Overview

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

Eligibility

Inclusion Criteria:

        Participants are eligible to be included in the study only if all of the following criteria
        apply:
          1. Male/female participants who are at least 18 years of age on the day of signing
             informed consent
          2. 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
          3. PD-L1 combined positive score (CPS) ≥1 (in sample prior to radiochemotherapy) by
             central pathology review
          4. Completed definitive radiochemotherapy up to at least 68Gy with at least 200mg/m² body
             surface area concomitant Cisplatin.
          5. 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.)
          6. 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.
          7. 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.
          8. The participant provides written informed consent for the trial.
          9. Have measurable disease based on RECIST 1.1.
         10. Have provided archival tumor tissue sample with sufficient tumor content.
             Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides.
         11. 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.
         12. 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:
          1. Have tumor infiltration/perforation of the skin or cervical fistula (either at
             timepoint of study inclusion or prior to radiochemotherapy)
          2. Have radiographic evidence of major blood vessel invasion/infiltration or tumor
             demonstrates >90-degree abutment or encasement of a major blood vessel.
          3. 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.
          4. 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.
          5. 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).
          6. Have received prior systemic anti-cancer therapy including investigational agents
             within 4 weeks prior to study drug administration (except from cisplatin concomitant
             to radiochemotherapy).
          7. 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.
          8. 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.
          9. 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.
         10. 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.
         11. Have distant metastases.
         12. Have severe hypersensitivity (≥Grade 3) to pembrolizumab, lenvatinib and/or any of
             their excipients.
         13. 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.
         14. Have a history of (non-infectious) pneumonitis/interstitial lung disease that required
             steroids or has current pneumonitis/interstitial lung disease.
         15. Have an active infection requiring systemic therapy.
         16. Have a known history of Human Immunodeficiency Virus (HIV) infection.
         17. 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.
         18. 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.
         19. Have known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.
         20. 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]).
         21. Have had an allogenic tissue/solid organ transplant.
         22. Have uncontrolled blood pressure (Systolic BP>140 mmHg or diastolic BP >90 mmHg) in
             spite of an optimized regimen of antihypertensive medication.
         23. Have clinically relevant electrolyte abnormalities that have not been corrected.
         24. 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.
         25. 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.
         26. 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.
         27. Have not recovered adequately from any toxicity from other anti- cancer treatment
             regimens and/or complications from major surgery prior to starting therapy. Withhold
             lenvatinib for at least 1 week prior to elective surgery. Do not administer for at
             least 2 weeks following major surgery and until adequate wound healing.
         28. Have prolongation of QTc interval to >480 ms in the ECG.
         29. Have a LVEF below the institutional (or local laboratory) normal range, as determined
             by multigated acquisition (MUGA) or echocardiogram (ECHO).
         30. Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to
             the first dose of study drug.