known history of hepatitis B (defined as hepatitis B surface antigen (HbsAg) reactive or known active hepatitis C virus (HCV) (defined as HCV RNA [qualitative] is detected) infection. • Note: No testing for hepatitis B and hepatitis C is required unless mandated by local health authority. 17. Has a history of any contraindication or has a severe hypersensitivity to any components of pembrolizumab (≥ Grade 3), lenvatinib or SOC chemotherapy. 18. Has pre-existing ≥ Grade 3 gastrointestinal or non-gastrointestinal fistula. 19. Has a history of a gastrointestinal condition or procedure that, in the opinion of the investigator, may affect oral study drug absorption. 20. 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. • Note: Participants must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study therapy. 21. Has clinically significant cardiovascular impairment within 12 months of the first dose of study drug, such as history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or cerebrovascular accident /transient ischemic attack (TIA)/stroke, cardiac revascularization, or cardiac arrhythmia associated with hemodynamic instability. • Note: Medically controlled arrhythmia that is stable with medication is permitted. 22. Has active tuberculosis. 23. Has difficulty swallowing capsules or ingesting a suspension either orally, by a nasogastric (NG) tube, or by a gastrostomy tube. Note: Gastrostomy tube (PVC, greater than or equal to 6 Fr) can be used to administer lenvatinib. 24. 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 pembrolizumab + lenvatinib (Arm 1) or lenvatinib monotherapy (Arm 3) or 180 days after the last dose of SOC chemotherapy. 25. Patients previously treated to one of the 5 SOC agents in this trial (ie, docetaxel, paclitaxel, capecitabine, methotrexate, or cetuximab) may not receive the same agent if randomized to the SOC chemotherapy arm. 26. Has had prior treatment with lenvatinib as monotherapy or in combination with an PD 1/PD-L1 inhibitor or other therapies. 27. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to Study Day 1 or has not recovered (ie, ≤ Grade 1 or baseline) from AEs due to a previously administered agent. Note: Events of ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia or laboratory values listed in Table 1 are allowed. Note: Participants must have recovered from all radiation-related toxicities and not have had radiation pneumonitis. 28. Has received a live vaccine within 30 days of planned start of study intervention. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, 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. 29. Was previously treated with 4 or more systemic regimens given for recurrent and/or metastatic disease. 30. Is 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. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks since the last dose of the previous investigational agent or device. 31. Has urine protein ≥ 1 g/24 hours Note: Participants with proteinuria > 1+ on urine dipstick testing/urinalysis will undergo 24 hour urine collection for quantitative assessment of proteinuria. 32. Has prolongation of QTc interval (calculated using Fridericia’s formula) to > 480 msec. 33. Has a left ventricular ejection fraction (LVEF) below the institutional (or local laboratory) normal range, as determined by multigated acquisition (MUGA) or echocardiogram (ECHO). 34. Is a WOCBP who has a positive urine pregnancy test within 24 hours prior to treatment allocation (see Appendix 5). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Note: In the event that 24 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for participant to start receiving study treatment. 35. Has a history or current evidence of any condition, therapy, or laboratory abnormality that may 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, in the opinion of the treating investigator. 36. Has a known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
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